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Neuropsychology: Traditional and New Methods of Investigation

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Summary: The neuropsychological assessment is an integral part of the clinical investigation of patients suffering from epilepsy. The aim of the evaluation is to determine disease‐related and treatm...

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A combined neuropsychological and brain imaging study of obstructive sleep apnea

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A combined neuropsychological and brain imaging study of obstructive sleep apnea

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Patients with obstructive sleep apnea (OSA) show neuropsychological impairments ranging from vigilance decrements, attentional lapses and memory gaps to decreased motor coordination, but their cognitive profile, and the origin of the impairments, remain unclear. We sought to establish the neuropsychological profile of 16 newly diagnosed apneics using an extensive neuropsychological test battery to investigate attention and vigilance, executive functions, episodic memory and motor domains. In terms of neurobehavioral performance, our patients displayed objective daytime somnolence but little impairment in memory and motor domains. To conclude our patients displayed significant cerebral changes in terms of both gray matter density and metabolic levels, and may have benefited from cognitive reserve and compensatory mechanisms. Thus, cerebral changes in OSA patients may precede the onset of notable neuropsychological consequences.

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A combined neuropsychological and brain imaging study of obstructive sleep apnea

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Patients with obstructive sleep apnea (OSA) show neuropsychological impairments ranging from vigilance decrements, attentional lapses and memory gaps to decreased motor coordination, but their cognit...

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Neuropsychology: Traditional and New Methods of Investigation 

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Neuropsychology: Traditional and New Methods of Investigation 

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This paper presents the benefits of using new methods of neuropsychological investigation, mainly in regards to patients that suffer from epilepsy. Also discusses some of the traditional techniques the new methods add value to or are beginning to replace.

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Neuropsychology: Traditional and New Methods of Investigation

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The incremental value of neuropsychological assessment: A critical review

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The incremental value of neuropsychological assessment: A critical review

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This paper discusses the advantages of neuropsychological assessment and the limitations

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The incremental value of neuropsychological assessment: A critical review

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Objective: The purpose of this critical review was to evaluate the current state of research regarding the incremental value of neuropsychological assessment in clinical practice, above and beyond what can be accounted for on the basis of demographic, medical, and other diagnostic variables.

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Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: correlation with neuropsychological tests and delayed recovery

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Abnormalities on magnetic resonance imaging seen acutely following mild traumatic brain injury: correlation with neuropsychological tests and delayed recovery

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This paper shows the importance of using both brain imaging and neuropsychological assessments with specific reference to traumatic brain injury. Assessments showed evidence for the longer term symptoms patients complained of (Memory loss, attention deficits)

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Neuropsychological Assessment and Brain Imaging Technologies in Evaluation of the Sequelae of Blunt Head Injury

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Abstract

A 43 year old man with a traumatic amnesic syndrome experienced only a brief, if any, loss of consciousness following an injury to the head. Four years after this injury, his results on standard psychometric assessment were normal. Long-latency evoked response potentials results were normal, and the neurological examination and computed tomography scans were unhelpful in explaining his amnesic symptoms. He had no history of alcohol abuse, yet his neuropsychological profile was that of a Korsakoff-like amnesia with frontal lobe features. Magnetic-resonance images demonstrated evidence of extensive frontal lobe damage, while cerebral blood flow studies provided additional evidence of bilateral frontal lobe dysfunction. The case highlights the need for those giving opinions in medico-legal head trauma cases to go beyond a reliance on routine indicators, such as duration of coma, results of standard psychometric assessment and computed tomography scans, to more specialised neuropsychological evaluations and magnetic-resonance imaging scans.

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Ruijs MB, Keyser A, Gabreëls FJ. Ruijs MB, et al. Clin Neurol Neurosurg. 1990;92(4):323-8. doi: 10.1016/0303-8467(90)90058-d. Clin Neurol Neurosurg. 1990. PMID: 1963822

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Montgomery EA, Fenton GW, McClelland RJ, MacFlynn G, Rutherford WH. Montgomery EA, et al. Psychol Med. 1991 May;21(2):375-84. doi: 10.1017/s0033291700020481. Psychol Med. 1991. PMID: 1876643

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national center for biotechnology information

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Neuropsychological assessment and brain imaging technologies in evaluation of the sequelae of blunt head injury - PubMed

# data[].attributes.attachment_link.description
A 43 year old man with a traumatic amnesic syndrome experienced only a brief, if any, loss of consciousness following an injury to the head. Four years after this injury, his results on standard psychometric assessment were normal. Long-latency evoked response potentials results were normal, and the ...

