# data[].attributes.headline
Ewan, E.E., Avraham, O., Carlin, D. et al. Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism. Sci Rep 11, 374 (2021). https://doi.org/10.1038/s41598-020-79624-0

# data[].attributes.subject
Ewan, E.E., Avraham, O., Carlin, D. et al. Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism. Sci Rep 11, 374 (2021). https://doi.org/10.1038/s41598-020-79624-0

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Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism - Scientific Reports

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Scientific Reports - Ascending dorsal column sensory neurons respond to spinal cord injury and downregulate genes related to lipid metabolism

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Natali, A. L., Reddy, V., & Bordoni, B. (2023, August 14). Neuroanatomy, corticospinal cord tract. In StatPearls. StatPearls Publishing. Treasure Island, FL. Retrieved July 14, 2025, from https://www.ncbi.nlm.nih.gov/books/NBK535423/

# data[].attributes.subject
Natali, A. L., Reddy, V., & Bordoni, B. (2023, August 14). Neuroanatomy, corticospinal cord tract. In StatPearls. StatPearls Publishing. Treasure Island, FL. Retrieved July 14, 2025, from https://www.ncbi.nlm.nih.gov/books/NBK535423/

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Introduction

The corticospinal tract, AKA, the pyramidal tract, is the major neuronal pathway providing voluntary motor function. This tract connects the cortex to the spinal cord to enable movement of the distal extremities.[1] As the corticospinal tract travels down the brain stem, a majority of its fibers decussate to the contralateral side within the medulla then continues to travel down the spinal cord to provide innervation to the distal extremities and muscle groups. Various collateral pathways exist which do not follow this pathway, leading to variability amongst individuals. This structure continues to develop after birth, with maturation taking place during puberty, due to rising levels of androgens. Clinically, the corticospinal tract is important in ischemic infarcts, rehabilitation, and various neurodegenerative disorders.

Structure and Function

The corticospinal tract originates primarily from the frontoparietal cortices, including the primary motor cortex, secondary motor area, and somatosensory cortex.[2] The corticospinal tracts then come together to form bundles, which travel through the internal capsule and cerebral peduncles. The bundles then travel down to the brainstem.[3] As the tract reaches the pons, the bundles take on a more compact structure and continue to condense as they descend. As a result, the neural structure of the corticospinal tract takes up more surface area in the upper pons than in the lower pons.[4] As the corticospinal tract continues to travel down into the medulla, 75 to 90% of the fibers will decussate to the contralateral side via the pyramidal decussation.[5][3] The 5 to 15% of fibers that do not decussate within the pyramidal decussation make up the anterior corticospinal tract. This tract extends into the spinal cord, but only travels down to the levels of the lower thoracic cord. Various collaterals also exist for the corticospinal tract, with the aberrant pyramidal tract being the most representative. The aberrant pyramidal tract separates from the corticospinal tract within the midbrain and pons, then descends through the medial lemniscus.[6] This collateral pathway may provide an alternative motor pathway in the case of a cerebral infarct, which will be a topic of discussion below.[2]

After leaving the brainstem and entering the spinal cord, the fibers run down through the anterior and lateral corticospinal tract. When they get to their target level, the fibers of the anterior corticospinal tract decussate through the anterior white commissure before synapsing to a neuron in the anterior horn of the gray matter. The lateral corticospinal tract fibers have previously decussated at the level of the pyramid and synapse at a neuron on the anterior horn when they get to the appropriate level. These neurons, known as anterior horn cells, then project to the limbs and axial muscles to provide voluntary motor function.[3]

Embryology

During embryologic development, there is an overgrowth of axons distributed throughout the cortex, which incorporate into the corticospinal tract, and as development progresses, many of these axons are eliminated. Gray matter development begins a few weeks after the corticospinal tract axons reach the spinal cord. As growth continues, the corticospinal tract axons will reach the lower part of the cervical spinal cord by 24 weeks gestation.[3][7] After birth, the corticospinal tract continues to develop. The tract is then refined, and motor control develops. The research proposes that refinement of the corticospinal tract happens through the elimination of transient termination and growth within the gray matter of the spinal cord.; this is followed by developing control of the corticospinal tract's role in voluntary motor function.[2] The tract continues development through puberty, which is when the gender differences in white matter emerge. Studies have shown that androgens play a role in axonal development through the proliferation of neural cell bodies and the prevention of cell death following axonal injury. As a result, the development of white matter in males and females diverges during adolescence.[8]

Physiologic Variants

Due to the complex nature of the corticospinal tract, many physiologic variants exist. The collateral pathway known as the aberrant pyramidal tract has been observed in some patients as traveling through the medial lemniscus from the midbrain to the pons until it reached the medulla where it rejoined the corticospinal tract.[6] Variants have also been observed between men and women following puberty, due to surges in androgens. The neuroprotective nature of testosterone leads to physiologic differences between individuals following adolescence.[8] Studies have shown anatomical and physiologic differences of this structure exist across individuals, and those differences are a continued topic of research.

Clinical Significance

Knowledge of the corticospinal tract is of the utmost importance in many clinical scenarios. Preservation and recovery of the corticospinal tract are necessary for the recovery of impaired motor function following a brain injury.[2] During the event of an acute ischemic stroke, hypo-perfused tissue may be potentially salvageable through timely reperfusion therapy. Areas where the corticospinal tract is contained within a small, dense area, such as the pons, have shown less of a correlation between motor impairment and the size of the ischemic lesion. Studies have proven that the extent of motor impairment during acute ischemic stroke depends on the extent of the corticospinal tract involved in the lesion.[1][4][9][4] Motor paralysis is a debilitating result of an ischemic infarct, for which rehabilitation has proven to be the most effective treatment modality.[10] Patients who have the highest degree of improvement following an acute ischemic stroke had superior integrity of the corticospinal tract than those with fewer improvements during rehabilitation.

Damage to the corticospinal tract has correlations with neuromyelitis optica (NMO) and multiple sclerosis (MS). Both autoimmune diseases involve an inflammatory process that causes extensive damage to neurologic structures involved in the corticospinal tract resulting in extensive neurologic disability, including optic neuritis and transverse myelitis.[11][12]

Compromise of the corticospinal tract during development presents may present as a tract that is completely absent, hypoplastic, or malformed. Disorders with the absence of corticospinal tracts include anencephaly, where there is a failure of the rostral neural tube to close; congenital aqueduct stenosis with a narrowing of the cerebral aqueduct; and microcephaly, which is a defect in proliferation. Underdeveloped corticospinal tracts present in lissencephaly, a defect in migration leading to absent gyration, Walker-Warburg syndrome, migration deficiencies yielding cerebro-ocular dysplasia with muscular atrophy; holoprosencephaly, and the failure of the brain hemispheres to separate. Corticospinal tract malformations usually involve diffuse brain malformation and are most often associated with an abnormal trajectory of the pathway.[3] These pathologies present with a range of problems, including the lack of motor control due to the involvement of the corticospinal tract.

References

Disclosure: Adriana Natali declares no relevant financial relationships with ineligible companies.

Disclosure: Vamsi Reddy declares no relevant financial relationships with ineligible companies.

Disclosure: Bruno Bordoni declares no relevant financial relationships with ineligible companies.

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The corticospinal tract, AKA, the pyramidal tract, is the major neuronal pathway providing voluntary motor function. This tract connects the cortex to the spinal cord to enable movement of the distal extremities.[1] As the corticospinal tract travels down the brain stem, a majority of its fibers decussate to the contralateral side within the medulla then continues to travel down the spinal cord to provide innervation to the distal extremities and muscle groups.

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Javed K, Reddy V, Lui F. Neuroanatomy, Lateral Corticospinal Tract. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 30521239.

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Javed K, Reddy V, Lui F. Neuroanatomy, Lateral Corticospinal Tract. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 30521239.

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Europe PMC is an archive of life sciences journal literature.

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Jang, Sung Ho MDa; Kim, Seong Ho MDb; Seo, Jeong Pyo PhDa,*. Recovery of an injured corticofugal tract from the supplementary motor area in a patient with traumatic brain injury: A case report. Medicine 97(7):p e9063, February 2018. | DOI: 10.1097/MD.0000000000009063

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Jang, Sung Ho MDa; Kim, Seong Ho MDb; Seo, Jeong Pyo PhDa,*. Recovery of an injured corticofugal tract from the supplementary motor area in a patient with traumatic brain injury: A case report. Medicine 97(7):p e9063, February 2018. | DOI: 10.1097/MD.0000000000009063

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Recovery of an injured corticofugal tract from the... : Medicine

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howed severe weakness of both upper and lower extremities [Motricity Index (MI, full score: 100/100): 9/30]. Diagnoses: A 29-year-old male patient underwent conservative management for traumatic hemorrhages in both frontal lobes and right thalamus resulting from a car accident. Interventions: The patient participated in a comprehensive rehabilitative management program, including movement therapy, dopaminergic drugs for improvement of apraxia (pramipexole: 2.5mg, amantadine: 300mg, ropinirole: 0.75 mg, and levodopa: 500mg), and neuromuscular electrical stimulation therapy of the right elbow extensors, finger extensors, both knee extensors, and ankle dorsiflexors. Outcomes: After 2 months’ intensive rehabilitation, his motor weakness rapidly recovered to the point that he was able to move all 4 extremities against some resistance (MI: 75/75). The right supplementary motor area (SMA)-CFT showed narrowing and partial tearing in the upper portion on 1-month DTT, and became thicker on 3-month DTT. Compared to the 12 normal control subjects, the fractional anisotropy (FA) values of the right corticospinal tract and both dorsal premotor cortex-CFT were more than 1 standard deviation lower than those of normal control subjects on both 1- and 3-month DTTs. Lessons: Although the tract volume of the right SMA-CFT was more than 1 standard deviation lower than normal control subjects on 1-month DTT, it increased to within 1 standard deviation on 3-month DTT. Recovery of the injured SMA-CFT concurrent with motor recovery was demonstrated in a patient with traumatic brain injury.…

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Lin, D. J., Cloutier, A. M., Erler, K. S., Cassidy, J. M., Snider, S. B., Ranford, J., Parlman, K., Giatsidis, F., Burke, J. F., Schwamm, L. H., Finklestein, S. P., Hochberg, L. R., & Cramer, S. C. (2019, October 25). Corticospinal tract injury estimated from acute stroke imaging predicts upper extremity motor recovery after stroke. Stroke, 50(12), 3569–3577. https://doi.org/10.1161/STROKEAHA.119.025898

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Lin, D. J., Cloutier, A. M., Erler, K. S., Cassidy, J. M., Snider, S. B., Ranford, J., Parlman, K., Giatsidis, F., Burke, J. F., Schwamm, L. H., Finklestein, S. P., Hochberg, L. R., & Cramer, S. C. (2019, October 25). Corticospinal tract injury estimated from acute stroke imaging predicts upper extremity motor recovery after stroke. Stroke, 50(12), 3569–3577. https://doi.org/10.1161/STROKEAHA.119.025898

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Li, J., Wei, X.H., Liu, Y.K. et al. Evidence of motor injury due to damaged corticospinal tract following acute hemorrhage in the basal ganglia region. Sci Rep 10, 16346 (2020). https://doi.org/10.1038/s41598-020-73305-8

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Li, J., Wei, X.H., Liu, Y.K. et al. Evidence of motor injury due to damaged corticospinal tract following acute hemorrhage in the basal ganglia region. Sci Rep 10, 16346 (2020). https://doi.org/10.1038/s41598-020-73305-8

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Evidence of motor injury due to damaged corticospinal tract following acute hemorrhage in the basal ganglia region - Scientific Reports

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Scientific Reports - Evidence of motor injury due to damaged corticospinal tract following acute hemorrhage in the basal ganglia region

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Common Spinal Cord Syndromes and the Neurological Deficits They May Cause

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Common Spinal Cord Syndromes and the Neurological Deficits They May Cause

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Corticospinal Tract (blue) Conveying Motor Signals from Motor Cortex to Skeletal Muscles

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Corticospinal Tract (blue) Conveying Motor Signals from Motor Cortex to Skeletal Muscles

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Sarica, A., Cerasa, A., Valentino, P., Yeatman, J., Trotta, M., Barone, S., Granata, A., Nisticò, R., Perrotta, P., Pucci, F. and Quattrone, A. (2017), The corticospinal tract profile in amyotrophic lateral sclerosis. Hum. Brain Mapp., 38: 727-739. https://doi.org/10.1002/hbm.23412

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Sarica, A., Cerasa, A., Valentino, P., Yeatman, J., Trotta, M., Barone, S., Granata, A., Nisticò, R., Perrotta, P., Pucci, F. and Quattrone, A. (2017), The corticospinal tract profile in amyotrophic lateral sclerosis. Hum. Brain Mapp., 38: 727-739. https://doi.org/10.1002/hbm.23412

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The trigeminal pathways - Journal of Neurology

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The role of the trigeminal system in facial and dural sensitivity has been recognized for a long time. More recently, the trigeminal system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, trigeminal neuralgia, and other orofacial pains. Appreciation of the delicate anatomical arrangement of the trigeminal pathway is one of the keys to understanding these conditions’ pathophysiology and to proposing innovative treatments. This review provides a structured presentation of existing knowledge about the trigeminal system, from classical anatomical data to the most recent literature. First, we present the organization of the trigeminal pathway from the trigeminal divisions, nerve, and nuclei to the thalamus and somatosensory cortex. We describe the neurons and fibers’ repartition at each level, depending on the location (somatotopic organization) and the type of receptors (modal organization). Such a dual somatotopic-modal arrangement of the trigeminal fibers is especially clear for the juxtapontine segment of the trigeminal nerve and the trigeminal nuclei of the brainstem. It has significant clinical consequences both for diagnosis and treatment. Second, we explore how the trigeminal system is modulated and involved in reflexes, for instance the trigemino-cardiac and the trigemino-autonomic reflexes, which could play an essential role in the autonomic symptoms observed in cluster headache. Finally, we present how to interact with this complex system to relieve pain mediated by the trigeminal system. This section covers both neuromodulatory and lesional approaches.

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Kim, H. K., Chung, K.-m., Xing, J., Kim, H. Y., & Youn, D.-h. (2024). The Trigeminal Sensory System and Orofacial Pain. International Journal of Molecular Sciences, 25(20), 11306. https://doi.org/10.3390/ijms252011306

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Kim, H. K., Chung, K.-m., Xing, J., Kim, H. Y., & Youn, D.-h. (2024). The Trigeminal Sensory System and Orofacial Pain. International Journal of Molecular Sciences, 25(20), 11306. https://doi.org/10.3390/ijms252011306

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The Trigeminal Sensory System and Orofacial Pain

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The trigeminal sensory system consists of the trigeminal nerve, the trigeminal ganglion, and the trigeminal sensory nuclei (the mesencephalic nucleus, the principal nucleus, the spinal trigeminal nucleus, and several smaller nuclei). Various sensory signals carried by the trigeminal nerve from the orofacial area travel into the trigeminal sensory system, where they are processed into integrated sensory information that is relayed to higher sensory brain areas. Thus, knowledge of the trigeminal sensory system is essential for comprehending orofacial pain. This review elucidates the individual nuclei that comprise the trigeminal sensory system and their synaptic transmission. Additionally, it discusses four types of orofacial pain and their relationship to the system. Consequently, this review aims to enhance the understanding of the mechanisms underlying orofacial pain.

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Kim, Y. E., Kim, M. K., Suh, S., & Kim, J. H. (2021). Altered trigeminothalamic spontaneous low-frequency oscillations in migraine without aura: a resting-state fMRI study. BMC Neurology, 21(1), Article 342. https://doi.org/10.1186/s12883-021-02374-7

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Kim, Y. E., Kim, M. K., Suh, S., & Kim, J. H. (2021). Altered trigeminothalamic spontaneous low-frequency oscillations in migraine without aura: a resting-state fMRI study. BMC Neurology, 21(1), Article 342. https://doi.org/10.1186/s12883-021-02374-7

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Altered trigeminothalamic spontaneous low-frequency oscillations in migraine without aura: a resting-state fMRI study - BMC Neurology

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Background Recent resting-state fMRI studies demonstrated functional dysconnectivity within the central pain matrix in migraineurs. This study aimed to investigate the spatial distribution and amplitude of low-frequency oscillations (LFOs) using fractional amplitude of low-frequency fluctuation (fALFF) analysis in migraine patients without aura, and to examine relationships between regional LFOs and clinical variables. Methods Resting-state fMRI data were obtained and preprocessed in 44 migraine patients without aura and 31 matched controls. fALFF was computed according to the original method, z-transformed for standardization, and compared between migraineurs and controls. Correlation analysis between regional fALFF and clinical variables was performed in migraineurs as well. Results Compared with controls, migraineurs had significant fALFF increases in bilateral ventral posteromedial (VPM) thalamus and brainstem encompassing rostral ventromedial medulla (RVM) and trigeminocervical complex (TCC). Regional fALFF values of bilateral VPM thalamus and brainstem positively correlated with disease duration, but not with migraine attack frequency or Migraine Disability Assessment Scale score. Conclusions We have provided evidence for abnormal LFOs in the brainstem including RVM/TCC and thalamic VPM nucleus in migraine without aura, implicating trigeminothalamic network oscillations in migraine pathophysiology. Our results suggest that enhanced LFO activity may underpin the interictal trigeminothalamic dysrhythmia that could contribute to the impairments of pain transmission and modulation in migraine. Given our finding of increasing fALFF in relation to increasing disease duration, the observed trigeminothalamic dysrhythmia may indicate either an inherent pathology leading to migraine headaches or a consequence of repeated attacks on the brain.

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Henssen, D. J. H. A., Mollink, J., Kurt, E., van Dongen, R., Bartels, R. H. M. A., Gräβel, D., Kozicz, T., Axer, M., & Van Cappellen van Walsum, A.-M. (2019). Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging. Brain Structure and Function, 224(1), 159–170. https://doi.org/10.1007/s00429-018-1767-1

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Henssen, D. J. H. A., Mollink, J., Kurt, E., van Dongen, R., Bartels, R. H. M. A., Gräβel, D., Kozicz, T., Axer, M., & Van Cappellen van Walsum, A.-M. (2019). Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging. Brain Structure and Function, 224(1), 159–170. https://doi.org/10.1007/s00429-018-1767-1

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Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging

Abstract

Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally. This study aims to provide an anatomical substrate for the hypothesized bilateral projection. Three post-mortem human brainstems were scanned for anatomical and diffusion magnetic resonance imaging at 11.7T. The trigeminal tracts were delineated in each brainstem using track density imaging (TDI) and tractography. To evaluate the reconstructed tracts, the same brainstems were sectioned for polarized light imaging (PLI). Anatomical 11.7T MRI shows a dispersion of the trigeminal tract ( tt) into a ventral and dorsal portion. This bifurcation was also seen on the TDI maps, tractography results and PLI images of all three specimens. Referring to a similar anatomic feature in primate brains, the dorsal and ventral tracts were named the dorsal and ventral trigeminothalamic tract ( dtt and vtt), respectively. This study shows that both the dtt and vtt are present in humans, indicating that each hemiface has a bilateral projection, although the functional relevance of these tracts cannot be determined by the present anatomical study. If both tracts convey noxious stimuli, this could open up new insights into and treatments for orofacial pain in patients.