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How brain imaging provides predictive biomarkers for therapeutic success in the context of virtual reality cognitive training.

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How brain imaging provides predictive biomarkers for therapeutic success in the context of virtual reality cognitive training.

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It is a new paper from 2021, so up to date research and it shows how using VR is useful for disorders like stroke, when combined with neuroimaging, as it shows how target areas of the brain respond to stimulation. Can also be a predictor of therapeutic success.

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Beyond localization: The role of traditional neuropsychological tests in an age of imaging

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Beyond localization: The role of traditional neuropsychological tests in an age of imaging

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This paper may highlight the strengths of noninvasive neuropsychological assessments compared to using localisation in the pre-surgical evaluation of epilepsy surgery patients.

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Beyond localization: The role of traditional neuropsychological tests in an age of imaging

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AN INTERRATER RELIABILITY STUDY OF THE TRAIL MAKING TEST (PARTS A AND B)

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AN INTERRATER RELIABILITY STUDY OF THE TRAIL MAKING TEST (PARTS A AND B)

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This paper is based on Halstead-Reitan test batteries and is an test for visual and mental tracking abilities. There might be information on here that benefits your coursework.

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In 1982 Lezak hypothesized that the current procedure used to administer and score the Trail Making Test had resulted in diminished reliability by increasing scorers' variance. 39 participants, trained in order to reduce subjects' performance variance, were given Parts A and B of the Trail Making Test by four different experienced psychometrists. The interrater reliability on both parts was high ( r Part A = .94; r Part b = .90), which suggests that, at least with experienced examiners, substantial variance of scorers is not introduced.

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An Interrater Reliability Study of the Trail Making Test (Parts A and B) - William Fals-Stewart, 1992

# data[].attributes.attachment_link.description
In 1982 Lezak hypothesized that the current procedure used to administer and score the Trail Making Test had resulted in diminished reliability by increasing scorers' variance. 39 participants, trained in order to reduce subjects' performance variance, were given Parts A and B of the Trail Making Test by four different experienced psychometrists.

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'Integrating Neuropsychology and Brain Imaging for a Referral of Possible Pseudodementia: A Case Report' (Tanner, Mellott, Dunne & Price, 2015). 

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'Integrating Neuropsychology and Brain Imaging for a Referral of Possible Pseudodementia: A Case Report' (Tanner, Mellott, Dunne & Price, 2015). 

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This paper is a case study that shows why it is important to use a combination of neuropsychological testing and brain imaging to create a more rounded assessment of a person.

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Abstract

We present the case of "CL," a 65 year-old, right-handed, Caucasian female referred for a neuropsychological evaluation of memory difficulties and depression with the rule out of pseudodementia. Mood measures showed elevated depression and apathy symptoms. The neuropsychological profile showed variable effort, intact comprehension but compromised confrontation naming and verbal memory deficits. A brain magnetic resonance imaging (MRI) scan was conducted within 24 hours of the neuropsychology exam. Using normative references from twenty female age and education matched healthy control peers, we identified marked differences in temporal cortex thickness and bilateral hippocampal, right amygdala, and right caudate volumes, supportive of a diagnosis of Semantic dementia. We discuss the neuroanatomical substrates involved in her neurocognitive and mood presentation and how standard measures of effort and malingering have questionable validity and rationale for dementia and pseudodementia referrals. This case highlights the importance of interdisciplinary collaboration and the value for combining normative neuropsychological and neuroradiological measures for clinical purposes.

Keywords: effort testing, pseudodementia, dementia, neuroradiology, MRI

Introduction

Pseudodementia is a cognitive and functional impairment mimicking a neurodegenerative disease but believed to be caused by neuropsychiatric symptoms. Pseudodementia is, in contrast to primary neurodegenerative disease, potentially reversible with management of psychiatric symptoms ( Caine, 1981; Nussbaum, 1994). Psychiatric symptoms and depression, however, are risk factors for dementia and associated brain structural changes ( Lamberty & Bieliauskas, 1993). Detecting and treating neuropsychiatric and/ or neurodegenerative disorders can thus be challenging. Clinically, red flags for pseudodementia include severe mood disturbance, questionable effort on measures of performance validity, and significant variability within cognitive domains on neuropsychological evaluation.

For neuropsychological assessment, our field has normative values available for comparison and classification of test performance. Normative neuroimaging data for clinical use is not widely available. In this paper we present the interesting case of an individual referred for clarification regarding dementia versus pseudodementia. We combined standardized neuropsychological with standardized norms from neuroimaging data to demonstrate the value of normative neuroimaging for differential diagnosis and clinical interpretation.

CASE PRESENTATION

"CL," is a 65-year old, Caucasian, right-hand dominant, former reading teacher with 16 years of education and a self-reported ten month history of memory difficulties and depression. Her neurologist referred her to neuropsychology to rule out a possible pseudodementia. Background information was acquired from medical records, patient interview, and a separate interview with CL's accompanying friend. Medical history from outside providers, including a prior neuropsychological evaluation, was not available at the time of the evaluation.

According to CL, her difficulties began approximately 10 months ago. At that time she began struggling to remember the names of her students and colleagues. Five months prior to our evaluation, she became lost driving to her primary care physician's (PCP) appointment. The PCP reportedly called the department of motor vehicles and required her to take a driving test. According to CL, she completed two road tests: she failed the first but then passed the second. Her driver's license had not been reinstated at the time of our evaluation. She reported feeling consequently "very sad" and "depressed". She stated that her memory problems were attributable to her distress over these recent events in her life. CL stated that she currently feels "depressed and worried" most of her day, every day. At the time of our evaluation she denied suicidal/homicidal ideation and was not receiving psychotherapy services.

By contrast, CL's accompanying friend and occasional caretaker reported that CL's memory difficulties began 2-3 years earlier (corroborated by CL's medical record), with a significant decline observed 6 months prior to her evaluation. Within the year before our assessment, CL's friend noted increased difficulties with word-finding, which gradually progressed to severe confusion and conversations "devoid of content." CL now frequently forgets the name of household objects and their purpose (what they are used for). According to her friend, CL's depression has been ongoing for at least 20 years; the referring neurologist indicated that CL's first major depressive episode occurred in her 20s. In addition to depression, her neurologist reported that CL's family was concerned about "personality changes", with inappropriate laughter, disinhibition, increased irritability, and affective flattening all noted. CL also developed difficulty in understanding humor and sarcasm and associated social strain with her siblings.

Medical system review was significant for sleep difficulties that began over the last year; specifically she wakes frequently during the night with an average of 1-3 hours nightly (per her friend). She reported only four and a half hours of sleep the night prior to our examination; she did not take her sleep medication for fear she would oversleep and miss the neuropsychological appointment. CL denied difficulties with olfaction, hearing, taste, or appetite (weight is stable). Her eyesight is corrected with eyeglasses. There is no past or current use of alcohol, tobacco, or illicit drugs.

Other medical history was remarkable for multiple fall-related head injuries and brief loss of consciousness caused by episodes of syncope (cause unknown), interstitial cystitis, depression, gastro esophageal reflux disease (GERD), and severe unregulated hyperlipidemia. Her medications at the time of the evaluation included Mirtazapine (nightly) for sleep, Prevacid (OTC), and Metamucil (OTC). She had recently discontinued use of Pravastatin (25mg, twice daily) for cholesterol because it reportedly made her body ache. She also recently ceased her antidepressant (type unknown) due to resulting drowsiness. Of note, she reported that her cholesterol level was well over 300 when last checked and stated she is overdue for her updated lab work as well as a brain MRI requested by her neurologist. Family medical history was significant for cancer and heart disease.

Psychosocially, CL lives alone and spends most of her time walking up the road to take care of her family members. She has a bachelor's degree and denied any history of cognitive or learning disabilities.

Previous neuropsychological testing

An outside provider conducted a neuropsychological evaluation three years prior to our assessment. At that time she had performance scores less than verbal abilities with this considered partially due to visuospatial impairment. Memory testing showed mild encoding difficulties with impaired recall. Semantic and lexical fluencies were mildly impaired and she showed a reduced motor control in her right hand. The report from this evaluation was acquired approximately one week after the current assessment.

Previous brain MRI/EEG

A brain MRI conducted two years prior was interpreted by the neuroradiologist as indicating right greater than left mild temporal lobe atrophy but minimal overall global volume loss. No diagnosis was suggested. She also had a normal EEG at the time. The radiology report was not available at the time of our neuropsychological evaluation.

At the time of our assessment CL had yet to complete a repeat brain MRI. Due to her cognitive performance pattern we arranged for a brain MRI on the same day as our evaluation. For non-clinical purposes and for this case report, her MRI was segmented for gray and white matter analyses. The resulting regions were compared to brain structures from female age normative peers.

For part one of our report, we present her overall cognitive profile. For part two, we separately present the neuroanatomical comparison relative to matched peers.