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Introduction

Classically, orofacial nociceptive afferents, running through the trigeminal nerve and the trigeminal tract (TT), are believed to synapse in the ipsilateral trigeminal sensory nucleus complex (Sessle 2000). Second-order neurons then cross and ascend as the trigeminothalamic tract to the contralateral ventro-posterior medial nucleus of the thalamus. From there, projections ascend to the primary and secondary somatosensory cortices and other cortical regions, such as the insula (Ralston 2005). However, the exact anatomy of the central portion of the trigeminal pathways in humans remains a point of discussion. Knowledge of the exact neuroanatomy of the trigeminal tracts will contribute to the understanding of orofacial pain and its treatment. Preclinical experiments provide evidence for a bilateral projection of the orofacial region causing activation of both thalami and both primary sensory cortices in healthy subjects, as well as patients suffering from chronic orofacial pain (Nash et al. 2009, 2010). This bilateral representation of the orofacial region can be explained by transcallosal pathways or by a bilateral trigeminothalamic system. The involvement of transcallosal pathways in the bilateral activation pattern of the aforementioned brain regions in the registration of orofacial pain seems to be of limited importance according to the split-brain study of Stein et al. However, proper interpretation of the results of this study is hampered due to the small sample size ( n = 1) (Stein et al. 1989). Additionally, Solstrand Dahlberg and colleagues report findings that a decreased connectivity of regions in the brainstem that are involved in orofacial pain with parts of the descending pain modulation system is present in patients suffering from migraine. However, they also conclude that the exact anatomy of the trigeminal pathways in the human brainstem remain elusive (Solstrand Dahlberg et al. 2018). In 2016, a review of tracing studies in animals and functional MRI studies in humans provided an overview of the trigeminal tracts in the brainstem (Henssen et al. 2016). Figure 1 depicts two trigeminothalamic tracts sprouting from the principal sensory nucleus (PSN), the ventral- and dorsal trigeminothalamic tract ( vtt and dtt, respectively). The vtt is a mainly contralateral pathway and is known to be present in human specimens. The dtt, on the other hand, is a mainly ipsilateral pathway and is predominantly known from animal-based studies and has only been hypothesized to exist in humans (Henssen et al. 2018).

Overview of the trigeminothalamic tracts that arise from the PSN in a dorsal view. Cranial nerves indicated in Roman numerals; dPSN dorsal principal sensory nucleus; vPSN ventral principal sensory nucleus; *dorsal trigeminothalamic tract ( dtt), **ventral trigeminothalamic tract ( vtt)

Based on the aforementioned results, we hypothesized that dtt would exist in the human brainstem too. To test this hypothesis, we investigated the neuroanatomy of the dtt in human brainstems using, multiple, advanced neuroimaging techniques, including post-mortem, 11.7 anatomical magnetic resonance imaging (MRI) and diffusion-weighted MRI (dMRI) and several post-processing techniques (e.g., tract density imaging (TDI) and tractography). To complement the MR findings, the same brainstems were sectioned to obtain histological transverse sections for polarized light imaging microscopy (PLI). PLI is a microscopy technique to quantify fiber orientation based on birefringence of the myelin sheath in histological brain sections and has been reported as a well-suited technique to validate MR findings (Axer et al. 2011b).

Materials and methods

Acquisition of the post-mortem material

Three post-mortem brains were derived from the body donor program of the department of Anatomy at Radboud University Medical Center, Nijmegen, The Netherlands. The three donors had no known neurological diseases and none of the brains showed pathological deformities after death. All specimens were perfused via the femoral artery using 10% formaldehyde and a relatively short postmortem interval (< 24 h) was employed to limit the reduction of several diffusion values [apparent diffusion coefficient (ADC) and fractional anisotropy (FA)] (D'Arceuil and de Crespigny 2007; Schmierer et al. 2008). After embalmment, the specimens were fixated in 7.7% formaldehyde for at least 3 months to a maximum of 3 years as it was suggested that diffusivity measures remain stable up to 3 years after fixation (Dyrby et al. 2007). Then the brain was extracted from the skull. The brainstem and cerebellum were separated from the cerebrum via a transverse section, perpendicular to the neural axis, at the level of the superior colliculus. The cerebellum was dissected from the brainstem by a coronal cut through the middle cerebellar peduncle. All three parts were fixated in 7.7% formaldehyde and preserved for another 2 months. See Table 1 for additional information. This study was carried out in accordance with the recommendations of the CMO (Commissie Mensgebonden Onderzoek) region Arnhem-Nijmegen, Netherlands. The post-mortem specimens were acquired via the body donor program at the department of Anatomy of the Radboud university medical centre, Nijmegen, Netherlands. All body donors in this program signed a written informed consent during their lifetime, permitting the use of their body and parts for science and teaching.

Table 1 Overview of the characteristics of the specimens used in this study

Magnetic resonance image acquisition

Prior to MR scanning, the three post-mortem brainstems were stored in a phosphate-buffered saline solution (PBS 0.1M, pH 7.4) for 1 week to reverse the decrease of the T2 relaxation rate of tissue introduced by formaldehyde (Shepherd et al. 2009). Next, the brainstems were placed for 24 h in Fomblin® ( Solvay Solexis Inc), a susceptibility-matched, hydrogen-free liquid. The brainstems were then placed in a vacuum chamber for 10 min to reduce free air in the lumina of the blood vessels. Ultimate maximum pressure within the vacuum chamber was set to 1350 mmHg to prevent cell membrane damages (Gonzalez-Rodriguez et al. 2016; Holzapfel et al. 2005), although the maximum pressure did not exceed 500 mmHg during the experiments as this was not necessary to remove air bubbles. Finally, each brainstem was placed in a 100 ml syringe, filled with Fomblin, for MR scanning. All imaging was performed on a 11.7T Bruker BioSpec Avance III preclinical MR system (Bruker BioSpin, Ettlingen, Germany) equipped with an actively shielded gradient set of 600 mT/m (slew rate 4570 T/m/s). A circular polarized resonator was used for signal transmission and an actively decoupled birdcage coil (Bruker Biospin) was used for receiving. Scanning was performed at room temperature (20 °C). T2* weighted images were acquired using a 3D multi-gradient echo sequence at 0.25 mm isotropic resolution with the following parameters: TR = 3314 ms; TE = 7 ms; and flip angle = 20°. The dMRI data were obtained using segmented spin-echo echo-planar imaging at 0.5 mm isotropic resolution. This sequence consisted out of four segments. A total of 256 gradient directions were employed at a b value of 4000 s/mm ², in addition to six images with no diffusion weighting ( b = 0 s/mm ²) and the following gradient and pulse parameters: Δ = 12.5 ms, δ = 4.0 ms, TE = 30.70 ms, and TR = 13.75 s. The applied MR protocol was adapted from an empirically designed protocol reported in the literature (Kleinnijenhuis et al. 2013).

Probabilistic tractography

All processing of the MR images was performed with FSL (Jenkinson et al. 2012). To correct for eddy current artifacts and displacement between the different diffusion images, an eddy current correction was applied (Andersson and Sotiropoulos 2015). The dMRI data were pre-processed for tractography with the bedpostX algorithm that models multiple fiber orientations ( n = 3) at each voxel (Behrens et al. 2007). To delineate the TT in our specimens, probabilistic tractography was performed using the Probtrackx2 algorithm. A manually defined seed mask (i.e., the starting point of tractography) was placed in the entry zone of the trigeminal nerve on the fractional anisotropy (FA) maps. To address the reproducibility of the drawing of the masks in each specimen, two neuroanatomists, independently, delineated the location of the trigeminal root entry zone on both sides of each brainstem. The overlap of both masks was used as the seeding masks for tractography on either the right or left side of each brainstem. Streamlines were drawn from each seed-voxel ( n = 50,000 streamlines per voxel). Only streamlines that reached the dorsal part of the brainstem near the PSN-defined by a waypoint mask-were kept to avoid the inclusion of other large dominating white tracts that run through the brainstem (Büttner-Ennever and Horn 2013). Maximum intensity projections (MIPs) of the trigeminal tract streamlines along aspecified encoded color direction, which improve the visualization of general tractography results as they provide stereoscopic visualization, were overlaid on the fractional anisotropy, which highlights the tract locations.

Track density imaging

Track density imaging (TDI) is typically used to investigate white matter microstructure smaller than the imaging resolution by reinterpolation of the quantitative maps by constrained spherical deconvolution based on the response function at a finer resolution (Calamante et al. 2010). TDI was applied to the dMRI data to study the TT trajectory and its possible bilateral projections. To generate the directionally encoded color TDI maps, whole brainstem probabilistic fiber-tracking was carried out with MRtrix as described by Calamante et al. ( 2010). Streamlines were generated (total number of streamlines: n = 500,000; 20 per seed voxel) from a large number of random seeds throughout the brainstem. Seeds are placed randomly throughout the brainstem as described by other before (Calamante et al. 2010, 2011). The total number of streamlines was calculated in each element of a grid that covers the brainstem. It should be noted that the sampling distance of the grid was smaller than the acquired voxel size, yielding TDI map with higher spatial resolution than the source dMRI data (0.1 mm isotropic). After tracking, the streamline density was used as intra-voxel information to construct a super-resolution TDI image (Calamante et al. 2010).

Histological tissue processing

Histological sectioning was performed for the TT at the level of the trigeminal nerve entry zone. This part was separated from the rest of the brainstem with a transverse cut through the inferior olivary nucleus and the inferior colliculus. To prevent the formation of ice crystals during freezing, the brainstems were stored in a 30% sucrose PBS solution (PBS 0.1M, pH 7.4) at 4 °C for 1 week. The specimen was frozen using dry ice and serially sectioned with a HM 450 Sliding Microtome ( Thermo Fisher Scientific Inc., Waltham, Massachusetts, USA) at a thickness of 100 microns. In a series of five axial sections, the first section was mounted on glass, creating an inter-slice gap of 500 microns.

Polarized light imaging

PLI utilizes the optical birefringence of nerve fibers, which can be attributed to the arrangement of lipid layers in the myelin sheaths wrapping the axons (Axer et al. 2011a, c). Birefringence alters the polarization state of the light that is passed through the specimen depending on the orientation of the myelinated nerve fibers. As such, taking a series of images while rotating the linear polarizer plane allows for quantification of fiber orientation at each pixel. The abovementioned principle of measurement is referred to as polarimetry. To realize PLI measurements of the transverse sections of the brainstems, two polarimeters were used: a large-area polarimeter (LAP) for single shot medium-resolution (64 microns per pixel) images covering the whole tissue section and a polarization microscope (PM) to scan a grid of high-resolution images (1.3 microns per pixel) in smaller regions of interest. Both types of polarimetric equipment work in a similar manner. Monochrome green light passes through a linear polarizer combined with a quarter wave retarder with its fast-axis oriented at 45° with respect to the polarizer plane. This creates circularly polarized light that passes through the specimen followed by another polarizer, which captures the change in polarization induced by tissue birefringence. By simultaneous rotation of all polarizing filters, the transmission intensity is systematically imaged at discrete filter rotation angles. A typical PLI raw image dataset comprised 18 snapshots at equidistant azimuth angles of 10°, ranging between 0° and 170°. On the LAP these measurements were supplemented by 8° tilt measurements to the cardinal points allowing for stereoscopic imaging to disambiguate the fiber elevation angle. Processing of all raw images created, due to the coarse resolution of the LAP-particular anatomical landmarks of the trigeminal pathways in the brainstem, were scanned additionally in the PM to obtain images of higher resolution. The PM used a reversed light pathway and rotates the polarizer only. A more extensive description of the polarimeters engaged during PLI is given by (Reckfort et al. 2015; Axer et al. 2011a, b).

Results

T2* weighted MR images

The trigeminal nerve can be clearly observed entering the ventrolateral part of the pons, after which the hypo-intense signal of the tt can be seen traversing the brainstem. The tt penetrates the middle cerebellar peduncle ( mcp) and slopes slightly through the pons towards a large hypo-intense bulge medial to the mcp. This enlarged portion of the tt represents the PSN (Fig. 2). The PSN is located lateral and dorsal to the medial lemniscus ( ml) and ventral to the central tegmental tract. At Fig. 2D, two hypo-intense extensions of the PSN, dorsal towards the fourth ventricle (most probably dtt) and ventral towards the center of the brainstem ( vtt), can be discriminated.

TDI-results

Figure 3 presents an overview of the results of the TDI analysis of the three specimens in transverse sections confirming the findings of T2* weighted MRI. It can be observed that the tt traverses through the mcp in a dorsomedial and caudal direction. A portion of it appears to join the ml, whereas the rest remains on its dorsomedial course through the tegmentum. After the bifurcation of the tt, two tracts can be observed: (1) a dorsomedial tract that courses in cranio-caudal direction and (2) a more ventral tract, dorsal to the ml. Figure 4 shows a ventral and a dorsal region of the brainstem as maximum intensity projection of multiple coronal sections near the bifurcation. Their location is shown in (A). The ventral region (C-E) shows that the majority of fibers from the tt join the ml crossing to the contralateral hemisphere. The dorsal region (B-D) reveals a smaller tract coursing towards the raphe without crossing. Instead it turns into a cranio-caudal direction. In principle, these models reconfirm a bifurcation of the tt near the transverse pontine fibers and the ml into a dorsal and ventral part. The dorsal tract appears to remain on the ipsilateral side with regard to the trigeminal root from which it sprouts, while the ventral one crosses to the contralateral side of the brainstem. The dorsal tract can, therefore, be determined to be the dtt; the ventral one to be the vtt.

TDI fiber orientation maps of one brainstem (specimen 1) in two directions: transverse sections at the trigeminal entry level and frontal sections at the level of the vtt and dtt. The RGB (red-green-blue) color cross indicates the principal eigenvector orientations, red = left-right, green = anterior-posterior, blue = cranio-caudal. Insets of b and c with a higher level of detail are shown in d and e. a Transverse TDI map of one brainstem (specimen 1) at the level of the entry of the trigeminal nerve. The bifurcation of the trigeminal tract into vtt and dtt is depicted. Section B is positioned at the level of the dtt and section C at the level of the vtt as indicated by dashed lines. b Frontal TDI map of one brainstem (specimen 1) at the level of the dtt. Initially the tt has a sagittal orientation after which it sprouts into a transversal. After sprouting from the tt, the dtt courses towards the dorsal wall of the brainstem. c Frontal TDI map of one brainstem (specimen 1) at the level of the vtt. The tt has a mixed anterior-posterior/left-right orientation. The vtt sprouts of from the inner face of the tt and attaches itself to the ml dorsally where it turns upward to the cranial part of the brainstem. d Enlargement of inset D in frontal TDI map depicted in section B. This inset shows the dtt in a frontal view and depicts that the tt has a anterior-posterior orientation, whereas the dtt has a mixed left-right/craniocaudal orientation in the dorsal area of the brainstem. dtt Dorsal trigeminothalamic tract, ml medial lemniscus, tt trigeminal tract, vtt ventral trigeminothalamic tract

Tractography results

Tractography results are depicted stereoscopically by use of MIP images. Results from tractography show a bifurcation of the left (blue) and right tt (red) in all three specimens. From this bifurcation, two tracts can be recognized: a dorsomedial one, which courses in cranio-caudal direction remaining ipsilateral, and a ventral one crossing to the contralateral side at the dorsal surface of the ml. The dorsal tract can, therefore, be identified as dtt, the ventral one as vtt (Fig. 5).

Polarized light images

On the PLI images (Fig. 6), the trigeminal root is observed to enter the ventrolateral aspect of the brainstem. The tt then crosses the mcp after which it bifurcates into a ventral and dorsal division. The ventral division, recognized as the vtt, bends alongside the ml. The dorsal division, recognized as the dtt, runs towards the tegmentum and the fourth ventricle (Fig. 6). Figure 7 depicts the tt coursing towards the dorsomedial aspect of the brainstem. After exiting the mcp, the tt shows a bifurcation into two tracts. The ventral branch runs posterior to the ml and courses towards the midline of the brainstem. The dorsal tract runs towards the dorsal aspect of the brainstem. The dorsal tract furthermore shows dispersing fibers that run towards the cerebellum via the mcp and towards the dorsomedial area of the brainstem.

PLI fiber orientation maps acquired at high resolution of transverse sections of the brainstem of specimen 1 at the level of the bifurcation of the trigeminal tract. The fiber orientation is defined by the color sphere in the upper left corner. a The tt can be observed in the mcp (green). The tt bifurcates into two tracts: the ventral portion (yellow) and dorsal portion (purple). b Detailed view of the bifurcation of the left tt shown in a. The vtt turns alongside the posterior wall of the ml and courses towards the raphe of the brainstem. The dtt runs towards the dorsal aspect of the brainstem splitting up again towards the cerebellum via the mcp (green-aquamarine) and towards the mesencephalic nucleus (purple). ml Medial lemniscus, tt trigeminal tract, vtt ventral trigeminothalamic tract, dtt dorsal trigeminothalamic tract

Discussion

For the first time, the existence of a bifurcation of the tt into a vtt and dtt in the human brainstem using (d)MRI, TDI and PLI has been reported. It is well known that the orofacial nociceptive afferents synapse in the ipsilateral trigeminal sensory nuclear complex (TSNC) cross the midline and ascend as the trigeminothalamic tract to the contralateral ventroposterior medial nucleus (VPM) of the thalamus. This study shows that the crossing tract can be identified as the vtt. The dorsal branch of the bifurcation could represent the hypothesized ipsilateral dtt.

Comparison with existing studies

In primates, evidence of this bilateral somatosensory pathway through the thalamus to the facial representation of the primary somatosensory cortex has been previously provided (Rausell and Jones 1991a, b). In humans, this bilateral representation pattern has been observed in functional MRI (fMRI) studies that investigated the activation patterns of orofacial pain in humans. These studies showed that unilateral noxious stimulation of the orofacial region evokes changes in both the contralateral and the ipsilateral thalami, insular and primary somatosensory cortices (Jantsch et al. 2005; Nash et al. 2010). Other studies suggested that a bifurcation of the trigeminal nerve can be found at the level of the brainstem, based on the blood oxygen level dependent (BOLD) activation patterns in experimental orofacial pain settings (Nash et al. 2009, 2010), which is consistent with the results of this paper. Furthermore, it is known from developmental brain research that the raphe of the brainstem is a generator of attractants and repellents that channel axonal growth to the proper side of the central nervous system, which causes the crossing of the major somatosensory and motor pathways. However, embryological development studies in mice have shown that a minority of the axons that sprout from the PSN do not cross the midline (Kivrak and Erzurumlu 2013).

The vtt has been described to consist of fibers that sprout from the ventral part of the PSN and the cranial two-thirds of the spinal nucleus (SN). The axons of the second-order neurons in the aforementioned nuclei decussate along the dorsal border of the ml and are, therefore, called the trigeminal lemniscus (Torvik 1957; Smith 1975; Matsushita et al. 1982). The function of the vtt is thought to be the conduction of vital sensory information, including nociceptive information. This study shows that the vtt indeed runs posterior to the ml and some imaging techniques even show that there is no clear distinction between the ml and the vtt. However, the high-resolution PLI images show that fibers of the ml and fibers of the vtt do not entwine along their courses.

The dtt has been described to consist of fibers originating from the dorsal part of the PSN and the caudal two-thirds of the SN (Burton and Craig 1979; Matsushita et al. 1982). It has been assumed that the dtt is responsible for conducting pain, temperature, and mechanoreceptive stimuli from the anterior part of the facial region and the intraoral cavity [for a review see (Henssen et al. 2016)].

This anatomical study provides further evidence of the existence of both the dtt and vtt; however, it cannot verify that both tracts are involved in the conduction of noxious stimuli. It is well known that the primary afferents of the somatosensory system can be subdivided according to myelinization and size. The different fiber types cluster the afferents into group A-C, of which the unmyelinated C-fibers and thin, myelinated Aδ-fibers subserve nociceptive transmission, whereas B-fibers represent thin preganglionic fibers of the autonomic nervous system (Erlanger and Gasser 1937). Central white matter, on the other hand, cannot be allocated to nociceptive systems on the basis of its architecture alone. For this reason, although the dtt seems to be present in humans as well, its function cannot be determined by this study.