Part 1: Neuropsychology Findings

Behavioral Observations

CL was oriented to person, place, time, and situation. Gait speed and balance appeared intact. Spontaneous speech was characterized by word-finding difficulties, some circumlocutions, and tangentiality. She frequently returned to the revocation of her driver's license as the trigger to her mood and current difficulties. She required frequent redirection and clarification of task instructions from the examiner. In the first hours of testing she was fidgety and inappropriately jocular. She talked through tests and made sound effects to accompany her hand gestures (e.g., when instructed to show what people do with scissors she made a cutting sound). Following lunch, she appeared to have very little energy and motivation. Her affect was flat and slightly confrontational in her interactions with examiner. She also began to display odd behaviors such as looking around the room and naming things aloud (e.g., "wall," "ceiling," "floor"). Overall, she demonstrated variability between and within cognitive domains. She was unable to complete many tasks due to appearing confused and requiring redirection. shows her current neuropsychological assessment scores and percentiles that overlap with those from a previous evaluation conducted in 2010.

Table 1

EXAMINATION RESULTS

Previous intellectual estimates

Medical reports indicate that CL was able to complete the full WAIS-III, demonstrating low average verbal and non-verbal intellectual abilities and average processing speed and working memory skills.

Current Mood

CL reported significant symptoms of depression ( Yesavage et al., 1982) indicating feeling dissatisfied with her life, having dropped activities, feeling her life is empty, feeling bored, helpless, feeling hopeless, and that most people are better than she is. She endorsed mild levels of apathy ( Marin, 1991) such as feeling indifferent to things and needing a push to get started.

Effort

CL completed two free-standing measures of effort and one embedded test of effort to evaluate the extent to which effort and variability might alter test performance (TOMM: Tombaugh, 1996; Reliable Digit Span: Greiffenstein et al., 1994; Rey-15: Rey, 1958). On the TOMM, CL's performance was suggestive of questionable effort; however, she exhibited difficulty identifying several objects. CL reported being unable to identify "spoon" from a set of two unrelated pictures. When asked to describe what the spoon was used for, she could not provide an answer, nor could she use gesturing to demonstrate its function. On the reliable digit span (longest forward span correct on both trials plus longest backwards span correct on both trials) she scored 8, indicating acceptable performance ( Greiffenstein et al., 1994).

On the Rey 15-Item Visual Memory Test, which requires the participant to reproduce a series of objects that are related in some way after a 10 second exposure, CL reported confusion. When prompted, she wrote the word "numbers" on the page. Upon further clarification, she drew three correct objects and one incorrect object, yielding a total score of 3/15 correct. By comparison, she scored 15/15 during her evaluation in 2010.

General Cognitive Screening

CL was administered the Dementia Rating Scale - 2 (DRS-2; Jurica, Leitten, & Mattis, 2001) and a clock drawing task to assess general 'global' cognitive functioning and dementia severity. Her DRS-2 performance was impaired relative to age and education-matched peers. Subtests scored at average levels for conceptualization, but low average for attention, memory, and visuoconstruction. She was impaired on initial/perseveration. She struggled more with language-based tasks relative to the movement and graphomotor items. On a clock drawing task CL correctly recalled the clock face and drew the clock proportionally correct but produced executive hand and number errors on the command and copy condition ( Price et al., 2011).

Attention and Processing Speed

Auditory attention span ( Wechsler, 1997a) scored average for both forward and backward digit span, with low average for DRS-2 Attention subtest. Trail Making Test Part A was average relative to peers, while WAIS-III Symbol Search was below average.

Language

CL's expressive and receptive language abilities were markedly compromised. Comprehension assessment via the Token Test (Florida Token Test; adapted from De Renzi & Vignolo, 1962) was intact for simple sentences but requiring additional trials on more syntactically complex sentences. Repetition was intact for simple sentences but impaired for grammatical complex sentences (i.e., "The phantom soared across the foggy heath" resulted in "The phanny heat"; "No ifs, ands, or buts" resulted in "no ifs or no buts"). Visual confrontational naming was strikingly impaired (Boston Naming Test; Kaplan, Goodglass, & Weintrab, 1983) with numerous semantic and circumlocutious errors but no perceptual deficits. Verbal fluency was impaired across letter and semantic conditions (Controlled Oral Word Association; Tombaugh, Kozak, & Rees, 1999); poor performance resulted from few responses rather than loss of set or rule violations. A written response of the Cookie Theft picture was in cursive and largely grammatically intact but with minimal content and limited appreciation for the gestalt (). During this task she laughed throughout and required multiple reminders of the instructions.

Regarding language-related skills, ideomotor praxis was bilaterally impaired (i.e., "Pound a nail into a board with a hammer" resulted in poking her finger into the table; "Use a hand saw to cut wood" resulted in a hammer motion). Finger gnosis was impaired bilaterally; she was unable to visually name her right hand fingers and two fingers on her left hand. Right left discrimination was intact for both self and examiner. An assessment for acalculia was significant for spatial misalignment and misusing addition for multiplication although this was later self-corrected.

Visuospatial

Her ability to identify and match a series of faces presented at alternating angles scored average relative to age and education-matched peers (Benton Facial Recognition; Benton, Sivan, Hamsher, Varney, & Spreen, 1994). CL was able to copy a circle, but made errors with a cube. She spontaneously drew a well-formed horse on the back of a piece of paper. Her copy of a clock included misplaced numbers.

Memory

With regard to memory, CL reported difficulty remembering both past and recent events. DRS-2 Memory subtest was low average. However, on a measure of verbal memory requiring recall of simple prose (Wechsler Memory Scale-III Logical Memory; Wechsler, 1997b) CL's performance was impaired across immediate and delayed recall trials with minor benefit from repetition on the second story. Recognition of the material was within the average range. On a nine-word list-learning task (Philadelphia (repeatable) Verbal Learning Test), CL produced a flat learning curve with five intrusion errors some of which were linguistic blends (i.e., 'strinapples'). The interference trial resulted in two recall items and one intrusion from the original list. Immediate and delay recall were impoverished and involved intrusions. She did not benefit from category cues. Recognition discriminability was significant for endorsement across all foil types (semantic, prototypical, interference, unrelated).

Abstraction and reasoning

Abstract reasoning of visual matrices scored at low average levels (Wechsler Abbreviated Scale of Intelligence Matrix Reasoning; Wechsler, 1999) and her visual conceptualization on the DRS-2 subtest was average.

Motor

Fine motor manual dexterity was within the average range bilaterally.

Part 1 Discussion

At our evaluation, limited outside medical information was available. In spite of variability on performance validity testing and reduced effort, based on neuropsychology alone, we considered her profile characteristic of an atypical cortical dementia. CL showed marked depression and questionable response consistency secondary to cognitive deficits. Language assessment was most striking with impoverished confrontation naming, letter and semantic fluency, followed secondarily by impaired ideomotor praxis, finger gnosis, and reduced repetition and comprehension for grammatically complex sentences. Learning and memory were significant for impoverished free recall on prose and list-learning, with intrusions suggestive of source error impairment. Recognition performance ranged from average to impaired. Basic attention and basic visual perception were a relative strength, although higher-level appreciation for the gestalt and complex figural integration were qualitatively poor. She also exhibited a range of processing speed (average to impaired), emotional incontinence ranging from jocularity/joyful to flat affect, and variable performance on effort measures. Overall, these findings suggested cortical atrophy of lateral/ medial temporal and possibly parietal lobes, with questionable orbitofrontal and medial frontal lobe integrity. Given the relative sparing of faces and her construction ability, her posterior inferior temporal lobes were considered less compromised.

Due to CL's overall cognitive pattern, we pushed for an MRI within the next 24 hours. These findings are provided in Part II below.

Part II: Neuroimaging

Methodology

A brain MRI was conducted within 24 hours of our evaluation. CL's MRI protocol involved clinical 2D T1, T2, T2 fluid attenuated inversion recovery (FLAIR; 320×196 matrix, 28 slices, 5mm gap, 0.625×0.625×4mm voxels, TR/TE=9000/90ms), and diffusion scans. She completed two 3D T1 MP-RAGE sequences (Siemens Avanto 1.5T; 384×384 matrix, 160 contiguous slices, 0.64×0.64×1.2mm voxels, TR/TE=1490/3.45ms) acquired axially without contrast. Her 3D T1 scans were of sufficient quality for automated segmentation and volumetric analysis.

Normative Comparison group

Structural MRI data were from a set of 20 non-demented age (mean = 65.20±2.44; range = 60-69) and education (mean = 15.90±2.84; range = 12-20) matched females who participated as part of separate federally funded investigations that included MRI and neuropsychological testing. Each individual completed a brain MRI from a Siemens 3T Verio scanner using an 8-channel head coil. The protocol included an MP-RAGE T1-weighted scan with the following parameters: 176 contiguous slices, 1×1×1mm voxel, TR/TE = 2500/3.77ms, sagittal acquisition. These data were used to provide a standardized reference point for CL's brain volumes.