Technical considerations

The use of diffusion magnetic resonance imaging (dMRI) and tractography has become a popular method to study white matter pathways (Catani and Thiebaut de Schotten 2008). However, due to the limited imaging resolution of in vivo dMRI (typically 1.0-2.0 mm), its outcomes should be interpreted with care, especially in the presence of small fiber bundles. However, a recent study of Setsompop showed that on a clinical 3T scanner, imaging resolution of whole-brain data could be acquired of 0.66 mm and 0.76 mm isotropic. This indicates that new efficient methods that are capable of acquiring high-resolution diffusion data in vivo might be possible in the near future (Setsompop et al. 2018). Nevertheless, the applied MRI protocol in this study was found to further increase resolution to a spatial resolution of 0.2 mm isotropic for the T2*-images and 0.5 mm for the diffusion data. Although this resolution is higher than the resolution obtained in the study of Setsompop et al., it must be underlined that the present data was acquired on a preclinical scanning system, using 11.7T in an ex-vivo setting, whereas the setting of Setsompop et al. was a clinical 3T in vivo setting. One of the limitations of this study is formed by the fact that MR imaging parameters were not based on distribution of quantitative longitudinal relaxation time (T1) and transverse relaxation time (T2) and mean diffusivity (D) (Beaujoin et al. 2017, 2018). Therefore, corresponding histograms of T1, T2 and D values which could have been used to optimize the imaging protocol, are lacking from this study. On the other hand, an adapted protocol that came forth from empirical investigation (Kleinnijenhuis et al. 2013) was applied and yielded the aforementioned results. Furthermore, it is known that tractography can produce plausible-looking bundles in locations where the white matter tract does not actually exist, indicating that tractography produces substantial amounts of false-positive fiber bundles (Maier-Hein et al. 2017). To optimize the investigation of white matter microstructure, TDI was used as this technique uses reinterpolation of the quantitative maps at a finer resolution than the imaging resolution, which allows researchers to study white matter structure smaller than the imaging resolution (Calamante et al. 2010). As such, dMRI of ex vivo tissue allows for further evaluation of the tractography results by direct comparison against histological reference measures within the same specimen (Miller et al. 2011). Furthermore, complementation of the tractography data by use of PLI has been suggested to overcome the coarse sensitivity of diffusion tractography with respect to the identification of sharp bends, twists, and undulations (Foxley et al. 2016).

One of the limitations of this study is formed by the fact that the trigeminal tracts were not followed up to the thalamus due to the size of the coil of the 11.7T MR-scanner. Therefore, we cannot confirm that the dtt is connected to the thalamus as has been proposed in animal-based studies (Torvik 1957). Furthermore, the restricted number of specimens and the lack of other complementary neuroimaging techniques like optical coherence tomography (OCT) form another limitation of this study. OCT provides high-resolution fiber architecture data at approximately 1 micron spatial resolution. OCT is analogous to ultrasound techniques as it measures the backscattered light of a sample. Specifically, it is sensitive to variations of the refraction index in different types of tissue. For example, in 2014, Magnain and colleagues suggested that OCT can be used to generate accurate 3D reconstructions of histological layers in the cerebral cortex (Magnain et al. 2014). Furthermore, polarization-sensitive OCT is a special form of OCT that uses the intrinsic optical properties of back-scattering and birefringence of neural tissue. In this way, polarization-sensitive OCT has been used to image the fiber orientation and cyto- and myeloarchitecture of human nervous tissue and to visualize volumetric reconstructions of human brain tissue (Wang et al. 2018). 3D-PLI, however, also provides the possibility to investigate three-dimensional fiber orientations in sectioned tissue. Each section is measured separately and basically provides a 3D vector field description of fiber orientations, forming the basis for tractography (Axer et al. 2011c). Finally, this study did not use tracers, whereas most of the knowledge on which we base our neuroanatomical insights regarding the trigeminal connections are derived from animal-based tracer studies [for a review see (Henssen et al. 2016)]. In 2013, Seehaus et al. used fluorescent, retrograde tracers to stain projection fibers in human tissue, showing that tracing studies can be performed in a post-mortem setting on adult human neural tissue. However, the tracer was injected into the subcortical white matter (approximately 500-1000 µm from the cortex) of the upper part of the temporal lobe. After 48 months, the tracer had traced a tract with a maximal length of 13 mm, which makes it unsuitable for human tracing studies. The same study, however, reported that DTI is capable of reflecting the shape and orientation of nerve pathways (Seehaus et al. 2013).

Future research should investigate the functionality of the vtt and the dtt to determine the clinical significance of functional entities like the TSNC with respect to different trigeminothalamic tracts.

Conclusion

This study shows that the tt bifurcates at the level of the human brainstem into two pathways which have previously been infrequently described in birds, reptiles, rodents, and non-human primates. These fiber tracts course in a ventral and dorsal direction and are, therefore, called the vtt and dtt, respectively. Connectivity, functionality, and clinical significance of these pathways must be determined in future studies.

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Authors and Affiliations

1. Department of Anatomy, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Geert Grooteplein Noord 21, 6525 EZ, Nijmegen, The Netherlands

Dylan J. H. A. Henssen, Jeroen Mollink, Tamas Kozicz & Anne-Marie Van Cappellen van Walsum

2. Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands

Dylan J. H. A. Henssen, Erkan Kurt & Ronald H. M. A. Bartels

3. Department of Clinical Neurosciences, Wellcome Centre for Integrative Neuroimaging, FMRIB, University of Oxford, Oxford, Nuffield, UK

Jeroen Mollink

4. Department of Anesthesiology, Pain and Palliative Care, Radboud University Medical Center, Nijmegen, The Netherlands

Robert van Dongen

5. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany

David Gräβel & Markus Axer

6. Department of Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA

Tamas Kozicz

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Correspondence to Dylan J. H. A. Henssen.

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Henssen, D.J.H.A., Mollink, J., Kurt, E. et al. Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging. Brain Struct Funct 224, 159-170 (2019). https://doi.org/10.1007/s00429-018-1767-1
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Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging - Brain Structure and Function

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Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally.

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Henssen DJ, Kurt E, Kozicz T, van Dongen R, Bartels RH, van Cappellen van Walsum AM. New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input. Front Neuroanat. 2016 May 10;10:53. doi: 10.3389/fnana.2016.00053. PMID: 27242449; PMCID: PMC4861896.

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Henssen DJ, Kurt E, Kozicz T, van Dongen R, Bartels RH, van Cappellen van Walsum AM. New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input. Front Neuroanat. 2016 May 10;10:53. doi: 10.3389/fnana.2016.00053. PMID: 27242449; PMCID: PMC4861896.

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doi: 10.3389/fnana.2016.00053.

Affiliations

¹ Department of Anatomy, Donders Institute for Brain Cognition and Behavior, Radboud University Medical CenterNijmegen, Netherlands; Department of Neurosurgery, Radboud University Medical CenterNijmegen, Netherlands.

² Department of Neurosurgery, Radboud University Medical Center Nijmegen, Netherlands.

³ Department of Anatomy, Donders Institute for Brain Cognition and Behavior, Radboud University Medical Center Nijmegen, Netherlands.

⁴ Department of Anaesthesiology, Pain and Palliative Care, Radboud University Medical Center Nijmegen, Netherlands.

doi: 10.3389/fnana.2016.00053.

Affiliations

¹ Department of Anatomy, Donders Institute for Brain Cognition and Behavior, Radboud University Medical CenterNijmegen, Netherlands; Department of Neurosurgery, Radboud University Medical CenterNijmegen, Netherlands.

² Department of Neurosurgery, Radboud University Medical Center Nijmegen, Netherlands.

³ Department of Anatomy, Donders Institute for Brain Cognition and Behavior, Radboud University Medical Center Nijmegen, Netherlands.

⁴ Department of Anaesthesiology, Pain and Palliative Care, Radboud University Medical Center Nijmegen, Netherlands.

Abstract

Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called trigeminothalamic tracts have been investigated before. In these animal-based studies from the previous century, the intracerebral pathways were mapped using different retro- and anterograde tracing methods. We review the literature on the trigeminothalamic tracts focusing on these animal tracer studies. Subsequently, we related the observations of these studies to clinical findings using fMRI trials. The intracerebral trigeminal pathways can be subdivided into three pathways: a ventral (contralateral) and dorsal (mainly ipsilateral) trigeminothalamic tract and the intranuclear pathway. Based on the reviewed evidence we hypothesize the co-existence of an ipsilateral nociceptive conduction tract to the cerebral cortex and we translate evidence from animal-based research to the human anatomy. Our hypothesis differs from the classical idea that orofacial pain arises only from nociceptive information via the contralateral, ventral trigeminothalamic pathway. Better understanding of the histology, anatomy and connectivity of the trigeminal fibers could contribute to the discovery of a more effective pain treatment in patients suffering from various orofacial pain syndromes.

Keywords: bilateral registration; orofacial pain; trigeminal nerve; trigeminal neuropathy; trigeminothalamic tract.

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national center for biotechnology information

# data[].attributes.attachment_link.title
New Insights in Trigeminal Anatomy: A Double Orofacial Tract for Nociceptive Input - PubMed

# data[].attributes.attachment_link.description
Orofacial pain in patients relies on the anatomical pathways that conduct nociceptive information, originating from the periphery towards the trigeminal sensory nucleus complex (TSNC) and finally, to the thalami and the somatosensorical cortical regions. The anatomy and function of the so-called tri ...

# data[].attributes.attachment_caption
Tewfik, T. L. (2025, February 20). Trigeminal nerve anatomy [Image]. In eMedicine. Medscape. https://emedicine.medscape.com/article/1873373-overview

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Trigeminal Nerve with Central Connections 

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Trigeminal Nerve with Central Connections 

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Van der Cruyssen, Frederic and Politis, Constantinus. "Neurophysiological aspects of the trigeminal sensory system: an update" Reviews in the Neurosciences, vol. 29, no. 2, 2018, pp. 115-123. https://doi.org/10.1515/revneuro-2017-0044

# data[].attributes.subject
Van der Cruyssen, Frederic and Politis, Constantinus. "Neurophysiological aspects of the trigeminal sensory system: an update" Reviews in the Neurosciences, vol. 29, no. 2, 2018, pp. 115-123. https://doi.org/10.1515/revneuro-2017-0044

# data[].attributes.attachment_link.title
Neurophysiological aspects of the trigeminal sensory system: an update

# data[].attributes.attachment_link.description
The trigeminal system is one of the most complex cranial nerve systems of the human body. Research on it has vastly grown in recent years and concentrated more and more on molecular mechanisms and pathophysiology, but thorough reviews on this topic are lacking, certainly on the normal physiology of the trigeminal sensory system. Here we review the current literature on neurophysiology of the trigeminal nerve from peripheral receptors up to its central projections toward the somatosensory cortex. We focus on the most recent scientific discoveries and describe historical relevant research to substantiate further. One chapter on new insights of the pathophysiology of pain at the level of the trigeminal system is added. A database search of Medline, Embase and Cochrane was conducted with the search terms ‘animal study’, ‘neurophysiology’, ‘trigeminal’, ‘oral’ and ‘sensory’. Articles were manually selected after reading the abstract and where needed the article. Reference lists also served to include relevant research articles. Fifty-six articles were included after critical appraisal. Physiological aspects on mechanoreceptors, trigeminal afferents, trigeminal ganglion and central projections are reviewed in light of reference works. Embryologic and anatomic insights are cited where needed. A brief description of pathophysiology of pain pathways in the trigeminal area and recent advances in dental stem cell research are also discussed. Neurophysiology at the level of the central nervous system is not reviewed. The current body of knowledge is mainly based on animal and cadaveric studies, but recent advancements in functional imaging and molecular neuroscience are elucidating the pathways and functioning of this mixed nerve system. Extrapolation of animal studies or functioning of peripheral nerves should be warranted.

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Kennedy MI, Claes S, Fuso FAF, et al. The Anterolateral Ligament: An Anatomic, Radiographic, and Biomechanical Analysis. The American Journal of Sports Medicine. 2015;43(7):1606-1615. doi:10.1177/0363546515578253

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Kennedy MI, Claes S, Fuso FAF, et al. The Anterolateral Ligament: An Anatomic, Radiographic, and Biomechanical Analysis. The American Journal of Sports Medicine. 2015;43(7):1606-1615. doi:10.1177/0363546515578253

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Al-Chalabi M, Reddy V, Gupta S. Neuroanatomy, Spinothalamic Tract. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 29939601.

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Al-Chalabi M, Reddy V, Gupta S. Neuroanatomy, Spinothalamic Tract. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 29939601.

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Introduction

The spinothalamic tract (STT) is a sensory tract that carries nociceptive, temperature, crude touch, and pressure from our skin to the somatosensory area of the thalamus. It is responsible for our quick withdraw reaction to a painful stimulus such as touching the stove burner. The spinothalamic tract is composed of two adjacent pathways: anterior and lateral. The anterior spinothalamic tract carries sensory input about crude touch. The lateral spinothalamic tract carries information about pain and temperature. These two divisions of the spinothalamic tract run next to each other indistinctly. Thus, they can be considered one pathway. The spinothalamic tract is part of the anterolateral system, which also encompasses the spinoreticulothalamic tract (SRTT) and the spinotectal tract (SpTT). Three types of sensory fibers are associated with the spinothalamic tract: type III fibers, unmyelinated c-fibers, and myelinated A-delta fibers. Peripheral receptors having associations with the spinothalamic tract pathway are nociceptors, thermal receptors, and thermal nociceptors. Nociceptors are associated with A-delta and type III fibers, which are small, lightly myelinated axons for the transmission of fast, sharp pain. Thermal receptors and thermal nociceptors are associated with A-delta and C fibers, which are small, unmyelinated axons that conduction the transmission of slow-burning pain.[1][2]

The pathway of the spinothalamic tract to the cerebral cortex starts with the dorsal root ganglions, which are composed of pseudounipolar neurons with the peripheral (distal) and central (proximal) axonal processes. These dorsal root ganglia lie adjacent to the spinal cord and represent the first-order neuron of the spinothalamic tract pathway. The axons of the central process of the first-order neurons enter the spinal cord through the lateral dorsal root entry zone to enter the Lissauer tract and synapses with second-order neurons in the substantia gelatinosa, located in the grey matter of the spinal cord. The axons of the second-order neurons cross over the spinal cord to the opposite side two segments above the level of entry via the anterior white commissure, unlike the posterior medial lemniscus pathway, which decussates in the brainstem. The decussating second-neuron fibers enter the anterolateral portion of the spinal cord and then enter the brainstem as the spinal lemniscus. The spinothalamic tract ascends in the ventrolateral aspect of the spinal white matter over the length of the spinal cord. The anterolateral system in the rostral medulla runs between the inferior olivary nucleus and the nucleus of the spinal trigeminal tract, whereas, in the pons and midbrain, the anterolateral system runs dorsolaterally to the medial lemniscus. The spinothalamic tract of the anterolateral system terminates in the ventral posterolateral nucleus (VPL) of the thalamus, the third-order neurons of this pathway. From the thalamus, axons of VPL neurons project out of the thalamus laterally and course somatotopically through the internal capsule's posterior limb of the and terminate in the postcentral gyrus primary somatosensory. In the spinal cord, the spinothalamic tract pathway has a certain somatotopic organization. The medial part of the track receives cervical input while the lateral part receives sacral input. Other pathways, such as cortical spinal tract and posterior medial lemniscus pathway, have a reversed somatotopy in comparison to the spinothalamic tract.[3][4][5][6]

Structure and Function

The main function of the spinothalamic tract is to carry pain and temperature via the lateral part of the pathway and crude touch via the anterior part. The spinothalamic tract pathway is an imperative sensory pathway in human survival because it enables one to move away from noxious stimuli by carrying pain and temperature information from the skin to the thalamus where it is processed and transmitted to the primary sensory cortex. The primary sensory cortex communicates with the primary motor cortex, which lies close to it, to generate rapid movement in response to potentially harmful stimuli. Furthermore, the spinothalamic tract has a role in responding to pruritogens, causing us to itch. Interestingly, itching suppresses the spinothalamic tract neuron response to the histamine effect.

Clinical Significance

The spinothalamic tract is especially important when dealing with any kind of spinal cord injury. The spinothalamic tract is an anterolateral pathway. Since it is on the same side of the body, a lesion on this side of the body will cause a deficit of anything controlled below that point. Several spinal cord syndromes have spinothalamic tract involvement. Spinothalamic tract deficit leads to loss of pain and temperature sensations on one side of the body at about two levels below the lesion but on the contralateral side. An example of spinal cord syndrome with such findings is Brown-Sequard syndrome, also known as a hemicord syndrome, which compromises multiple tracts of the spinal cord, including the spinothalamic tract. However, bilateral loss of pain and temperature in a dermatomal fashion can be present in syringomyelia where the anterior white commissure becomes obliterated due to cavitation in the central spinal cord. Similar clinical presentations to syringomyelia also present in acute central cervical cord syndrome.[7][8][9]

In addition to trauma and cavitation, the spinothalamic tract can be compromised due to vascular issues as well. One example is anterior spinal artery syndrome, which is caused by infarction of the anterior spinal artery territory. Patients with anterior spinal artery syndrome present with pain and temperature loss bilaterally below the level of the lesion. However, vibratory and proprioceptive senses are preserved due to posterior column sparing. Lateral medullary syndrome caused by occlusion of posterior inferior cerebellar artery affects the spinothalamic tract as STT runs in the lateral aspect of the medulla, resulting in loss of pain and temperature sensations over the entire contralateral side of the body as well as on the ipsilateral face due to the spinal trigeminal tract involvement. Similarly, lateral pontine syndrome caused by the anterior inferior cerebellar artery can impact the spinothalamic tract giving a clinical picture that resembles that of lateral medullary syndrome. In lateral medullary and pontine syndrome, however, cranial nerve deficits and cerebellar findings coexist with STT deficit findings as well as Horner syndrome.

A lesion localized to a ventral posterolateral in the thalamus will lead to an initial loss of all sensations from the contralateral side of the body, including pain. Over time, the patient may experience pain in all, or part, of the contralateral side of the body; this is referred to as thalamic pain syndrome (Déjérine-Roussy syndrome). This phenomenon of sensing the pain on the opposite side of the body can be detrimental to both the patient and practitioner. If the lesion is not obvious, the sensation and location described by patients can lead physicians to think that the pain is more psychological rather than physical. Practitioners need to keep this phenomenon in mind when evaluating patients for pain management.

References

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Anthony K Allam, Michael Benjamin Larkin, Ishan A Patel, Mohammed Hasen, David Mears, Patrick Dougherty, Ashwin Viswanathan, The human spinothalamic tract: lessons from cordotomy, Brain Communications, Volume 7, Issue 3, 2025, fcaf237, https://doi.org/10.1093/braincomms/fcaf237

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Anthony K Allam, Michael Benjamin Larkin, Ishan A Patel, Mohammed Hasen, David Mears, Patrick Dougherty, Ashwin Viswanathan, The human spinothalamic tract: lessons from cordotomy, Brain Communications, Volume 7, Issue 3, 2025, fcaf237, https://doi.org/10.1093/braincomms/fcaf237

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C. Mo,I. Petrof,A.N. Viaene,& S.M. Sherman,  Synaptic properties of the lemniscal and paralemniscal pathways to the mouse somatosensory thalamus, Proc. Natl. Acad. Sci. U.S.A. 114 (30) E6212-E6221, https://doi.org/10.1073/pnas.1703222114 (2017).

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C. Mo,I. Petrof,A.N. Viaene,& S.M. Sherman,  Synaptic properties of the lemniscal and paralemniscal pathways to the mouse somatosensory thalamus, Proc. Natl. Acad. Sci. U.S.A. 114 (30) E6212-E6221, https://doi.org/10.1073/pnas.1703222114 (2017).

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Martinez‑Sarmiento, J. A., Cosma, M. P., & Lakadamyali, M. (2024). Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming. Cell Reports, 43(5), 114170. https://doi.org/10.1016/j.celrep.2024.114170

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Martinez‑Sarmiento, J. A., Cosma, M. P., & Lakadamyali, M. (2024). Dissecting gene activation and chromatin remodeling dynamics in single human cells undergoing reprogramming. Cell Reports, 43(5), 114170. https://doi.org/10.1016/j.celrep.2024.114170

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Choi, S., Hachisuka, J., Brett, M.A. et al. Parallel ascending spinal pathways for affective touch and pain. Nature 587, 258–263 (2020). https://doi.org/10.1038/s41586-020-2860-1

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Choi, S., Hachisuka, J., Brett, M.A. et al. Parallel ascending spinal pathways for affective touch and pain. Nature 587, 258–263 (2020). https://doi.org/10.1038/s41586-020-2860-1

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Abstract

The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain1,2,3,4. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain. However, the organizational logic of the anterolateral pathway remains poorly understood. Here we show that two populations of projection neurons that express the structurally related G-protein-coupled receptors (GPCRs) TACR1 and GPR83 form parallel ascending circuit modules that cooperate to convey thermal, tactile and noxious cutaneous signals from the spinal cord to the lateral parabrachial nucleus of the pons. Within this nucleus, axons of spinoparabrachial (SPB) neurons that express Tacr1 or Gpr83 innervate distinct sets of subnuclei, and strong optogenetic stimulation of the axon terminals induces distinct escape behaviours and autonomic responses. Moreover, SPB neurons that express Gpr83 are highly sensitive to cutaneous mechanical stimuli and receive strong synaptic inputs from both high- and low-threshold primary mechanosensory neurons. Notably, the valence associated with activation of SPB neurons that express Gpr83 can be either positive or negative, depending on stimulus intensity. These findings reveal anatomically, physiologically and functionally distinct subdivisions of the SPB tract that underlie affective aspects of touch and pain.