MRI Segmentation

For both CL and the normative peers, cortical reconstruction and volumetric segmentation was completed with FreeSurfer image analysis suite version 5.3, which is documented and freely available for download online ( http://surfer.nmr.mgh.harvard.edu/; Fischl, 2012). The technical details of these procedures are described in prior publications ( Dale, Fischl, & Sereno, 1999; Fischl & Dale, 2000; Fischl et al., 2002; Fischl, Salat, et al., 2004a; Fischl, Sereno, & Dale, 1999; Fischl, van der Kouwe, et al., 2004b; Han et al., 2006). FreeSurfer morphometric procedures have been demonstrated to show good test-retest reliability across field strengths ( Han et al., 2006), which is important given the different field strengths used for CL's MRI and the normative group's MRI. Both CL and the normative group had adequate white matter signal to noise and gray/white contrast.

Primary neuroimaging variables of interest included cortical thickness by brain lobe, hippocampus, amygdala, caudate, thalamus, and white matter volume by hemisphere, as well as leukoaraiosis (LA) volume. Hippocampal volumes from the normative group match reported volumes for healthy older adults ( Sánchez-Benavides et al., 2010). Procedures for the measurement of cortical thickness have been validated against histological analysis ( Rosas et al., 2002) and manual measurements ( Kuperberg et al., 2003; Salat et al., 2004). FreeSurfer segmentations were checked for accuracy. CL's segmentation required manual 'control points' placed in fusiform gyral white matter and reprocessing to fix suboptimal temporal lobe segmentation. All volumes were calculated as a ratio to total intracranial volume (TICV). TICV was derived from FreeSurfer's brainmask volume, which has high correlation with manual TICV measurements (r = 0.93; ICC = 0.92; p < 0.01) and high spatial overlap (Dice Similarity Coefficient = 0.95). T1-weighted volumes and thickness values are reported in FreeSurfer conformed space (1mm ³ voxels, 256×256×256 matrix, coronal reslice). Leukoaraiosis (LA) volumes for controls and CL were created using in-house tools using methods previously reported ( Price et al., 2014).

Results

. Supplemental . . CL's total intracranial volume and total brain volume were below the mean of the peer sample (CL's TICV z = −1.00; brain volume correcting for TICV = −2.24).

Table 2

Cortical gray matter thickness metrics show CL had thinner temporal cortices with thinning more pronounced on the right side (temporal left z = −3.15; right z = −7.04); temporal atrophy was primarily anterior (). The right parietal lobe was below the peer sample mean (parietal left z = −0.13; right = −1.80). Frontal metrics were within the average range (frontal left z = 0.74; right z = −0.04).

Hippocampus, amygdala, caudate, and thalamus volumetrics (TICV corrected) were asymmetric (R < L). Hippocampal volumes were bilaterally smaller than peers (left z = −3.08; right z = −3.25). Amygdala volumes were strikingly asymmetric (left z = −0.60; right z = −3.42). Caudate volumes were also dramatically asymmetric (left z = −0.94; right z = −3.33). Thalamus volumes were asymmetric but within reasonable ranges relative to peers (left z = −0.59, right z = −1.19).

White matter volumetric (TICV corrected) comparisons showed asymmetry relative to the peers (white matter left z = −1.38; right z = −2.39). Leukoaraiosis load was minimal and consistent with peer ranges (z = −.27).

Part 2 Discussion

Neuroimaging comparisons showed a remarkable brain volume difference relative to peers involving an asymmetric pattern (right < left). There was clear temporal lobe disruption as evidenced by bilateral thinness and severely reduced bilateral hippocampi. Although asymmetric, there was evidence of disease in both hemispheres. The subcortical regions revealing the most striking asymmetry included the amygdala, caudate, and general white matter metrics. Asymmetry was noted in parietal cortex and, to a lesser extent, in the thalamic hemispheres; these structures were in the low average range relative to peers. The overall volume loss corresponds to the larger ventricles seen in . Of all regions, the frontal lobe appeared the most preserved with thickness values well within the average range relative to peers. Based on leukoaraiosis metrics, there was also no convincing evidence that small vessel vascular disease contributed to her profile.

For her current MRI, the neuroradiologist commented on global cerebral volume loss, severe bilateral temporal lobe atrophy, moderate parietal lobe atrophy, mild symmetric hippocampal loss, and "normal" basal ganglia. The neuroradiologist interpreted the MRI as "suggestive of Alzheimer's type dementia." Our data add to this reading. First, we found strong asymmetry of atrophy in the amygdala, caudate, and white matter as well as temporal and parietal cortex. Second, moderate bilateral hippocampal atrophy was also apparent relative to the normative sample.

DISCUSSION

In this case report we presented data from a 65-year old woman, "CL," who was referred for neuropsychological evaluation to assist with differential diagnosis and rule out pseudodementia. CL had variability in her scores, mood disturbance, and poor performance on measures of effort. Using information from just effort and mood measures one could surmise pseudodementia. With full neuropsychological assessment, however, there are clear strengths and weaknesses that demonstrate a marked pattern. Data from assessment revealed global cognitive impairment as well as language and memory impairment. CL exhibited heterogeneity of performance across and within domains but generally struggled on language and memory tasks. While there was evidence of language and memory decline compared to her 2010 assessment, other domains, visuospatial in particular, did not show dramatic declines. Her overall neuropsychological pattern strongly suggested a neurodegenerative process although some could consider her profile suggestive of pseudodementia due to the extent of her mood disturbance, her behavioral presentation, and her variable effort.

Neuroimaging results demonstrated marked anterior temporal atrophy with reduced bilateral hippocampal and right amygdala and caudate volumes (). The extent and asymmetry of her atrophy is clear relative to peers. Neuroimaging thus confirmed the impairment, ruling out pseudodementia.

CL was first diagnosed with depression in her 20s but struggled with it more particularly within the past 2-3 years. Early depressive and emotional signs can herald developing dementia ( Cummings, 1986) and are associated with limbic system changes ( Catani, Dell'Acqua, & Thiebaut de Schotten, 2013). CL's emotional variability observed throughout the exam and stated in medical record reports is consistent with right hemisphere disruption. Although CL did not have striking evidence of reduced global frontal thickness, she had significantly impoverished temporal thickness (right > left) and asymmetric atrophy of amygdala, caudate, and white matter. CL's right hemisphere changes possibly explain her performance variability and likely explain her emotional variability ( Bickart et al., 2014). Additionally, right hemisphere damage is likely one of the causes of her reduced humor appreciation ( W. Liu et al., 2004; Rosen et al., 2002; Shammi & Stuss, 1999).

CL's language difficulties are supported by her bilateral temporal atrophy. It is important to note that although CL had strikingly impoverished confrontation naming, she was fluent in writing and wrote in cursive. Consequently, she had adequate use of her right hand for accessing graphemic systems (e.g., her description of the 'cookie theft' was fluently written in script). CL's written language was significant only for the paucity of nouns and an integration of the overall picture gestalt. This is a possible symptom of right parietal thinning.

CL's memory deficits are supported by her bilateral atrophy in temporal cortex and medial temporal structures. CL's observed memory impairment includes encoding and retrieval deficits with significant recognition intrusions. In general, increasing entorhinal cortex volume or blood flow associates with aspects of verbal memory ( Cabeza, Dolcos, Graham, & Nyberg, 2002; Goto et al., 2011; Price et al., 2010; Rodrigue & Raz, 2004). The cingulum and entorhinal cortices are components of the limbic system, which supports both memory and emotion; CL's MRI demonstrates the extent of her limbic system disruption. In addition, the temporo-amygdala-orbitofrontal network is certainly affected given CL's extensive amygdala and temporal atrophy; this network is important for integrating cognition and emotion ( Catani, de Schotten, & Slater, 2013).

CL's right caudate was much smaller than peers. The caudate plays a role in integrating attentional systems and mediating communication to the frontal lobes. CL's right frontal lobe, while within the normal range, was approximately one standard deviation below the left frontal lobe with regard to thickness, likely indicative of asymmetric atrophy. Additionally, both the caudate and medial temporal lobe connect directly to the frontal lobes. CL's overall frontal cortex is largely intact but closely connected network regions are impaired, likely reducing the integrity of the white matter connections to frontal regions. Specifically, right caudate input and output could be disrupted thereby resulting in understimulation and reduced communication to the right frontal lobe.

CL's relative sparing of frontal lobes and thalamus is consistent with intact basic attention; there is, however, a suggestion of frontal disease progression due to CL's reduced repetition and comprehension of complex syntax ( Grossman & Moore, 2005). CL's thalamic volumes were within normal ranges, indicating that disease progression/ pathology, while likely affecting the caudate, has not spread measurably to the thalamus. It is not known if white matter pathways to and from the thalamus are affected, although it is likely given the extent of brain regions directly connected to the thalamus. CL's clinical diffusion-weighted neuroimaging data were not of sufficient quality for such analyses.