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Data availability

The data generated in this study are available from the corresponding author upon reasonable request. Source data are provided with this paper.

Code availability

The custom codes used in the study are available at GitHub ( https://github.com/SebastianChoi/Choi-et-al-Nature2020) or upon request.

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Acknowledgements

We thank all members of the Ginty laboratory for discussions and critical feedback during the course of the project; D. Paul and C. Woolf for feedback and critical evaluation of the manuscript; S. Dymecki for providing Rosa26 LSL-FSF-TeTx and Rosa26 FSF-LSL-SYN-GFP mouse lines; L. Crawford and T. Dickendesher for help with initial characterization of the Calca-FlpE BAC transgenic and Avil FlpO knock-in mouse lines, respectively; C. Cepko for providing AAV1-FLEX-PLAP viruses; S. Arber for providing Cre-dependent AAV expression vector encoding synaptophysin-GFP; C. Guo and the Gene Targeting and Transgenic Facility at the Janelia Research Campus of the Howard Hughes Medical Institute for generating mouse lines; and B. Kun, M. Streeter, C. Breton and O. Gabriel for their assistance with mouse husbandry and histological and behavioural experiments. This work was supported by the Alice and Joseph E. Brooks Funds (S.C.), the Blavatnik Biomedical Accelerator Fund (S.C., D.D.G.), NIH grants NS097344 and AT011447 (D.D.G.), AR063772 (S.E.R.), NS096705 (H.R.K.) and NS111643 (M.G.), the Bertarelli Foundation (D.D.G.), The Hock E. Tan and Lisa Yang Center for Autism Research at Harvard University (D.D.G.) and the Edward R. and Anne G. Lefler Center for Neurodegenerative Disorders (D.D.G). D.D.G. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

1. Junichi Hachisuka

Present address: Institute of Neuroscience and Psychology, University of Glasgow, Glasgow, UK

2. Yu Omori

Present address: Toray Industries, Inc., Pharmaceutical Research Laboratories, Kanagawa, Japan

Authors and Affiliations

1. Department of Neurobiology, Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA

Seungwon Choi, Matthew A. Brett, Alexandra R. Magee, Noor-ul-Aine Iqbal, Dawei Zhang, Michelle M. DeLisle, Rachel L. Wolfson, Ling Bai, Celine Santiago & David D. Ginty

2. Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, USA

Junichi Hachisuka, Yu Omori, H. Richard Koerber & Sarah E. Ross

3. Pittsburgh Center for Pain Research, University of Pittsburgh, Pittsburgh, PA, USA

Junichi Hachisuka, Yu Omori, H. Richard Koerber & Sarah E. Ross

4. The Laboratory of Molecular Biology, Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA

Shiaoching Gong & Nathaniel Heintz

5. Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA, USA

Martyn Goulding

Contributions

S.C. and D.D.G. conceived and designed the project. S.C. screened and characterized the new anterolateral pathway PN mouse lines and designed, executed and analysed the histology, behaviour and spinal cord slice recording experiments. M.A.B., A.R.M. and N.I. helped execute and analyse histology and behavioural experiments. D.Z. helped with RNAscope analyses. M.M.D. and R.L.W. helped execute and analyse behavioural experiments. The ex vivo spinal cord physiological recordings were done by J.H., Y.O. and S.C. and analysed by J.H., Y.O., S.E.R. and H.R.K. N.H. and S.G. generated the Calca-FlpE BAC transgenic mouse line. L.B. and C.S. characterized the Calca-FlpE and Avil FlpO and the Tau FSFiAP mouse lines, respectively. M.G. provided the Lbx1 FlpO mouse line. S.C. and D.D.G. wrote the manuscript with input from all authors.

Corresponding author

Correspondence to David D. Ginty.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Peer review information Nature thanks Robert Gereau, Richard Palmiter and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data figures and tables

a- c, Gene targeting strategies used to generate the Robo3 IRES-CreERT2 ( a), Tacr1 CreERT2 ( b) and Gpr83 CreERT2 ( c) mouse lines. a, A 3X-STOP-IRES-CreERT2 cassette was introduced via homologous recombination into the first common coding exon that is shared by different splice variants of the Robo3 gene. b, A CreERT2 cassette was introduced via homologous recombination into the Tacr1 gene, replacing the first coding ATG. c, A CreERT2 cassette was introduced via homologous recombination into the Gpr83 gene, replacing the first coding ATG. IRES, internal ribosome entry site; s.int, synthetic intron; WPRE, Woodchuck hepatitis virus (WHP) posttranscriptional regulatory element; pA, poly(A); f, FRT site; kz, Kozak sequence. d- f, A horizontal section of the lumbar spinal cord. 93.7 ± 2.6% of tdTomato⁺ neurons were Tacr1⁺, while 96.6 ± 2.4% of Tacr1⁺ neurons were tdTomato⁺. n = 3 mice. g, A transverse section of a Gpr83-GFP mouse. Green and red dots represent GFP and Gpr83 mRNA molecules, respectively, detected with gene-specific RNAscope probes. 96.0 ± 1.2% of GFP⁺ cells were Gpr83⁺, while 84.5 ± 5.0% of Gpr83⁺ cells were GFP⁺. n = 2 mice. h, Distribution of tdTomato-expressing Robo3⁺ neurons in the spinal cord dorsal horn (top) and their thalamic projections terminating in the VPL (bottom). n = 2 mice. i- m, Characterization of the Avil FlpO mouse line. n = 4 mice. i- k, The Avil FlpO mouse line labels the majority of DRG neurons (99.0 ± 0.1% of NeuN⁺ neurons are tdTomato⁺) ( i), nodose ganglia neurons (80.8 ± 5.1% of NeuN⁺ neurons are tdTomato⁺) ( j) and sympathetic ganglia neurons (98.6 ± 0.3% of TH⁺ neurons are tdTomato⁺) ( k). l, A transverse section of the vertebral column. tdTomato⁺ advillin-expressing neurons and their axons are visualized in the spinal cord (asterisk), DRGs (arrows), and sympathetic ganglia (arrowheads). m, A coronal section of the brainstem. tdTomato⁺ axons of advillin-expressing neurons innervate the nucleus of the solitary tract (arrowhead), the dorsal column nuclei (arrow), and the trigeminal nucleus (asterisk). n- q, Characterization of the Calca-FlpE mouse line. n = 2 mice. A cross section of the lumbar DRG ( n- p) and a transverse section of the lumbar spinal cord ( q). n- p, 91.9 ± 1.5% of tdTomato⁺ neurons were CGRP⁺, while 92.3 ± 1.5% of CGRP⁺ neurons were tdTomato⁺. q, tdTomato-expressing axons of CGRP⁺ DRG neurons are CGRP immunoreactive in the spinal cord dorsal horn.

a, Distribution of EYFP-expressing Tacr1⁺ (top) or Gpr83⁺ (bottom) spinal neurons and mCherry-expressing Gad2⁺ neurons in the superficial lamina of the spinal cord dorsal horn. b, Quantification of % of Gad2-negative neurons in EYFP⁺ neurons. 97.5 ± 1.4% of Tacr1⁺ neurons and 99.5 ± 0.5% of Gpr83⁺ neurons were Gad2-negative. c, Distribution of tdTomato-expressing Tacr1⁺ neurons and GFP-expressing Gpr83⁺ neurons in the spinal cord dorsal horn. d, Quantification of co-expression of tdTomato and GFP. 80.2 ± 1.5% and 87.0 ± 2.5% of tdTomato-expressing Tacr1⁺ neurons are not positive for GFP expression in laminae I and IIo and lamina IIid, respectively. Conversely, 78.0 ± 1.8% and 92.0 ± 1.4% of GFP-expressing Gpr83⁺ neurons are not positive for tdTomato expression in laminae I and IIo and lamina IIid, respectively. e, Distribution of EYFP-expressing Tacr1⁺ neurons, Gpr83⁺ neurons or both in the superficial lamina of the spinal cord dorsal horn. The SPB neurons were retrogradely labelled with CTB injected into the PBN L. Arrowheads, CTB and EYFP double-positive neurons. f, Quantification for % of Tacr1⁺ SPB neurons, Gpr83⁺ SPB neurons, and either Tacr1⁺ or Gpr83⁺ SPB neurons. g, % of Tacr1⁺, Gpr83⁺, Tacr1⁺ Gpr83⁺ and Tacr1- Gpr83- SPB neurons calculated from experiments in e, f. h, i, Coronal sections of the ventral brain stem of Tacr1 CreERT2 ( h) or Gpr83 CreERT2 ( i) mice whose lumbar spinal cords were injected with AAV1-FLEX-synaptophysin-GFP viruses. MAO, medial accessory olivary nucleus; DAOdf, dorsal accessory olivary nucleus dorsal fold; DAOvf, dorsal accessory olivary nucleus ventral fold; PO, primary olivary nucleus. j, Distribution of tdTomato-expressing Tac1⁺ neurons in the superficial lamina of the spinal cord dorsal horn. The SPB neurons were retrogradely labelled with CTB injected into the PBN L. Arrowhead, CTB and tdTomato double-positive neuron. k, Quantification of % of Tac1⁺ SPB neurons. l, Schematic of injections of AAV2-retro-FlpO viruses into the PBN L. m, Distribution of tdTomato-expressing Tacr1⁺ (left) or Gpr83⁺ (right) SPB neurons and Tac1⁺ neurons in the spinal cord dorsal horn. tdTomato (red) and Tac1 (green) mRNA molecules were detected with gene-specific RNAscope probes. Filled arrowheads, double-positive neurons; empty arrowheads, tdTomato⁺ SPB neurons that do not express Tac1. n, Quantification of co-expression of tdTomato and Tac1 in laminae I and IIo. o, Schematic of lumbar injections of an AAV1-FLEX-synaptophysin-tdTomato virus. p, Distribution of tdTomato-positive synaptic terminals of Tac1⁺ SPB neurons in the PBN L. q, Quantification of distribution of tdTomato-positive synaptic terminals of Tac1⁺ SPB neurons in the PBN L. n = number of mice (indicated in the graph). Error bars, s.e.m.
Source data

a, d, g, Schematics of lumbar spinal cord injections of AAV1-C on/F on-EYFP viruses and brain injections of AAV2-retro-FlpO viruses into the SCig of Tacr1 CreERT2 mice ( a) ( n = 3 mice), the MGm/SPFp of Tacr1 CreERT2 ( d) ( n = 2 mice) or Gpr83 CreERT2 mice ( g) ( n = 3 mice). b, e, h, Transverse sections of cervical spinal cords of Tacr1 CreERT2 ( b, e) or Gpr83 CreERT2 mice ( h). White dotted lines, tdTomato-expressing axons travelling through spinal cord white matter. DLF, dorsal lateral funiculus; VLF, ventral lateral funiculus. c, f, i, Coronal sections of target brain regions of Tacr1⁺ ( c, f) or Gpr83⁺ ( i) spinal PNs. AQ, cerebral aqueduct.

a, Association of synaptic terminals of Tacr1⁺ and Gpr83⁺ SPB neurons with Calca-GFP-expressing cell bodies and neurites in the PBN EL. b, Quantification of the number of synaptophysin-tdTomato puncta associated with GFP⁺ cell bodies and neurites. The numbers were normalized with the total GFP⁺ area (to normalize for the variability of total GFP⁺ area) and the total number of synaptophysin-tdTomato puncta within the entire PBN L (to normalize for the variability of virus injections). AU, arbitrary unit. Two-tailed t-test; n = 4 mice each for Tacr1⁺ and Gpr83⁺ SPB neurons. c, Quantification of average speed during light-off periods following light-on periods (473 nm, 6.5 mW, 10 ms pulse width). One-way ANOVA (Dunnett's multiple-comparisons test); F 2,16 = 10.60 (2 Hz), F 2,16 = 40.12 (5 Hz), F 2,16 = 20.48 (10 Hz). d, Average velocity of mice over time (6.5 mW, 2 Hz, 10 ms pulse width). Positive values indicate forward movement whereas negative values indicate backward movement. Shaded areas, s.e.m. e, f, Quantification of average velocity during light-on periods with 2 Hz ( e) and 5 Hz ( f) photostimulation. Note that mice receiving Tacr1⁺ SPB neuron terminal stimulation exhibited net negative velocity during the 2 Hz photostimulation and lack a velocity increase despite the dramatic increase in speed during 5 Hz photostimulation. Two-tailed t-test; n = 6, 5 mice for Tacr1⁺, Gpr83⁺, respectively. g, Distribution of Fos⁺ neurons in the spinal cord dorsal horn following either photostimulation of axon terminals of SPB neurons ( Tacr1⁺ or Gpr83⁺) or a capsaicin (0.1%) injection into a hindpaw. Photostimulation of axon terminals of SPB neurons did not induce significant Fos expression in the spinal cord, whereas a hindpaw injection of capsaicin induced strong Fos expression in the medial region of the superficial lamina of the spinal cord dorsal horn. d, dorsal; v, ventral, m, medial; l, lateral. n = 4, 3, 5, 2 mice for control, Gpr83⁺, Tacr1⁺, capsaicin, respectively. h, Quantification of the number of Fos⁺ neurons in laminae I and II. The number of Fos⁺ cells was quantified in the medial 200 μm of the spinal cord dorsal horn. One-way ANOVA (Tukey's multiple-comparisons test). Error bars, s.e.m.
Source data

a, b, Summary violin plots of peak instantaneous firing rates of Gpr83⁺ (a) and Tacr1⁺ (b) SPB neurons in response to von Frey indentations and thermal stimuli. Red lines indicate median, while blue lines indicate quartiles. Friedman test (Dunn's multiple-comparisons test). n = 16, 15 neurons for Tacr1⁺, Gpr83⁺, respectively. c, Representative traces of action potential firing evoked by topical capsaicin (0.05%) treatment. Arrows, time when capsaicin was applied to the skin. d, Quantification of peak instantaneous firing rates upon capsaicin application. Mann-Whitney test (two-tailed); P value is indicated; n = 11, 7 neurons for Tacr1⁺, Gpr83⁺, respectively; error bars, s.e.m.
Source data

a, Hindpaw-licking was scored while Tacr1 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-TeTx mice, Gpr83 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-TeTx mice or Tacr1 CreERT2; Gpr83 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-TeTx mice were placed on the 55 °C hot plate (cut-off time, 20 s). These intersectional strategies target the entire Tacr1⁺ and Gpr83⁺ spinal populations, of which 34.2% (20.5% PBN L-projecting, 6.6% PAG-projecting and 7.1% MGm/SPFp-projecting PNs are combined) and 30.9% (14.0% PBN L-projecting, 4.6% PAG-projecting and 12.3% MGm/SPFp-projecting PNs are combined) are Tacr1⁺ and Gpr83⁺ PNs (laminae I and IIo and the LSN are combined), respectively (a detailed description of the quantification is in the methods). Two-tailed t-test. b, Forepaw licking was scored while mice were placed on the 5 °C cold plate (cut-off time, 3 min). Two-tailed t-test. c, Paw withdrawal frequency following hindpaw skin indentation using von Frey filaments. Two-way ANOVA; P value is indicated; F 1,43 = 8.65 for Tacr1/Gpr83-TeTx. d, Real-time texture aversion assay (150 grit sand paper vs 400 grit sand paper). % of time spent in rough side of sand paper (150 grit) was measured (normalized to baseline preference). Two-tailed t-test. e, f, The suppression of neurotransmission in the quadruple transgenic mice was confirmed by reduced Fos induction in the PBN L following exposure of mice to noxious thermal stimuli. e, Distribution of Fos⁺ neurons in the PBN L following thermal stimulation. f, Quantification of the number of Fos⁺ neurons in the PBN L. One-way ANOVA (Tukey's multiple-comparisons test); F 2,9 = 8.97 (5 °C), F 2,8 = 27.09 (55 °C). n = number of mice (indicated in the graphs). Error bars, s.e.m.
Source data

a, Distribution of CGRP⁺, Mrgprb4⁺, Mrgprd⁺ and Ntrk2⁺ primary afferent synaptic terminals in the spinal cord dorsal horn. The Rosa26 FSF-LSL-SYN-GFP reporter mouse line33 was used in combination with sensory neuron Cre/FlpE mouse lines and Avil FlpO/ Avil Cre mouse lines. Note that CGRP⁺, Mrgprb4⁺, Mrgprd⁺ and Ntrk2⁺ primary afferent synaptic terminals mainly innervate laminae I and IIo, IIid, IIid, and IIiv and III, respectively. b- d, Quantifications of peak current density in Tacr1⁺ ( c, d) and Gpr83⁺ ( b) SPB neurons elicited by long light pulse-stimulation (1 ms and 10 ms) of CGRP⁺ ( b), Mrgprb4⁺ ( c) and Ntrk2⁺ ( d) primary afferent terminals. The same neurons, stimulated with different durations of light stimulation, are connected by dotted lines. Note that only a small fraction of Gpr83⁺ SPB neurons exhibited long-latency (21.68 ± 2.66 ms), high-jitter (2.97 ± 0.85 ms) polysynaptic EPSCs with 10-ms-long photostimulation of CGRP⁺ afferent terminals and, conversely, only a small fraction of Tacr1⁺ SPB neurons exhibited long-latency (14.29 ± 3.49 ms), high-jitter (4.31 ± 2.31 ms) polysynaptic EPSCs with 10-ms-long photostimulation of Mrgprb4⁺ afferent terminals. 2 out of 7 Tacr1⁺ SPB neurons exhibited long-latency (11.89 ± 4.18 ms) but relatively low-jitter (0.57 ± 0.21 ms) synaptic EPSCs after 10-ms-long photostimulation of Ntrk2⁺ afferent terminals. e, Representative traces of light-activated currents (left) and AP firing (right) upon photostimulation of Mrgprd⁺ primary afferent terminals. Turquoise bars, 0.1 ms (EPSCs) and 1 ms (APs) LED (473 nm) stimulations. f, Quantifications of peak current density. Mann-Whitney test (two-tailed); n = number of neurons. g, Schematic of injections of AAV2-retro-FlpO viruses into the PBN L. h, Distribution of tdTomato-expressing dendrites of Tacr1⁺ (top) and Gpr83⁺ (bottom) SPB neurons. Lamina IIid is labelled using IB4 binding. Arrowheads, Gpr83⁺ dendrites that are extended into deeper laminae of the spinal cord dorsal horn. i, Quantification of distance between the cell bodies and the outer boundary of IB4⁺ lamina IIid (dotted line). #, note that a small number of Gpr83⁺ SPB neurons have their cell bodies located within lamina IIid. n = 65, 60 neurons for Tacr1⁺, Gpr83⁺, respectively. j, k, Quantifications of total length of dendrites in a spinal cord section image within ( j) or below ( k) IB4⁺ lamina IIid (normalized to the total length of the IB4⁺ lamina IIid in the same spinal cord section image). Two-tailed t-test; n = 18, 23 sections (40 μm) for Tacr1⁺, Gpr83⁺, respectively. Error bars, s.e.m.
Source data

a, Schematic of dual-CTB injections into the PBN L. b, Distribution of CTB-labelled neurons in the spinal cord laminae I and IIo and the LSN. c, Quantification of % of SPB neurons that innervate the PBN L contralaterally, ipsilaterally or bilaterally. n = 3 mice. Error bars, s.e.m. d, Bottom view of a single axon trace of sparsely labelled Gpr83⁺ spinal PN that innervate the inferior olivary complex. Arrowhead, an axon branch travelling up to the rostral brain. r, rostral; c, caudal, m, medial; l, lateral. e, Quantification of the number of inferior olivary complex-projecting spinal PNs that exhibit dedicated vs. collateral-forming axons. f, Synaptic terminals of Tacr1⁺ (left) or Gpr83⁺ (right) PNs, representing hindlimb regions (GFP) and forelimb regions (tdTomato), are segregated in the inferior olivary complex. n = 3 mice each for Tacr1⁺ and Gpr83⁺ PNs.
Source data

a, Duration of rostral grooming of control (black line), Gpr83 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-ReaChR (green line) or Tacr1 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-ReaChR (red line) mice over time. Bin size, 30 s. Axon terminals in the PBN L were stimulated with blue LED (473 nm, 1 mW, 10 Hz, 10 ms pulse width) for 30 s 4 times (with 1-min light-off periods between photostimulation periods). Turquoise bars, 30-s-long light-on periods. b, Quantification of average duration of rostral grooming during light-on periods for 0.4 mW, 1 mW, and 6.5 mW photostimulation. One-way ANOVA (Dunnett's multiple-comparisons test); F 2,18 = 7.60 (1 mW), F 2,16 = 7.49 (6.5 mW); n = 6, 6, 9 mice (0.4 mW), 6, 7, 9 mice (1 mW), 8, 5, 6 mice (6.5 mW) for control, Gpr83, Tacr1, respectively. c, Schematic of lumbar injections of AAV1-hSyn-FlpO viruses. d, Quantification of total duration of grooming of different body parts during light-on periods. Axon terminals in the PBN L were stimulated with blue LED (473 nm, 10 mW, 5 or 10 Hz, 10 ms pulse width) 4 times for 1 min each (with 1-min light-off periods between photostimulation periods). n = 4 trials (2 mice; 2 trials per mouse, 5 Hz and 10 Hz stimulation) for Tacr1⁺ SPB neuron terminal stimulation, n = 6 trials (3 mice; 2 trials per mouse, 5Hz and 10 Hz stimulation) for Gpr83⁺ SPB neuron terminal stimulation. Paired t-test (two-tailed). e, Weak self-administered photostimulation (0.4 mW) of Gpr83⁺ SPB neuron terminals led to an increase in the number of presses for the active lever, but not the inactive lever over time. f, Self-administered photostimulation (1 mW) of Tacr1⁺ SPB neurons led to a decrease in the number of presses for the active lever, but not inactive lever over time. Turquoise boxes indicate 8 d of light-on sessions. n = 7 mice (Gpr83, 0.4 mW; Tacr1, 1 mW). Two-way repeated measures ANOVA; F 1,6 = 8.23 (Gpr83, 0.4 mW), F 1,6 = 9.43 (Tacr1, 1 mW). Error bars, s.e.m.
Source data

a, Summary cartoon of two parallel ascending SPB pathways for affective touch and pain. b, A phylogenetic tree generated using a multiple sequence alignment algorithm, ClustalW2 (EMBL-EBI). The top 14 mouse proteins that have the highest amino acid sequence similarity to mouse GPR83 were used for this analysis.

Supplementary information

Supplementary Table 1. p-values for statistical comparisons. Exact p-values for each statistical comparison.

Freezing behavior is induced during light-off periods, following strong activation of either Gpr83⁺ or Tacr1⁺ SPB terminals. A video of a Gpr83 CreERT2; Lbx1 FlpO; Rosa26 LSL-FSF-ReaChR mouse after receiving high-intensity photostimulation (6.5 mW, 5Hz, 10 ms pulse width).

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Choi, S., Hachisuka, J., Brett, M.A. et al. Parallel ascending spinal pathways for affective touch and pain. Nature 587, 258-263 (2020). https://doi.org/10.1038/s41586-020-2860-1
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Parallel ascending spinal pathways for affective touch and pain - Nature

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The anterolateral pathway consists of ascending spinal tracts that convey pain, temperature and touch information from the spinal cord to the brain1-4. Projection neurons of the anterolateral pathway are attractive therapeutic targets for pain treatment because nociceptive signals emanating from the periphery are channelled through these spinal projection neurons en route to the brain.

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M. Condés-Lara, G. Martínez-Lorenzana, G. Rojas-Piloni, I.A. Tello-García, A. Manzano-García, E. Rubio-Beltran, A. González-Hernández, Axons of Individual Dorsal Horn Neurons Bifurcated to Project in Both the Anterolateral and the Postsynaptic Dorsal Column Systems, Neuroscience, Volume 371, 2018, Pages 178-190,ISSN 0306 4522, https://doi.org/10.1016/j.neuroscience.2017.11.050 (https://www.sciencedirect.com/science/article/pii/S0306452217308679)

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M. Condés-Lara, G. Martínez-Lorenzana, G. Rojas-Piloni, I.A. Tello-García, A. Manzano-García, E. Rubio-Beltran, A. González-Hernández, Axons of Individual Dorsal Horn Neurons Bifurcated to Project in Both the Anterolateral and the Postsynaptic Dorsal Column Systems, Neuroscience, Volume 371, 2018, Pages 178-190,ISSN 0306 4522, https://doi.org/10.1016/j.neuroscience.2017.11.050 (https://www.sciencedirect.com/science/article/pii/S0306452217308679)

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Hernandez-Godinez, B., Bonilla-Jaime, H., Poblano, A., Silva, M., Bautista-Rodríguez, M., Solís-Chávez, S., Heras-Romero, Y., Tena, E., & Ibáñez-Contreras, A. (2014). Ontogeny of somatosensory evoked potentials of median and tibial nerves in rhesus monkeys (Macaca mulatta): Influence of dissociative anesthetic mixtures under captivity conditions [Image]. (ISBN 978-1-63117-851-1).

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Posterior Column-Medial Lemniscus Pathway, the Spinothalamic Pathway

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Posterior Column-Medial Lemniscus Pathway, the Spinothalamic Pathway

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Haliloglu, G., Becker, K., Temucin, C. et al. Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects. J Hum Genet 62, 497–501 (2017). https://doi.org/10.1038/jhg.2016.153

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Haliloglu, G., Becker, K., Temucin, C. et al. Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects. J Hum Genet 62, 497–501 (2017). https://doi.org/10.1038/jhg.2016.153

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Abstract

The genetic work-up of arthrogryposis is challenging due to the diverse clinical and molecular etiologies. We report a-18 3/12-year-old boy, from a 2nd degree consanguineous family, who presented at 3 6/12 years with hypotonia, distal laxity, contractures, feeding difficulties at birth. He required surgery for progressive scoliosis at 16 years of age, and walked independently since then with an unstable gait and coordination defects. His latest examination at 18 years of age revealed a proprioceptive defect and loss-of-joint position sense in the upper limbs. Somatosensory evoked potentials supported bilateral involvement of dorsal column-medial lemniscal sensory pathways and nerve conduction studies revealed a mild axonal neuropathy. Muscle biopsy showed myopathic changes with neonatal myosin expression. Mendeliome sequencing led to the discovery of a recessive stop mutation in piezo-type mechanosensitive ion channel component 2 ( PIEZO2, NM_022068, c.1384C>T, p.R462*). PIEZO2 is a nonselective cation channel, expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs. Dominant PIEZO2 mutations were described in patients with distal arthrogryposis type 5 and Marden-Walker syndrome. Sensory ataxia and proprioception defect with dorsal column involvement together with arthrogryposis, myopathy, scoliosis and progressive respiratory failure may represent a distinct clinical phenotype, and indicate recessive mutations in PIEZO2.

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Acknowledgements

We acknowledge our patient and his parents. This work was supported by Muscular Dystrophy Association, USA, and Deutsche Forschungsgemeinschaft, Germany grants to Dr SC.

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Goknur Haliloglu and Kerstin Becker: These authors contributed equally to this work.

Authors and Affiliations

1. Department of Pediatric Neurology, Hacettepe University, Ankara, Turkey

Goknur Haliloglu & Haluk Topaloglu

2. Department of Pediatrics, University Hospital Cologne, Cologne, Germany

Kerstin Becker, Matthias Pergande & Sebahattin Cirak

3. Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany

Kerstin Becker, Matthias Pergande & Sebahattin Cirak

4. Department of Neurology, Hacettepe University, Ankara, Turkey

Cagri Temucin & Nalan Küçükşahin

5. Department of Pediatrics, Pediatric Pathology Unit, Hacettepe University, Ankara, Turkey

Beril Talim

6. Cologne Center for Genomics, University of Cologne, Cologne, Germany

Susanne Motameny & Peter Nürnberg

7. Department of Radiology, Hacettepe University, Ankara, Turkey

Ustun Aydingoz

Corresponding author

Correspondence to Sebahattin Cirak.

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The authors declare no conflict of interest.

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Supplementary Information accompanies the paper on Journal of Human Genetics website

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Haliloglu, G., Becker, K., Temucin, C. et al. Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects. J Hum Genet 62, 497-501 (2017). https://doi.org/10.1038/jhg.2016.153
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# data[].attributes.attachment_link.title
Recessive PIEZO2 stop mutation causes distal arthrogryposis with distal muscle weakness, scoliosis and proprioception defects - Journal of Human Genetics

# data[].attributes.attachment_link.description
The genetic work-up of arthrogryposis is challenging due to the diverse clinical and molecular etiologies. We report a-183/12-year-old boy, from a 2nd degree consanguineous family, who presented at 36/12 years with hypotonia, distal laxity, contractures, feeding difficulties at birth.

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Dorsal Column-Medial Lemniscal System and the Anterolateral System

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Dorsal Column-Medial Lemniscal System and the Anterolateral System

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Kramer, J., Liem, L., Russo, M., Smet, I., Van Buyten, J. – P., & Huygen, F. (2015). Lack of body positional effects on paresthesias when stimulating the dorsal root ganglion (DRG) in the treatment of chronic pain. Neuromodulation: Technology at the Neural Interface, 18(1), 50–57. https://doi.org/10.1111/ner.12217 

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Biscevic, M., Sehic, A., & Krupic, F. (2020). Intraoperative neuromonitoring in spine deformity surgery: Modalities, advantages, limitations, medico‑legal issues – surgeons’ views. EFORT Open Reviews, 5(1), 9–16. https://doi.org/10.1302/2058-5241.5.180032

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Biscevic, M., Sehic, A., & Krupic, F. (2020). Intraoperative neuromonitoring in spine deformity surgery: Modalities, advantages, limitations, medico‑legal issues – surgeons’ views. EFORT Open Reviews, 5(1), 9–16. https://doi.org/10.1302/2058-5241.5.180032

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Intraoperative neuromonitoring in spine deformity surgery: modalities, advantages, limitations, medicolegal issues - surgeons' views

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In spine deformity surgery, iatrogenic neurologic injuries might occur due to the mechanical force applied to the spinal cord from implants, instruments, and bony structures, or due to ischemic changes from vessel ligation during exposure and cord distraction/compression during corrective manoeuvres.

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Mohammed, H., & Hollis, E. R., 2nd. (2018). Cortical reorganization of sensorimotor systems and the role of intracortical circuits after spinal cord injury. Neurotherapeutics, 15(3), 588–603. https://doi.org/10.1007/s13311-018-0638-z 

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Mohammed, H., & Hollis, E. R., 2nd. (2018). Cortical reorganization of sensorimotor systems and the role of intracortical circuits after spinal cord injury. Neurotherapeutics, 15(3), 588–603. https://doi.org/10.1007/s13311-018-0638-z 

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Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury - Neurotherapeutics

# data[].attributes.attachment_link.description
The plasticity of sensorimotor systems in mammals underlies the capacity for motor learning as well as the ability to relearn following injury. Spinal cord injury, which both deprives afferent input and interrupts efferent output, results in a disruption of cortical somatotopy. While changes in corticospinal axons proximal to the lesion are proposed to support the reorganization of cortical motor maps after spinal cord injury, intracortical horizontal connections are also likely to be critical substrates for rehabilitation-mediated recovery. Intrinsic connections have been shown to dictate the reorganization of cortical maps that occurs in response to skilled motor learning as well as after peripheral injury. Cortical networks incorporate changes in motor and sensory circuits at subcortical or spinal levels to induce map remodeling in the neocortex. This review focuses on the reorganization of cortical networks observed after injury and posits a role of intracortical circuits in recovery.

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Raju H, Tadi P. Neuroanatomy, Somatosensory Cortex. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 32310375.

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Raju H, Tadi P. Neuroanatomy, Somatosensory Cortex. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2025. PMID: 32310375.

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Europe PMC is an archive of life sciences journal literature.

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Abstract

The role of the trigeminal system in facial and dural sensitivity has been recognized for a long time. More recently, the trigeminal system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, trigeminal neuralgia, and other orofacial pains. Appreciation of the delicate anatomical arrangement of the trigeminal pathway is one of the keys to understanding these conditions' pathophysiology and to proposing innovative treatments. This review provides a structured presentation of existing knowledge about the trigeminal system, from classical anatomical data to the most recent literature. First, we present the organization of the trigeminal pathway from the trigeminal divisions, nerve, and nuclei to the thalamus and somatosensory cortex. We describe the neurons and fibers' repartition at each level, depending on the location (somatotopic organization) and the type of receptors (modal organization). Such a dual somatotopic-modal arrangement of the trigeminal fibers is especially clear for the juxtapontine segment of the trigeminal nerve and the trigeminal nuclei of the brainstem. It has significant clinical consequences both for diagnosis and treatment. Second, we explore how the trigeminal system is modulated and involved in reflexes, for instance the trigemino-cardiac and the trigemino-autonomic reflexes, which could play an essential role in the autonomic symptoms observed in cluster headache. Finally, we present how to interact with this complex system to relieve pain mediated by the trigeminal system. This section covers both neuromodulatory and lesional approaches.

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Acknowledgements

We thank the French Academy of Medicine, the French Society of Neurosurgery, and the Foundation "Les Gueules Cassées" for their financial support.

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Authors and Affiliations

1. UMR 1253, ibrain, Université de Tours, Inserm, 10 Boulevard Tonnellé, 37032, Tours, France

Louis-Marie Terrier & Christophe Destrieux

2. CHRU de Tours, Tours, France

Louis-Marie Terrier & Christophe Destrieux

3. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital/Harvard Medical School, Charlestown, MA, USA

Nouchine Hadjikhani

4. GNC, Sahlgrenska Academy, Gothenburg University, Gothenburg, Sweden

Nouchine Hadjikhani

Authors

1. Louis-Marie Terrier

2. Nouchine Hadjikhani

3. Christophe Destrieux

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Correspondence to Louis-Marie Terrier.

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On behalf of all authors, the corresponding author states that there is no conflict of interest.

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Terrier, LM., Hadjikhani, N. & Destrieux, C. The trigeminal pathways. J Neurol 269, 3443-3460 (2022). https://doi.org/10.1007/s00415-022-11002-4
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The trigeminal pathways - Journal of Neurology

# data[].attributes.attachment_link.description
The role of the trigeminal system in facial and dural sensitivity has been recognized for a long time. More recently, the trigeminal system has also been considered a prominent actor in brain nociceptive innervation. It is the anatomical substrate of several frequent conditions, such as primary or secondary headaches, trigeminal neuralgia, and other orofacial pains.

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Sitnikova, E.Y., Raevskii, V.V. The Lemniscal and Paralemniscal Pathways of the Trigeminal System in Rodents Are Integrated at the Level of the Somatosensory Cortex. Neurosci Behav Physi 40, 325–331 (2010). https://doi.org/10.1007/s11055-010-9259-7

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Sitnikova, E.Y., Raevskii, V.V. The Lemniscal and Paralemniscal Pathways of the Trigeminal System in Rodents Are Integrated at the Level of the Somatosensory Cortex. Neurosci Behav Physi 40, 325–331 (2010). https://doi.org/10.1007/s11055-010-9259-7

# data[].attributes.attachment_link.title
The Lemniscal and Paralemniscal Pathways of the Trigeminal System in Rodents Are Integrated at the Level of the Somatosensory Cortex - Neuroscience and Behavioral Physiology

# data[].attributes.attachment_link.description
The studies reported here demonstrate that the projection representation of the whiskers in the somatosensory cortex in rats is the area at which afferent streams arriving via the lemniscal and paralemniscal projections interact. The responses of neurons in layers IV, Va, and Vb to mechanical stimulation of single whiskers were studied. Neurons in layers IV and Vb were found to show more frequent phasic responses (typical of the lemniscal system), while those in layer Va produced predominantly tonic responses (typical of the paralemniscal system). These characteristics of adaptive-plastic rearrangements of cortical neuron activity in response to constant stimuli may result from intracortical cooperative interactions between the lemniscal and paralemniscal projection systems, which, overall, produces a precise qualitative assessment of the perceived stimulus in its specific context.

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Michael F Esposito, Rudy Malayil, Michael Hanes, Timothy Deer, Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation, Pain Medicine, Volume 20, Issue Supplement_1, June 2019, Pages S23–S30, https://doi.org/10.1093/pm/pnz012

# data[].attributes.subject
Michael F Esposito, Rudy Malayil, Michael Hanes, Timothy Deer, Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation, Pain Medicine, Volume 20, Issue Supplement_1, June 2019, Pages S23–S30, https://doi.org/10.1093/pm/pnz012

# data[].attributes.attachment_link.title
Unique Characteristics of the Dorsal Root Ganglion as a Target for Neuromodulation

# data[].attributes.attachment_link.description
AbstractObjective. The dorsal root ganglion (DRG) is a novel target for neuromodulation, and DRG stimulation is proving to be a viable option in the treatm

# data[].attributes.headline
Rodríguez‑Mena, R., & Türe, U. (2017). The medial and lateral lemnisci: Anatomically adjoined but functionally distinct fiber tracts. World Neurosurgery, 99, 241–250. https://doi.org/10.1016/j.wneu.2016.11.095 

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Rodríguez‑Mena, R., & Türe, U. (2017). The medial and lateral lemnisci: Anatomically adjoined but functionally distinct fiber tracts. World Neurosurgery, 99, 241–250. https://doi.org/10.1016/j.wneu.2016.11.095 

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Jang, Sung Ho MD; Lee, Han Do MS*. Recovery of an injured medial lemniscus with concurrent recovery of pusher syndrome in a stroke patient: a case report. Medicine 97(22):p e10963, June 2018. | DOI: 10.1097/MD.0000000000010963

# data[].attributes.subject
Jang, Sung Ho MD; Lee, Han Do MS*. Recovery of an injured medial lemniscus with concurrent recovery of pusher syndrome in a stroke patient: a case report. Medicine 97(22):p e10963, June 2018. | DOI: 10.1097/MD.0000000000010963

# data[].attributes.attachment_link.title
Recovery of an injured medial lemniscus with concurrent... : Medicine

# data[].attributes.attachment_link.description
re motor weakness of left extremities, impairment of proprioception, and severe pusher syndrome at the start of rehabilitation. Diagnoses: He was diagnosed as ICH in the right thalamus and basal ganglia. Interventions: The patient received comprehensive rehabilitative therapy, movement therapy, and somatosensory stimulation. Outcomes: Four months after onset, left leg motor function (Motricity Index [MI] = 51) did not show significant recovery from that at two months after onset (MI = 41); however, in the same period, Nottingham Sensory Assessment and scale for contraversive pushing significantly improved. At four months, the patient was able to stand independently but required manual contact of one person during independent walking on an even floor. At seven months after onset, he was able to walk independently on an even floor. Lessons: Recovery of a severely injured medial lemniscus with concurrent recovery of impaired proprioception and pusher syndrome.…

# data[].attributes.headline
Mohammed H, Hollis ER 2nd. Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury. Neurotherapeutics. 2018 Jul;15(3):588-603. doi: 10.1007/s13311-018-0638-z. PMID: 29882081; PMCID: PMC6095783.

# data[].attributes.subject
Mohammed H, Hollis ER 2nd. Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury. Neurotherapeutics. 2018 Jul;15(3):588-603. doi: 10.1007/s13311-018-0638-z. PMID: 29882081; PMCID: PMC6095783.

# data[].attributes.attachment_link.title
Cortical Reorganization of Sensorimotor Systems and the Role of Intracortical Circuits After Spinal Cord Injury - PubMed

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The plasticity of sensorimotor systems in mammals underlies the capacity for motor learning as well as the ability to relearn following injury. Spinal cord injury, which both deprives afferent input and interrupts efferent output, results in a disruption of cortical somatotopy. While changes in cort …

# data[].attributes.headline
Homma NY, Bajo VM. Lemniscal Corticothalamic Feedback in Auditory Scene Analysis. Front Neurosci. 2021 Aug 19;15:723893. doi: 10.3389/fnins.2021.723893. PMID: 34489635; PMCID: PMC8417129.

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Homma NY, Bajo VM. Lemniscal Corticothalamic Feedback in Auditory Scene Analysis. Front Neurosci. 2021 Aug 19;15:723893. doi: 10.3389/fnins.2021.723893. PMID: 34489635; PMCID: PMC8417129.

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doi: 10.3389/fnins.2021.723893.

Affiliations

¹ Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA, United States.

² Coleman Memorial Laboratory, Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, United States.

³ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

doi: 10.3389/fnins.2021.723893.

Affiliations

¹ Center for Integrative Neuroscience, University of California, San Francisco, San Francisco, CA, United States.

² Coleman Memorial Laboratory, Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, CA, United States.

³ Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom.

Abstract

Sound information is transmitted from the ear to central auditory stations of the brain via several nuclei. In addition to these ascending pathways there exist descending projections that can influence the information processing at each of these nuclei. A major descending pathway in the auditory system is the feedback projection from layer VI of the primary auditory cortex (A1) to the ventral division of medial geniculate body (MGBv) in the thalamus. The corticothalamic axons have small glutamatergic terminals that can modulate thalamic processing and thalamocortical information transmission. Corticothalamic neurons also provide input to GABAergic neurons of the thalamic reticular nucleus (TRN) that receives collaterals from the ascending thalamic axons. The balance of corticothalamic and TRN inputs has been shown to refine frequency tuning, firing patterns, and gating of MGBv neurons. Therefore, the thalamus is not merely a relay stage in the chain of auditory nuclei but does participate in complex aspects of sound processing that include top-down modulations. In this review, we aim (i) to examine how lemniscal corticothalamic feedback modulates responses in MGBv neurons, and (ii) to explore how the feedback contributes to auditory scene analysis, particularly on frequency and harmonic perception. Finally, we will discuss potential implications of the role of corticothalamic feedback in music and speech perception, where precise spectral and temporal processing is essential.

Keywords: descending projections; harmonicity; layer VI cortical neurons; medial geniculate body; music; speech; thalamus; tonotopy.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Abstract

Introduction

Recently, an additional trigeminothalamic tract - the dorsal trigeminothalamic tract - has been described in human brainstems by our group next to the known ventral trigeminothalamic tract. As various elements of the trigeminal system are known to be organised in a somatotopic fashion, the question arose whether the fibres within the trigeminal root show specific distributions patterns in their contribution to the ventral trigeminothalamic tract and dorsal trigeminothalamic tract specifically.

Methods

This study investigated the arrangement of the fibres in the trigeminal root by combining various imaging methods in the pons of 11 post-mortem specimens. The pons were investigated by polarised light imaging (PLI) (n = 4; to quantify fibre orientation; 100 µm interslice distance), histochemical staining methods (n = 3; to visualise the internal myeloarchitecture; 60 µm) and ultra-high field, post-mortem magnetic resonance imaging (MRI) (n = 4; for tractography; 500 µm interslice distance).

Results

This study shows that the fibres, from the point where the trigeminal root enters the brainstem, are distinctly arranged by their contribution to the ventral trigeminothalamic tract and dorsal trigeminothalamic tract. This finding is supported by both post-mortem, ultra-high dMRI and different light microscopy techniques.

Conclusion

The data from this study suggest that the fibres in the superior half of the root contribute mainly to the ventral trigeminothalamic tract, whereas the fibres in the inferior half mainly contribute to the dorsal trigeminothalamic tract. Such a somatotopic organisation could possibly create new insights into the anatomical origin of trigeminal neuralgia and the clinical relevance of this somatotopic organisation should therefore be further explored.

Keywords: Anatomy, arrangement, somatotopy trigeminal nerve, trigeminal root, trigeminothalamic tract

Introduction

The trigeminal nerve (TN) is composed of three main sensory divisions (ophthalmic, maxillary and mandibular) and one motor component. Deficits of the trigeminal system are the cause of numerous acute and chronic neuropathic orofacial pain conditions, including trigeminal neuralgia and trigeminal neuropathic pain conditions ( 1). Previous research reported on a correlation between the location of vascular compression of the trigeminal nerve and the origin of facial pain (e.g. superomedial compression gave pain in the V1 region) ( 2). These findings are also supported by the work of Sindou et al. ( 3), which showed a relationship between the location of conflict of the retro-Gasserian trigeminal root and the distribution of pain. Such functional segregation of the fibres in the trigeminal root has been proposed before ( 4), although it is regarded as rather controversial ( 5, 6). In general, a gross somatotopic representation of the three major peripheral trigeminal divisions is reasonably well maintained within the trigeminal root, although entwinement of fibres occur as fibres progress from distal to proximal to the brainstem ( 7). The somatotopy is, however, not exclusive to the trigeminal root and is also maintained in the trigeminal ganglion from its embryological development ( 8). In the trigeminal ganglion, the afferent fibres of the ophthalmic division are located anteromedially, the mandibular posterolaterally and the maxillary in between ( 8). The same fundamental spatial organisation is also seen in foetuses of soft-shelled turtles and mouse foetuses ( 9). Others, on the other hand, specify that somatotopic localisation does not appear to be maintained ( 10). Nevertheless, improved knowledge on this matter can progress understanding of clinical symptoms, which will aid in diagnostic imaging and more effective treatment ( 11). Although many studies have contributed to our knowledge about the somatotopy of the peripheral trigeminal nerve, little is known about this segregation within the brainstem.

We therefore investigated the trigeminal root entry zone and pons, to map the arrangement of the trigeminal nerve within the brainstem of four post-mortem samples using polarised light imaging microscopy (PLI). PLI microscopy is capable of quantifying the orientation of fibres and is based on the birefringence of the myelin sheath in histological brain sections ( 12, 13). Findings of the PLI microscopy were thereafter reconstructed by using various advanced neuroimaging techniques, including tractography at 11.7 Tesla (diffusion-weighted) post-mortem magnetic resonance imaging ((d)MRI). This gave a three-dimensional presentation of the trigeminal nerve, further specifying its anatomical and somatotopic basis.

Methods and materials

Ethics statement

The brainstems studied herein were part of the anatomical collection of the Department of Anatomy of the Radboud University Medical Center, Nijmegen, the Netherlands. All body donors signed a written informed consent during their lifetime, permitting the use of their body and parts for scientific research and educational purposes. All protocols concerning the acquisition of data and tissue processing were approved by the CMO (Commissie Mensgebonden Onderzoek) region Arnhem-Nijmegen, the Netherlands, and are legislated under Dutch national law (BWBR0005009).

Specimens

Eleven brains that showed no signs of neurological diseases were included in this study. The brains were extracted from the skull and immersion-fixed using 7.7% formaldehyde at a short post-mortem interval (<48 h). The brains of specimens with a post-mortem interval under 24 h were included for MR scanning, as the post-mortem reduction of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) is limited in such specimens ( 14, 15). See Table 1 for information on the specimens used in this study.

Table 1.

Specimen

1

2

3

4

5

6

7

8

9

10

11

Preparation of tissues and magnetic resonance image acquisition

Prior to MR scanning, the four included specimens were soaked in a phosphate-buffered saline solution (PBS 0.1M, pH 7.4) for 7 days in order to reverse the decrease of the T2 relaxation rate of tissue induced by formaldehyde fixation ( 16). Next, the pontes were placed for 24 hours in Fomblin® ( Solvay Solexis Inc, https://www.solvay.com/en/brands/fomblin-pfpe-lubricants), a susceptibility-matched, hydrogen-free liquid. Finally, each pons was placed in a 100 ml syringe filled with Fomblin® for MR scanning.

All experiments were performed using an 11.7 T Bruker BioSpec Avance III preclinical MR system (Bruker BioSpin, Ettlingen, Germany) running Paravision 6.0.1, equipped with an actively shielded gradient set of 600 mT/m (slew rate 4570 T/m/sec). A circular polarised resonator was used for signal transmission and an actively decoupled birdcage coil was used for receiving (Bruker BioSpin, Ettlingen, Germany). All scanning was performed at 20 degrees Celsius. Further detailed information concerning the applied MR protocol is provided in Table 2 and has been described extensively before by our group ( 17).

Table 2.

Anatomical imaging with True Fast Imaging with SteadyState Free Precession (TRUFI)

T E

7.0 ms

T R

3.3 ms

α

20 degrees

Voxel size

0.25 mm isotropic

Diffusion weighted spin echo planar imaging

T E

30.7 ms

T R

13.8 ms

α

30 degrees

Δ

12.5 ms

δ

4.0 ms

Number of directions

256 gradientdirections

Number of averages

2.0

Number of q = 10 mm −1  (b = 0 equivalent)

6.0

Voxel size

0.50 mm isotropic

b-value (equivalent)

≈ 4000 s/mm ²

Probabilistic tractography

Processing of MR data was performed with the software package FSL ( 18). To correct for eddy current artifacts and displacement between the different diffusion images, an eddy current correction was applied ( 19). The bedpostX algorithm was used to model multiple fibre orientations (n = 3) at each voxel ( 20). To delineate the different tracts sprouting from the trigeminal root in our specimens, probabilistic tractography was performed using the Probtrackx2 algorithm (20,21). A manually defined seed mask (i.e. the starting point of tractography) was placed in the trigeminal root in the mean diffusivity (MD) maps by two neuroanatomists separately (DH and AMvCvW). The placed inferior and superior seeding masks were correlated with the PLI and histological sections based on fixed anatomical landmarks. Seed masks were placed on both sides of each trigeminal root. Streamlines were drawn from each seed-voxel (n = 50000 streamlines/voxel). A waypoint mask was placed manually at the level of the Pr5 in order to prevent the inclusion of other large dominating white tracts that course through the pons ( 22). Final probabilistic tractography results were converted into region of interest (ROI) masks. ROI-masks were converted into colour-coded maps using the vector map, which shows the principal diffusion tensor direction (V1 map).

Histological tissue processing and polarised light imaging

Histological sectioning of four of the remaining pontes for PLI microscopy was performed in order to optimally visualise all trigeminal fibres sprouting from the trigeminal root coursing in the ventral and dorsal trigeminothalamic tract (VTTH and DTTH, respectively). First, the pontes were bisected midsagitally in order to fit within the maximum field of view of the PLI microscope. Prior to histological sectioning, all pontes were immersed in a 30% sucrose-solution in 0.1M PBS at 4°C for 7 days as cryoprotection to prevent crystallisation during the freezing process prior to sectioning. The specimens were serially sectioned with an HM 450 Sliding Microtome (Thermo Fisher Scientific Inc., Waltham, MA, USA) at a thickness of 100 microns. All sections were mounted on glass and cover-slipped using the mounting medium polyvinylpyrrolidone, creating an interslice distance of 100 µm.

A Zeiss Axio Imager A2 microscope (Carl Zeiss Microscopy LLC, USA) was upgraded with a stationary polariser, a quarter wave plate and a rotating polarise and thereafter used as polarisation microscope. This setup has been described extensively before ( 17, 23) and has been shown to yield a spatial resolution of 4 μm/pixel. PLI post-processing was carried out by in-house written software in MATLAB (MathWorks, Inc., Natick, MA, USA, 1994-2017).

Histological tissue processing and histochemical staining

Three brainstems were embedded in paraffin prior to sectioning for histochemical myelin staining. The first stain involved Klüver-Barrera staining, which is a commonly used stain to observe myelin under light microscopy ( 24). The second stain involved Nauta silver stain, which can be used to visualise neurofilaments. This stain can be used to observe neurodegenerative changes of white matter, but can also be used to study myelinated and non-myelinated fibres ( 25, 26). The third stain comprised modified Heidenhain-Woelke stain (data previously published by Mollink et al. ( 27)), which contributes to optimal visualisation and differentiation between degrees of myelination within white matter fibre bundles ( 28, 29). Sectioning was performed with an LKB 2260 Macrotome (LKB Instruments, Bromma, Sweden). The knife was positioned at a 15 degree angle with respect to the sectioning plane. The tissue was serially sectioned at 4 µm thickness and every 15th slice was kept for staining, resulting in an interplane resolution of 60 µm. Each successful section was mounted and dried overnight in a stove at 37°C. Macrophotographs of the stained sections (referred to hereafter as the histological slices) were taken with a Canon EOS 550D camera using a Canon 100 mm autofocus lens to digitise the data.

Anatomical findings were reported in agreement with the standardised Paxinos-Watson abbreviation system, which has been adopted by the majority of the available anatomical atlases, including the atlases of Paxinos and Huang ( 30) and Mai et al. ( 31).

Results

Polarised light images

On the PL images, the trigeminal root can be observed to enter the ventrolateral aspect of each of the collected pontes. Within the pons, the trigeminal tract (TT) can be observed to penetrate the fibres of the middle cerebellar peduncle (MCP) as it courses towards the fourth ventricle. The superior part of the TT fibres can be seen to bend off in the direction of the medial lemniscus (ML). These superior fibres course towards the raphe of the brainstem while partially entwining with the fibers of the ML and are partially bounded ventrally by the ML. These fibres represent the VTTH. The fibres that make up the DTTH sprout from the TT as well and can be seen to course in between the MCP fibres in the direction of the dorsal aspect of the pons. These fibres bend downwards, as they are covered by MCP fibres cranially and continue their course towards the floor of the fourth ventricle. This dorsal division, recognised as the DTTH, runs towards the tegmentum and the fourth ventricle. At the dorsal aspect, after exiting the MCP, the DTTH shows the sprouting of a dispersing tract that runs in the direction of the cerebellum, bounded laterally by the superior cerebellar peduncle. Figure 1 provides a general overview of the anatomy of the pons at the level of trigeminal root entry zone as appreciated on MR and PL images. In Figure 2, consecutive PL images (from A to E) are shown from rostral to caudal. On this figure, it can be appreciated that the trigeminal fibres that course in the upper half of the trigeminal root and TT make up the VTTH. Furthermore, the fibres that contribute to the DTTH are found in the lower half of the trigeminal root and TT in this figure. Figures 2 and 3 depict PL images of consecutive slices of two of the included specimens and the contributions of the trigeminal root to the VTTH and DTTH, respectively.

Figure 1.

Overview of the anatomy of the pons at the level of the trigeminal entry zone. Exemplary images of MRI and PLI modalities. Anatomical orientation depicted by the anatomical anemone in the above-left corner. The fibre orientation is defined by the colour sphere on the right-hand side of the image. (a) A transverse T2* MR image of the human pons at the level of the entrance of the trigeminal entry zone. (b) Schematic drawing of the same MR image with annotations. (c) PL images of two sides of a bisected brainstem at the level of the trigeminal entry zone.

dtth: dorsal trigeminothalamic tract; ml: medial lemniscus; pt: pyramidal tract; tn: trigeminal nerve; tt: trigeminal tract; vtth: ventral trigeminothalamic tract.

Figure 2.

Consecutive polarised light imaging slices showing the fibre distribution patterns of the trigeminal root. Anatomical orientation depicted by the anatomical anemone in the above-left corner. The fibre orientation is defined by the colour sphere in the above-right corner. Figures 2(a)-(e) show consecutive PLI images of the trigeminal nerve. Figures 2(a)-(e) show consecutive PLI images of the trigeminal nerve. (a) is the most rostral part of the trigeminal nerve, (e) represents the most caudal part of the trigeminal nerve. In (a), (b) and (c) one can appreciate the branch coursing to the left, towards the pontine fibres. This branch represents the VTTH. The other branch, which has its trajectory towards the dorsal side of the pons, represents the DTTH.

dtth: dorsal trigeminothalamic tract; tt: trigeminal tract; vtth: ventral trigeminothalamic tract.

Figure 3.

Exemplary images of the trigeminal tracts, the ventral and dorsal trigeminothalamic tracts. Anatomical orientation depicted by the anatomical anemone in the above-left corner. The fibre orientation is defined by the colour sphere on the right-hand side of the image. (a), (b), (c) and (d) represent the four included specimens. For each specimen, three consecutive PLI images of the trigeminal nerve are shown. The four figures on the left side all represent the most rostral part of the trigeminal nerve, while the figures on the right side represent the most caudal part of the trigeminal nerve. The figures in between represent the middle part. The VTTH branch can be seen on the rostral part of the figures, while the DTTH can be seen on the caudal part of the figures.

dtth: dorsal trigeminothalamic tract; tt: trigeminal tract; vtth: ventral trigeminothalamic tract.

Histochemical staining patterns

The consecutive Heidenhain-Woelke stained sections, the Klüver-Barrera stained sections and the Nauta stained sections ( Figure 4) show a similar distribution pattern of the trigeminal root fibres. The upper half of the trigeminal root contributes primarily to the VTTH, whereas the lower half of the fibres course to join the DTTH.

Figure 4.

Histochemical staining results.

dtth: dorsal trigeminothalamic tract; pt: pyramidal tract; tt: trigeminal tract; vtth: ventral trigeminothalamic tract.

Probabilistic tractography results

Tractography results confirm the results of the PLI microscopy results. When a seeding mask was placed in the superior half of the trigeminal root, tracts can be seen to course towards the location of the Pr5 within the MCP. From that point, superiorly orientated voxels that lie adjacent to the ML can be appreciated as tracts crossing over to the other side of the brainstem (VTTH) ( Figure 5). Tracts seeded from the inferior seeding mask were shown to transverse the MCP. Within the MCP, these tracts bend in a medial direction towards the centre of the brainstem. After emerging from the MCP, the fibres change from a dorsoventral orientation to a craniocaudal orientation. This craniocaudal tract runs in the posterior aspect of the pons near the superior cerebellar peduncle (SCP). These fibres predominantly course on the ipsilateral side of the brainstem (DTTH) ( Figure 6).

Figure 5.

Tractography results when the seeding mask is placed in the superior part of the trigeminal root. Anatomical orientation depicted by the anatomical anemone in the above-left corner. A transection of the trigeminal root showing the definition of the superior part of the trigeminal root. Tractography results of dMRI overlain on 11.7 T mean diffusivity maps. The RGB (red-green-blue) colour cross indicates the principal eigenvector orientations, red = left-right, green = anterior-posterior, blue = cranial-caudal. Tractography results from the superior half TT can be observed to contribute to the VTTH.

*Transverse sections (white line shows the level of transection).

**Coronal sections (white line shows the level of transection).

tt: trigeminal tract; vtth: ventral trigeminothalamic tract.

Figure 6.

Tractography results when the seeding mask is placed in the inferior part of the trigeminal root. Anatomical orientation depicted by the anatomical anemone in the above-left corner. A transection of the trigeminal root showing the definition of the inferior part of the trigeminal root. Tractography results of dMRI overlain on 11.7 T mean diffusivity maps. The RGB (red-green-blue) colour cross indicates the principal eigenvector orientations, red = left-right, green = anterior-posterior, blue = cranial-caudal. Tractography results from the inferior half TT can be observed to contribute to the DTTH.

*Transverse sections (white line shows the level of transection).

**Coronal sections (white line shows the level of transection).

dtth: dorsal trigeminothalamic tract; tt: trigeminal tract.

Discussion

This study shows that the fibres, from the point where the trigeminal root enters the brainstem, are distinctly arranged by their contribution to the VTTH and DTTH. This finding is supported by both post-mortem, ultra-high dMRI and different light microscopy techniques.

Even though these results show that the superior part of the trigeminal nerve contributes to the VTTH and the inferior part to the DTTH, the controversy regarding whether the somatotopic arrangement of the trigeminal nerve is maintained within the brainstem is not fully answered by these results. The data of the present study do not provide insight into the somatotopic arrangement of the main divisions of the trigeminal nerve (V1, V2 and V3) within the pons. However, Lipari et al. ( 8) proposed that the spinal nucleus (SN) receives fibres of all three divisions and that the somatotopic arrangement is preserved within the nucleus with the face represented in upside-down fashion. It can therefore be hypothesised that the somatotopic arrangement is preserved in case either the VTTH or the DTTH are responsible for afferent fibres to the spinal nucleus. However, further research will be needed to conclude this. Furthermore, the data show that the bifurcation of the VTTH and DTTH approximates the location of the principal sensory nucleus (PSN). The provided data therefore show the trajectory of the trigeminal tract from the trigeminal root entry zone to the PSN. The course of the two fibre tracts (VTTH and DTTH) originating from the PSN, however, is rather obscure. The classic interpretation is that the trigeminal tract synapses in the PSN and from there projections towards the thalamic nuclei, the trigeminal spinal nucleus and the mesencephalic nucleus arise. However, the classical subdivision that the nociceptive trigeminal input is conveyed by the VTTH and that tactile input is relayed via the DTTH seems to be more complex ( 32- 34). Various authors reported that the fibres that sprout from the dorsal aspect of the PSN (i.e. the DTTH) course towards the ipsilateral posterior ventral nucleus of the thalamus ( 32- 34). This could therefore indicate that the VTTH is responsible for the contralateral and the DTTH for the ipsilateral sensory input to the thalamus. Nevertheless, it remains difficult to assign a functionality to the VTTH and DTTH based on the anatomical results provided here. Another interesting insight is whether these results can improve future therapeutic interventions for trigeminal neuralgia, which will become more target specific. Sindou et al. ( 2, 3), showed that patients suffering from pain in the ophthalmic division are more likely to have a conflict on the superomedial part of the trigeminal root entry zone, which would indicate a somatotopic arrangement of the trigeminal root entry zone. Selective destruction of fibres in the trigeminal root has been proposed by others as a method to relieve pain with only minimal sensory loss ( 32- 35). Although our results do confirm a superior and inferior arrangement, further research is needed to confirm that patients who are undergoing selective destruction of the trigeminal root have fewer consequences than those undergoing non-selective destruction.

Strengths and limitations

This paper used a multimodality approach to investigate the internal architecture of the trigeminal root and found in all these imaging methods a distribution pattern of the trigeminal fibres that form the origins of the trigeminothalamic connections. Another strength is that, by combining 11.7 T structural and diffusion MRI with PLI microscopy, the imaging resolution from this study bridged from 0.1 mm to 5.0 mm ( 36). Furthermore, the present study concerns the use of PLI validation ( 37) and direct implementation of the findings by use of tractography, although this technique is also known to produce false-positive, plausible-looking bundles of white matter anatomy ( 38). The absence of other imaging methods, including tracer studies, can be regarded as a relative limitation of the present study. Nonetheless, Seehaus et al. showed that tracing studies can be performed in a post-mortem setting on adult human neural tissue over short trajectories (with a maximal length of 13 mm), which could possibly be long enough to observe the distribution of fibres of the trigeminal root in the human brainstem ( 39). Finally, the precise clinical relevance of this data cannot be determined by the current study protocol and the applied methodologies; for example, due to the fact that the current data provide no insights into the somatotopic arrangement of the trigeminal main divisions in the trigeminal nerve within the pons. Further anatomical research and improved clinical phenotyping of patients suffering from trigeminal neuralgia, combined with new interpretation of radiological data, must be carried out to conclude whether a somatotopic arrangement of the trigeminal nerve is preserved within the pons. Although the sample size was relatively limited, the included specimens showed consistent anatomic features, which decreased the chances of having observed anatomical variants.

Conclusion

The present study showed that the origins of the VTTH and DTTH can be traced back to specific fibre bundles within the trigeminal root, indicating a distinct organisation of the trigeminal root. The superior half of the trigeminal root was found to contribute mostly to the VTTH, whereas the inferior half of the trigeminal root contains the fibres that constitute the DTTH. Future clinical implications must be further elucidated.

Article highlights

The superior half of the trigeminal root was found to contribute mostly to the ventral trigeminothalamic tract (VTTH);

The inferior half of the trigeminal root contains the fibres that constitute the dorsal trigeminothalamic tract (DTTH).

Data

All data can be acquired upon reasonable request by contacting the corresponding author.

Footnotes

Declaration of conflicting interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors received no financial support for the research, authorship, and/or publication of this article.

Reference

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28. Burgel U, Mecklenburg I, Blohm U, et al. Histological visualization of long fiber tracts in the white matter of adult human brains. J Hirnforsch 1997; 38: 397-404. [PubMed] [Google Scholar]

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# data[].attributes.attachment_link.title
Mapping the trigeminal root entry zone and its pontine fibre distribution patterns

# data[].attributes.attachment_link.description
Recently, an additional trigeminothalamic tract - the dorsal trigeminothalamic tract - has been described in human brainstems by our group next to the known ventral trigeminothalamic tract. As various elements of the trigeminal system are known to ...

# data[].attributes.headline
Xie G, Zhang F, Leung L, Mooney MA, Epprecht L, Norton I, Rathi Y, Kikinis R, Al-Mefty O, Makris N, Golby AJ, O'Donnell LJ. Anatomical assessment of trigeminal nerve tractography using diffusion MRI: A comparison of acquisition b-values and single- and multi-fiber tracking strategies. Neuroimage Clin. 2020;25:102160. doi: 10.1016/j.nicl.2019.102160. Epub 2020 Jan 8. PMID: 31954337; PMCID: PMC6962690.

# data[].attributes.subject
Xie G, Zhang F, Leung L, Mooney MA, Epprecht L, Norton I, Rathi Y, Kikinis R, Al-Mefty O, Makris N, Golby AJ, O'Donnell LJ. Anatomical assessment of trigeminal nerve tractography using diffusion MRI: A comparison of acquisition b-values and single- and multi-fiber tracking strategies. Neuroimage Clin. 2020;25:102160. doi: 10.1016/j.nicl.2019.102160. Epub 2020 Jan 8. PMID: 31954337; PMCID: PMC6962690.

# data[].attributes.attachment_link.title
Anatomical assessment of trigeminal nerve tractography using diffusion MRI: A comparison of acquisition b-values and single- and multi-fiber tracking strategies - PubMed

# data[].attributes.attachment_link.description
Overall, the results of the study suggest that researchers and clinicians may benefit from tailoring their acquisition and tracking methodology to the specific anatomical portion of the TGN that is of the greatest interest. For example, tracking of branching structures and TGN-T2 overlap can be best …

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Upadhyay J, Knudsen J, Anderson J, Becerra L, Borsook D. Noninvasive mapping of human trigeminal brainstem pathways. Magn Reson Med. 2008 Nov;60(5):1037-46. doi: 10.1002/mrm.21682. PMID: 18956455; PMCID: PMC2597480.

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Upadhyay J, Knudsen J, Anderson J, Becerra L, Borsook D. Noninvasive mapping of human trigeminal brainstem pathways. Magn Reson Med. 2008 Nov;60(5):1037-46. doi: 10.1002/mrm.21682. PMID: 18956455; PMCID: PMC2597480.

# data[].attributes.attachment_link.title
Noninvasive mapping of human trigeminal brainstem pathways - PubMed

# data[].attributes.attachment_link.description
The human trigeminal system mediates facial pain and somatosensory processing. The anatomic location of neuronal substrates and axonal pathways of the trigeminal system have previously been characterized with conventional in vitro methods. The present investigation implemented diffusion tensor imagi …

# data[].attributes.headline
Sandwell SE, El-Naggar AO. Nucleus caudalis lesioning: Case report of chronic traumatic headache relief. Surg Neurol Int. 2011;2:128. doi: 10.4103/2152-7806.85467. Epub 2011 Sep 27. PMID: 22059123; PMCID: PMC3205483.

# data[].attributes.subject
Sandwell SE, El-Naggar AO. Nucleus caudalis lesioning: Case report of chronic traumatic headache relief. Surg Neurol Int. 2011;2:128. doi: 10.4103/2152-7806.85467. Epub 2011 Sep 27. PMID: 22059123; PMCID: PMC3205483.

# data[].attributes.attachment_link.title
Nucleus caudalis lesioning: Case report of chronic traumatic headache relief

# data[].attributes.attachment_link.description
The nucleus caudalis dorsal root entry zone (DREZ) surgery is used to treat intractable central craniofacial pain. This is the first journal publication of DREZ lesioning used for the long-term relief of an intractable chronic traumatic headache. A…

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Henssen DJHA, Pritsch C, Nazari P, Mulleners W, Vissers K. The non-decussating and decussating trigeminothalamic tracts in humans: A combination of connectome-based tractography and histological validation. Cephalalgia. 2024 Apr;44(4):3331024241235168. doi: 10.1177/03331024241235168. PMID: 38613234.

# data[].attributes.subject
Henssen DJHA, Pritsch C, Nazari P, Mulleners W, Vissers K. The non-decussating and decussating trigeminothalamic tracts in humans: A combination of connectome-based tractography and histological validation. Cephalalgia. 2024 Apr;44(4):3331024241235168. doi: 10.1177/03331024241235168. PMID: 38613234.

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Affiliations

¹ Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands.

² Donders Institute for Brain, Cognition & Behaviour, Radboud University, Nijmegen, The Netherlands.

³ Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

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Free article

Affiliations

¹ Department of Medical Imaging, Radboud University Medical Center, Nijmegen, The Netherlands.

² Donders Institute for Brain, Cognition & Behaviour, Radboud University, Nijmegen, The Netherlands.

³ Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.

Abstract

Background: Functional anatomical research proposed the existence of a bilateral trigeminal ascending system although the anatomy trajectories of the trigeminothalamic connections cranial to the pons remain largely elusive. This study therefore aimed to clarify the anatomical distributions of the trigeminothalamic connections in humans.

Methods: Advanced deterministic tractography to an averaged template of diffusion tensor imaging data from 1065 subjects from the Human Connectome Project was used. Seedings masks were placed in Montreal Neurological Institute standard space by use of the BigBrain histological dataset. Waypoint masks of the sensory thalamus was obtained from the Brainnetome Atlas.

Results: Tractography results were validated by use of the BigBrain histological dataset and Polarized Light Imaging microscopy. The trigeminothalamic tract bifurcated into a decussating ventral and a non-decussating dorsal tract. The ventral and dorsal tracts ascended to the contralateral thalamus and ipsilateral thalamus and reflected the ventral trigeminothalamic tract and the dorsal trigeminothalamic tract, respectively. The projection of the ventral trigeminothalamic tract and the dorsal trigeminothalamic tract to both thalami confirm the existence of a bilateral trigeminothalamic system in humans.

Conclusions: Because our study is strictly anatomical, no further conclusions can be drawn with regard to physiological functionality. Future research should explore if the dorsal trigeminothalamic tract and the ventral trigeminothalamic tract actually transmit signals from noxious stimuli, this offers potential in understanding and possibly treating neuropathology in the orofacial region.

Keywords: Anatomy; trigeminal nerve; trigeminothalamic tracts.

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Conflict of interest statement

Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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# data[].attributes.attachment_link.title
The non-decussating and decussating trigeminothalamic tracts in humans: A combination of connectome-based tractography and histological validation - PubMed

# data[].attributes.attachment_link.description
Because our study is strictly anatomical, no further conclusions can be drawn with regard to physiological functionality. Future research should explore if the dorsal trigeminothalamic tract and the ventral trigeminothalamic tract actually transmit signals from noxious stimuli, this offers potential ...

# data[].attributes.headline
Henssen, D. J. H. A., Mollink, J., Kurt, E., van Dongen, R., Bartels, R. H. M. A., Grässel, D., Kozicz, T., Axer, M., & Van Cappellen van Walsum, A.-M. (2019). Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7 T diffusion MRI combined with microscopy polarized light imaging. Brain Structure and Function, 224(1), 159–170. https://doi.org/10.1007/s00429-018-1767-1

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Henssen, D. J. H. A., Mollink, J., Kurt, E., van Dongen, R., Bartels, R. H. M. A., Grässel, D., Kozicz, T., Axer, M., & Van Cappellen van Walsum, A.-M. (2019). Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7 T diffusion MRI combined with microscopy polarized light imaging. Brain Structure and Function, 224(1), 159–170. https://doi.org/10.1007/s00429-018-1767-1

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Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging

Abstract

Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally. This study aims to provide an anatomical substrate for the hypothesized bilateral projection. Three post-mortem human brainstems were scanned for anatomical and diffusion magnetic resonance imaging at 11.7T. The trigeminal tracts were delineated in each brainstem using track density imaging (TDI) and tractography. To evaluate the reconstructed tracts, the same brainstems were sectioned for polarized light imaging (PLI). Anatomical 11.7T MRI shows a dispersion of the trigeminal tract ( tt) into a ventral and dorsal portion. This bifurcation was also seen on the TDI maps, tractography results and PLI images of all three specimens. Referring to a similar anatomic feature in primate brains, the dorsal and ventral tracts were named the dorsal and ventral trigeminothalamic tract ( dtt and vtt), respectively. This study shows that both the dtt and vtt are present in humans, indicating that each hemiface has a bilateral projection, although the functional relevance of these tracts cannot be determined by the present anatomical study. If both tracts convey noxious stimuli, this could open up new insights into and treatments for orofacial pain in patients.

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Introduction

Classically, orofacial nociceptive afferents, running through the trigeminal nerve and the trigeminal tract (TT), are believed to synapse in the ipsilateral trigeminal sensory nucleus complex (Sessle 2000). Second-order neurons then cross and ascend as the trigeminothalamic tract to the contralateral ventro-posterior medial nucleus of the thalamus. From there, projections ascend to the primary and secondary somatosensory cortices and other cortical regions, such as the insula (Ralston 2005). However, the exact anatomy of the central portion of the trigeminal pathways in humans remains a point of discussion. Knowledge of the exact neuroanatomy of the trigeminal tracts will contribute to the understanding of orofacial pain and its treatment. Preclinical experiments provide evidence for a bilateral projection of the orofacial region causing activation of both thalami and both primary sensory cortices in healthy subjects, as well as patients suffering from chronic orofacial pain (Nash et al. 2009, 2010). This bilateral representation of the orofacial region can be explained by transcallosal pathways or by a bilateral trigeminothalamic system. The involvement of transcallosal pathways in the bilateral activation pattern of the aforementioned brain regions in the registration of orofacial pain seems to be of limited importance according to the split-brain study of Stein et al. However, proper interpretation of the results of this study is hampered due to the small sample size ( n = 1) (Stein et al. 1989). Additionally, Solstrand Dahlberg and colleagues report findings that a decreased connectivity of regions in the brainstem that are involved in orofacial pain with parts of the descending pain modulation system is present in patients suffering from migraine. However, they also conclude that the exact anatomy of the trigeminal pathways in the human brainstem remain elusive (Solstrand Dahlberg et al. 2018). In 2016, a review of tracing studies in animals and functional MRI studies in humans provided an overview of the trigeminal tracts in the brainstem (Henssen et al. 2016). Figure 1 depicts two trigeminothalamic tracts sprouting from the principal sensory nucleus (PSN), the ventral- and dorsal trigeminothalamic tract ( vtt and dtt, respectively). The vtt is a mainly contralateral pathway and is known to be present in human specimens. The dtt, on the other hand, is a mainly ipsilateral pathway and is predominantly known from animal-based studies and has only been hypothesized to exist in humans (Henssen et al. 2018).

Overview of the trigeminothalamic tracts that arise from the PSN in a dorsal view. Cranial nerves indicated in Roman numerals; dPSN dorsal principal sensory nucleus; vPSN ventral principal sensory nucleus; *dorsal trigeminothalamic tract ( dtt), **ventral trigeminothalamic tract ( vtt)

Based on the aforementioned results, we hypothesized that dtt would exist in the human brainstem too. To test this hypothesis, we investigated the neuroanatomy of the dtt in human brainstems using, multiple, advanced neuroimaging techniques, including post-mortem, 11.7 anatomical magnetic resonance imaging (MRI) and diffusion-weighted MRI (dMRI) and several post-processing techniques (e.g., tract density imaging (TDI) and tractography). To complement the MR findings, the same brainstems were sectioned to obtain histological transverse sections for polarized light imaging microscopy (PLI). PLI is a microscopy technique to quantify fiber orientation based on birefringence of the myelin sheath in histological brain sections and has been reported as a well-suited technique to validate MR findings (Axer et al. 2011b).

Materials and methods

Acquisition of the post-mortem material

Three post-mortem brains were derived from the body donor program of the department of Anatomy at Radboud University Medical Center, Nijmegen, The Netherlands. The three donors had no known neurological diseases and none of the brains showed pathological deformities after death. All specimens were perfused via the femoral artery using 10% formaldehyde and a relatively short postmortem interval (< 24 h) was employed to limit the reduction of several diffusion values [apparent diffusion coefficient (ADC) and fractional anisotropy (FA)] (D'Arceuil and de Crespigny 2007; Schmierer et al. 2008). After embalmment, the specimens were fixated in 7.7% formaldehyde for at least 3 months to a maximum of 3 years as it was suggested that diffusivity measures remain stable up to 3 years after fixation (Dyrby et al. 2007). Then the brain was extracted from the skull. The brainstem and cerebellum were separated from the cerebrum via a transverse section, perpendicular to the neural axis, at the level of the superior colliculus. The cerebellum was dissected from the brainstem by a coronal cut through the middle cerebellar peduncle. All three parts were fixated in 7.7% formaldehyde and preserved for another 2 months. See Table 1 for additional information. This study was carried out in accordance with the recommendations of the CMO (Commissie Mensgebonden Onderzoek) region Arnhem-Nijmegen, Netherlands. The post-mortem specimens were acquired via the body donor program at the department of Anatomy of the Radboud university medical centre, Nijmegen, Netherlands. All body donors in this program signed a written informed consent during their lifetime, permitting the use of their body and parts for science and teaching.

Table 1 Overview of the characteristics of the specimens used in this study

Magnetic resonance image acquisition

Prior to MR scanning, the three post-mortem brainstems were stored in a phosphate-buffered saline solution (PBS 0.1M, pH 7.4) for 1 week to reverse the decrease of the T2 relaxation rate of tissue introduced by formaldehyde (Shepherd et al. 2009). Next, the brainstems were placed for 24 h in Fomblin® ( Solvay Solexis Inc), a susceptibility-matched, hydrogen-free liquid. The brainstems were then placed in a vacuum chamber for 10 min to reduce free air in the lumina of the blood vessels. Ultimate maximum pressure within the vacuum chamber was set to 1350 mmHg to prevent cell membrane damages (Gonzalez-Rodriguez et al. 2016; Holzapfel et al. 2005), although the maximum pressure did not exceed 500 mmHg during the experiments as this was not necessary to remove air bubbles. Finally, each brainstem was placed in a 100 ml syringe, filled with Fomblin, for MR scanning. All imaging was performed on a 11.7T Bruker BioSpec Avance III preclinical MR system (Bruker BioSpin, Ettlingen, Germany) equipped with an actively shielded gradient set of 600 mT/m (slew rate 4570 T/m/s). A circular polarized resonator was used for signal transmission and an actively decoupled birdcage coil (Bruker Biospin) was used for receiving. Scanning was performed at room temperature (20 °C). T2* weighted images were acquired using a 3D multi-gradient echo sequence at 0.25 mm isotropic resolution with the following parameters: TR = 3314 ms; TE = 7 ms; and flip angle = 20°. The dMRI data were obtained using segmented spin-echo echo-planar imaging at 0.5 mm isotropic resolution. This sequence consisted out of four segments. A total of 256 gradient directions were employed at a b value of 4000 s/mm ², in addition to six images with no diffusion weighting ( b = 0 s/mm ²) and the following gradient and pulse parameters: Δ = 12.5 ms, δ = 4.0 ms, TE = 30.70 ms, and TR = 13.75 s. The applied MR protocol was adapted from an empirically designed protocol reported in the literature (Kleinnijenhuis et al. 2013).

Probabilistic tractography

All processing of the MR images was performed with FSL (Jenkinson et al. 2012). To correct for eddy current artifacts and displacement between the different diffusion images, an eddy current correction was applied (Andersson and Sotiropoulos 2015). The dMRI data were pre-processed for tractography with the bedpostX algorithm that models multiple fiber orientations ( n = 3) at each voxel (Behrens et al. 2007). To delineate the TT in our specimens, probabilistic tractography was performed using the Probtrackx2 algorithm. A manually defined seed mask (i.e., the starting point of tractography) was placed in the entry zone of the trigeminal nerve on the fractional anisotropy (FA) maps. To address the reproducibility of the drawing of the masks in each specimen, two neuroanatomists, independently, delineated the location of the trigeminal root entry zone on both sides of each brainstem. The overlap of both masks was used as the seeding masks for tractography on either the right or left side of each brainstem. Streamlines were drawn from each seed-voxel ( n = 50,000 streamlines per voxel). Only streamlines that reached the dorsal part of the brainstem near the PSN-defined by a waypoint mask-were kept to avoid the inclusion of other large dominating white tracts that run through the brainstem (Büttner-Ennever and Horn 2013). Maximum intensity projections (MIPs) of the trigeminal tract streamlines along aspecified encoded color direction, which improve the visualization of general tractography results as they provide stereoscopic visualization, were overlaid on the fractional anisotropy, which highlights the tract locations.

Track density imaging

Track density imaging (TDI) is typically used to investigate white matter microstructure smaller than the imaging resolution by reinterpolation of the quantitative maps by constrained spherical deconvolution based on the response function at a finer resolution (Calamante et al. 2010). TDI was applied to the dMRI data to study the TT trajectory and its possible bilateral projections. To generate the directionally encoded color TDI maps, whole brainstem probabilistic fiber-tracking was carried out with MRtrix as described by Calamante et al. ( 2010). Streamlines were generated (total number of streamlines: n = 500,000; 20 per seed voxel) from a large number of random seeds throughout the brainstem. Seeds are placed randomly throughout the brainstem as described by other before (Calamante et al. 2010, 2011). The total number of streamlines was calculated in each element of a grid that covers the brainstem. It should be noted that the sampling distance of the grid was smaller than the acquired voxel size, yielding TDI map with higher spatial resolution than the source dMRI data (0.1 mm isotropic). After tracking, the streamline density was used as intra-voxel information to construct a super-resolution TDI image (Calamante et al. 2010).

Histological tissue processing

Histological sectioning was performed for the TT at the level of the trigeminal nerve entry zone. This part was separated from the rest of the brainstem with a transverse cut through the inferior olivary nucleus and the inferior colliculus. To prevent the formation of ice crystals during freezing, the brainstems were stored in a 30% sucrose PBS solution (PBS 0.1M, pH 7.4) at 4 °C for 1 week. The specimen was frozen using dry ice and serially sectioned with a HM 450 Sliding Microtome ( Thermo Fisher Scientific Inc., Waltham, Massachusetts, USA) at a thickness of 100 microns. In a series of five axial sections, the first section was mounted on glass, creating an inter-slice gap of 500 microns.

Polarized light imaging

PLI utilizes the optical birefringence of nerve fibers, which can be attributed to the arrangement of lipid layers in the myelin sheaths wrapping the axons (Axer et al. 2011a, c). Birefringence alters the polarization state of the light that is passed through the specimen depending on the orientation of the myelinated nerve fibers. As such, taking a series of images while rotating the linear polarizer plane allows for quantification of fiber orientation at each pixel. The abovementioned principle of measurement is referred to as polarimetry. To realize PLI measurements of the transverse sections of the brainstems, two polarimeters were used: a large-area polarimeter (LAP) for single shot medium-resolution (64 microns per pixel) images covering the whole tissue section and a polarization microscope (PM) to scan a grid of high-resolution images (1.3 microns per pixel) in smaller regions of interest. Both types of polarimetric equipment work in a similar manner. Monochrome green light passes through a linear polarizer combined with a quarter wave retarder with its fast-axis oriented at 45° with respect to the polarizer plane. This creates circularly polarized light that passes through the specimen followed by another polarizer, which captures the change in polarization induced by tissue birefringence. By simultaneous rotation of all polarizing filters, the transmission intensity is systematically imaged at discrete filter rotation angles. A typical PLI raw image dataset comprised 18 snapshots at equidistant azimuth angles of 10°, ranging between 0° and 170°. On the LAP these measurements were supplemented by 8° tilt measurements to the cardinal points allowing for stereoscopic imaging to disambiguate the fiber elevation angle. Processing of all raw images created, due to the coarse resolution of the LAP-particular anatomical landmarks of the trigeminal pathways in the brainstem, were scanned additionally in the PM to obtain images of higher resolution. The PM used a reversed light pathway and rotates the polarizer only. A more extensive description of the polarimeters engaged during PLI is given by (Reckfort et al. 2015; Axer et al. 2011a, b).

Results

T2* weighted MR images

The trigeminal nerve can be clearly observed entering the ventrolateral part of the pons, after which the hypo-intense signal of the tt can be seen traversing the brainstem. The tt penetrates the middle cerebellar peduncle ( mcp) and slopes slightly through the pons towards a large hypo-intense bulge medial to the mcp. This enlarged portion of the tt represents the PSN (Fig. 2). The PSN is located lateral and dorsal to the medial lemniscus ( ml) and ventral to the central tegmental tract. At Fig. 2D, two hypo-intense extensions of the PSN, dorsal towards the fourth ventricle (most probably dtt) and ventral towards the center of the brainstem ( vtt), can be discriminated.

TDI-results

Figure 3 presents an overview of the results of the TDI analysis of the three specimens in transverse sections confirming the findings of T2* weighted MRI. It can be observed that the tt traverses through the mcp in a dorsomedial and caudal direction. A portion of it appears to join the ml, whereas the rest remains on its dorsomedial course through the tegmentum. After the bifurcation of the tt, two tracts can be observed: (1) a dorsomedial tract that courses in cranio-caudal direction and (2) a more ventral tract, dorsal to the ml. Figure 4 shows a ventral and a dorsal region of the brainstem as maximum intensity projection of multiple coronal sections near the bifurcation. Their location is shown in (A). The ventral region (C-E) shows that the majority of fibers from the tt join the ml crossing to the contralateral hemisphere. The dorsal region (B-D) reveals a smaller tract coursing towards the raphe without crossing. Instead it turns into a cranio-caudal direction. In principle, these models reconfirm a bifurcation of the tt near the transverse pontine fibers and the ml into a dorsal and ventral part. The dorsal tract appears to remain on the ipsilateral side with regard to the trigeminal root from which it sprouts, while the ventral one crosses to the contralateral side of the brainstem. The dorsal tract can, therefore, be determined to be the dtt; the ventral one to be the vtt.

TDI fiber orientation maps of one brainstem (specimen 1) in two directions: transverse sections at the trigeminal entry level and frontal sections at the level of the vtt and dtt. The RGB (red-green-blue) color cross indicates the principal eigenvector orientations, red = left-right, green = anterior-posterior, blue = cranio-caudal. Insets of b and c with a higher level of detail are shown in d and e. a Transverse TDI map of one brainstem (specimen 1) at the level of the entry of the trigeminal nerve. The bifurcation of the trigeminal tract into vtt and dtt is depicted. Section B is positioned at the level of the dtt and section C at the level of the vtt as indicated by dashed lines. b Frontal TDI map of one brainstem (specimen 1) at the level of the dtt. Initially the tt has a sagittal orientation after which it sprouts into a transversal. After sprouting from the tt, the dtt courses towards the dorsal wall of the brainstem. c Frontal TDI map of one brainstem (specimen 1) at the level of the vtt. The tt has a mixed anterior-posterior/left-right orientation. The vtt sprouts of from the inner face of the tt and attaches itself to the ml dorsally where it turns upward to the cranial part of the brainstem. d Enlargement of inset D in frontal TDI map depicted in section B. This inset shows the dtt in a frontal view and depicts that the tt has a anterior-posterior orientation, whereas the dtt has a mixed left-right/craniocaudal orientation in the dorsal area of the brainstem. dtt Dorsal trigeminothalamic tract, ml medial lemniscus, tt trigeminal tract, vtt ventral trigeminothalamic tract

Tractography results

Tractography results are depicted stereoscopically by use of MIP images. Results from tractography show a bifurcation of the left (blue) and right tt (red) in all three specimens. From this bifurcation, two tracts can be recognized: a dorsomedial one, which courses in cranio-caudal direction remaining ipsilateral, and a ventral one crossing to the contralateral side at the dorsal surface of the ml. The dorsal tract can, therefore, be identified as dtt, the ventral one as vtt (Fig. 5).

Polarized light images

On the PLI images (Fig. 6), the trigeminal root is observed to enter the ventrolateral aspect of the brainstem. The tt then crosses the mcp after which it bifurcates into a ventral and dorsal division. The ventral division, recognized as the vtt, bends alongside the ml. The dorsal division, recognized as the dtt, runs towards the tegmentum and the fourth ventricle (Fig. 6). Figure 7 depicts the tt coursing towards the dorsomedial aspect of the brainstem. After exiting the mcp, the tt shows a bifurcation into two tracts. The ventral branch runs posterior to the ml and courses towards the midline of the brainstem. The dorsal tract runs towards the dorsal aspect of the brainstem. The dorsal tract furthermore shows dispersing fibers that run towards the cerebellum via the mcp and towards the dorsomedial area of the brainstem.

PLI fiber orientation maps acquired at high resolution of transverse sections of the brainstem of specimen 1 at the level of the bifurcation of the trigeminal tract. The fiber orientation is defined by the color sphere in the upper left corner. a The tt can be observed in the mcp (green). The tt bifurcates into two tracts: the ventral portion (yellow) and dorsal portion (purple). b Detailed view of the bifurcation of the left tt shown in a. The vtt turns alongside the posterior wall of the ml and courses towards the raphe of the brainstem. The dtt runs towards the dorsal aspect of the brainstem splitting up again towards the cerebellum via the mcp (green-aquamarine) and towards the mesencephalic nucleus (purple). ml Medial lemniscus, tt trigeminal tract, vtt ventral trigeminothalamic tract, dtt dorsal trigeminothalamic tract

Discussion

For the first time, the existence of a bifurcation of the tt into a vtt and dtt in the human brainstem using (d)MRI, TDI and PLI has been reported. It is well known that the orofacial nociceptive afferents synapse in the ipsilateral trigeminal sensory nuclear complex (TSNC) cross the midline and ascend as the trigeminothalamic tract to the contralateral ventroposterior medial nucleus (VPM) of the thalamus. This study shows that the crossing tract can be identified as the vtt. The dorsal branch of the bifurcation could represent the hypothesized ipsilateral dtt.

Comparison with existing studies

In primates, evidence of this bilateral somatosensory pathway through the thalamus to the facial representation of the primary somatosensory cortex has been previously provided (Rausell and Jones 1991a, b). In humans, this bilateral representation pattern has been observed in functional MRI (fMRI) studies that investigated the activation patterns of orofacial pain in humans. These studies showed that unilateral noxious stimulation of the orofacial region evokes changes in both the contralateral and the ipsilateral thalami, insular and primary somatosensory cortices (Jantsch et al. 2005; Nash et al. 2010). Other studies suggested that a bifurcation of the trigeminal nerve can be found at the level of the brainstem, based on the blood oxygen level dependent (BOLD) activation patterns in experimental orofacial pain settings (Nash et al. 2009, 2010), which is consistent with the results of this paper. Furthermore, it is known from developmental brain research that the raphe of the brainstem is a generator of attractants and repellents that channel axonal growth to the proper side of the central nervous system, which causes the crossing of the major somatosensory and motor pathways. However, embryological development studies in mice have shown that a minority of the axons that sprout from the PSN do not cross the midline (Kivrak and Erzurumlu 2013).

The vtt has been described to consist of fibers that sprout from the ventral part of the PSN and the cranial two-thirds of the spinal nucleus (SN). The axons of the second-order neurons in the aforementioned nuclei decussate along the dorsal border of the ml and are, therefore, called the trigeminal lemniscus (Torvik 1957; Smith 1975; Matsushita et al. 1982). The function of the vtt is thought to be the conduction of vital sensory information, including nociceptive information. This study shows that the vtt indeed runs posterior to the ml and some imaging techniques even show that there is no clear distinction between the ml and the vtt. However, the high-resolution PLI images show that fibers of the ml and fibers of the vtt do not entwine along their courses.

The dtt has been described to consist of fibers originating from the dorsal part of the PSN and the caudal two-thirds of the SN (Burton and Craig 1979; Matsushita et al. 1982). It has been assumed that the dtt is responsible for conducting pain, temperature, and mechanoreceptive stimuli from the anterior part of the facial region and the intraoral cavity [for a review see (Henssen et al. 2016)].

This anatomical study provides further evidence of the existence of both the dtt and vtt; however, it cannot verify that both tracts are involved in the conduction of noxious stimuli. It is well known that the primary afferents of the somatosensory system can be subdivided according to myelinization and size. The different fiber types cluster the afferents into group A-C, of which the unmyelinated C-fibers and thin, myelinated Aδ-fibers subserve nociceptive transmission, whereas B-fibers represent thin preganglionic fibers of the autonomic nervous system (Erlanger and Gasser 1937). Central white matter, on the other hand, cannot be allocated to nociceptive systems on the basis of its architecture alone. For this reason, although the dtt seems to be present in humans as well, its function cannot be determined by this study.

Technical considerations

The use of diffusion magnetic resonance imaging (dMRI) and tractography has become a popular method to study white matter pathways (Catani and Thiebaut de Schotten 2008). However, due to the limited imaging resolution of in vivo dMRI (typically 1.0-2.0 mm), its outcomes should be interpreted with care, especially in the presence of small fiber bundles. However, a recent study of Setsompop showed that on a clinical 3T scanner, imaging resolution of whole-brain data could be acquired of 0.66 mm and 0.76 mm isotropic. This indicates that new efficient methods that are capable of acquiring high-resolution diffusion data in vivo might be possible in the near future (Setsompop et al. 2018). Nevertheless, the applied MRI protocol in this study was found to further increase resolution to a spatial resolution of 0.2 mm isotropic for the T2*-images and 0.5 mm for the diffusion data. Although this resolution is higher than the resolution obtained in the study of Setsompop et al., it must be underlined that the present data was acquired on a preclinical scanning system, using 11.7T in an ex-vivo setting, whereas the setting of Setsompop et al. was a clinical 3T in vivo setting. One of the limitations of this study is formed by the fact that MR imaging parameters were not based on distribution of quantitative longitudinal relaxation time (T1) and transverse relaxation time (T2) and mean diffusivity (D) (Beaujoin et al. 2017, 2018). Therefore, corresponding histograms of T1, T2 and D values which could have been used to optimize the imaging protocol, are lacking from this study. On the other hand, an adapted protocol that came forth from empirical investigation (Kleinnijenhuis et al. 2013) was applied and yielded the aforementioned results. Furthermore, it is known that tractography can produce plausible-looking bundles in locations where the white matter tract does not actually exist, indicating that tractography produces substantial amounts of false-positive fiber bundles (Maier-Hein et al. 2017). To optimize the investigation of white matter microstructure, TDI was used as this technique uses reinterpolation of the quantitative maps at a finer resolution than the imaging resolution, which allows researchers to study white matter structure smaller than the imaging resolution (Calamante et al. 2010). As such, dMRI of ex vivo tissue allows for further evaluation of the tractography results by direct comparison against histological reference measures within the same specimen (Miller et al. 2011). Furthermore, complementation of the tractography data by use of PLI has been suggested to overcome the coarse sensitivity of diffusion tractography with respect to the identification of sharp bends, twists, and undulations (Foxley et al. 2016).

One of the limitations of this study is formed by the fact that the trigeminal tracts were not followed up to the thalamus due to the size of the coil of the 11.7T MR-scanner. Therefore, we cannot confirm that the dtt is connected to the thalamus as has been proposed in animal-based studies (Torvik 1957). Furthermore, the restricted number of specimens and the lack of other complementary neuroimaging techniques like optical coherence tomography (OCT) form another limitation of this study. OCT provides high-resolution fiber architecture data at approximately 1 micron spatial resolution. OCT is analogous to ultrasound techniques as it measures the backscattered light of a sample. Specifically, it is sensitive to variations of the refraction index in different types of tissue. For example, in 2014, Magnain and colleagues suggested that OCT can be used to generate accurate 3D reconstructions of histological layers in the cerebral cortex (Magnain et al. 2014). Furthermore, polarization-sensitive OCT is a special form of OCT that uses the intrinsic optical properties of back-scattering and birefringence of neural tissue. In this way, polarization-sensitive OCT has been used to image the fiber orientation and cyto- and myeloarchitecture of human nervous tissue and to visualize volumetric reconstructions of human brain tissue (Wang et al. 2018). 3D-PLI, however, also provides the possibility to investigate three-dimensional fiber orientations in sectioned tissue. Each section is measured separately and basically provides a 3D vector field description of fiber orientations, forming the basis for tractography (Axer et al. 2011c). Finally, this study did not use tracers, whereas most of the knowledge on which we base our neuroanatomical insights regarding the trigeminal connections are derived from animal-based tracer studies [for a review see (Henssen et al. 2016)]. In 2013, Seehaus et al. used fluorescent, retrograde tracers to stain projection fibers in human tissue, showing that tracing studies can be performed in a post-mortem setting on adult human neural tissue. However, the tracer was injected into the subcortical white matter (approximately 500-1000 µm from the cortex) of the upper part of the temporal lobe. After 48 months, the tracer had traced a tract with a maximal length of 13 mm, which makes it unsuitable for human tracing studies. The same study, however, reported that DTI is capable of reflecting the shape and orientation of nerve pathways (Seehaus et al. 2013).

Future research should investigate the functionality of the vtt and the dtt to determine the clinical significance of functional entities like the TSNC with respect to different trigeminothalamic tracts.

Conclusion

This study shows that the tt bifurcates at the level of the human brainstem into two pathways which have previously been infrequently described in birds, reptiles, rodents, and non-human primates. These fiber tracts course in a ventral and dorsal direction and are, therefore, called the vtt and dtt, respectively. Connectivity, functionality, and clinical significance of these pathways must be determined in future studies.

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Authors and Affiliations

1. Department of Anatomy, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Geert Grooteplein Noord 21, 6525 EZ, Nijmegen, The Netherlands

Dylan J. H. A. Henssen, Jeroen Mollink, Tamas Kozicz & Anne-Marie Van Cappellen van Walsum

2. Department of Neurosurgery, Radboud University Medical Center, Nijmegen, The Netherlands

Dylan J. H. A. Henssen, Erkan Kurt & Ronald H. M. A. Bartels

3. Department of Clinical Neurosciences, Wellcome Centre for Integrative Neuroimaging, FMRIB, University of Oxford, Oxford, Nuffield, UK

Jeroen Mollink

4. Department of Anesthesiology, Pain and Palliative Care, Radboud University Medical Center, Nijmegen, The Netherlands

Robert van Dongen

5. Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, Germany

David Gräβel & Markus Axer

6. Department of Clinical Genomics and Biochemistry and Molecular Biology, Mayo Clinic, Rochester, USA

Tamas Kozicz

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Correspondence to Dylan J. H. A. Henssen.

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Henssen, D.J.H.A., Mollink, J., Kurt, E. et al. Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging. Brain Struct Funct 224, 159-170 (2019). https://doi.org/10.1007/s00429-018-1767-1
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# data[].attributes.attachment_link.title
Ex vivo visualization of the trigeminal pathways in the human brainstem using 11.7T diffusion MRI combined with microscopy polarized light imaging - Brain Structure and Function

# data[].attributes.attachment_link.description
Classic anatomical atlases depict a contralateral hemispheral representation of each side of the face. Recently, however, a bilateral projection of each hemiface was hypothesized, based on animal studies that showed the coexistence of an additional trigeminothalamic tract sprouting from the trigeminal principal sensory nucleus that ascends ipsilaterally.