Other contributing factors to her degeneration include reported unregulated hyperlipidemia and previously reported head injuries. Blood lab work conducted the day following her neuropsychological evaluation revealed severely elevated cholesterol levels, with the exception of HDL, which was within normal limits. Remarkably, however, the T2 FLAIR brain image revealed only one small spot of very intense signal, indicating minimal white matter disease. This indicates that her depression is not driven by cerebrovascular changes. Elevated cholesterol and history of head injury (she experienced minor but repeated head injuries due to falls) have been linked with fronto-temporal changes and so perhaps played a role in her disease progression ( Deutsch, Mendez, & Teng, 2014).

Diagnosis

Considering only her behavioral profile, differential diagnoses could include Semantic dementia and Alzheimer's disease given the extent of her memory and language impairment. Her first-reported symptoms were "memory problems", although it is possible that word-finding difficulty was reported as a "memory" problem. However, when combining neuropsychology with neuroimaging, her pattern of atrophy on MRI, particularly when compared to normative imaging data, revealed marked temporal cortex loss that exceeded her hippocampal volume loss (right temporal thickness was 7.04 standard deviations below peers whereas right hippocampus was 3.25 standard deviations below peers); her results thus indicate a primary temporal cortex process with pronounced but less hippocampal atrophy. The neuroradiologist commented on bilateral temporal, parietal, and hippocampus atrophy but interpreted the pattern as suggestive of Alzheimer's disease, rather than frontotemporal dementia. The results from our analyses, in contrast, indicated a pattern that is not typical of Alzheimer's disease, though it is possible she has comorbid Alzheimer's disease given her moderate bilateral hippocampal atrophy.

Medial temporal lobe atrophy is a hallmark of early Alzheimer's disease ( Fox et al., 1996; Jack et al., 1997; Jack et al., 1998). Atrophy in Alzheimer's disease is usually bilateral and does not typically occur in anterior temporal lobes early in the disease process, initially affecting medial temporal lobes ( Chan et al., 2001). In contrast, Semantic dementia commonly presents with asymmetric anterior temporal atrophy ( Chan et al., 2001; Galton et al., 2001) with left prominent atrophy more common than right ( Thompson, Patterson, & Hodges, 2003).

Semantic dementia is a subtype of frontotemporal dementia (FTD; Neary et al., 1998), which is a term encapsulating a broad array of deficits and symptoms and thus has limited utility for deficit specificity. CL's age is typical age of onset for Semantic dementia ( Hodges & Patterson, 2007). Her pattern of extensive anterior temporal atrophy matched what is commonly seen in Semantic dementia. While left hemisphere atrophy in Semantic dementia is more common than right, right atrophy is well-documented in the literature ( Thompson et al., 2003); CL's right>left atrophy was only surprising given the extent of her language difficulties and her mild to unimpaired visuospatial abilities ( Hodges & Patterson, 2007). CL exhibited visuospatial difficulties on her 2010 neuropsychological evaluation but our assessment yielded only mild deficits, indicating little or no decline in abilities over time. She did have striking isolated instances of object recognition impairment (such as on the TOMM) but visuoperceptual and visuospatial deficits were not remarkable relative to her overall profile, suggesting that object recognition deficits were likely a result of decline in the semantic system.

Irritability, impulsiveness, and bizarre changes in behaviors are common in individuals with Semantic dementia with greater right side atrophy ( Edwards-Lee et al., 1997). CL exhibited increased negativity, depression, and apathy but her friend and occasional caretaker did not report increased irritability or impulsiveness; she was overly jocular at times during the evaluation but external report places more emphasis on her word finding and language than on her behavioral changes. In general, however, CL's behavioral and cognitive profile is expected given the extent of her right and left temporal atrophy. It is also possible that language functions for CL are right hemisphere lateralized or are bilaterally distributed, although this would be unexpected given her right-handedness.

While CL's neuropsychological and neuroimaging data are supportive of a diagnosis of Semantic dementia the heterogeneity of behavior, atrophy, and pathology within Semantic dementia limit the utility of the label. Applying specific labels, while concise and useful for clinical billing, does not adequately summarize CL's behavioral and brain deficits. The argument for describing deficits rather than or in addition to diagnosis has been made previously and is worth repeating ( Cosentino et al., 2004; Lamberty & Bieliauskas, 1993).

Effort

The case of CL is also useful to demonstrate the value of performance validity measures on neuropsychological testing. She 'failed' one stand-alone measure (Rey-15), had marginal performance on another (TOMM), but performed adequately on an embedded measure (reliable digit span). While symptom and performance validity testing play an important role in neuropsychological evaluations, some cautions are in order. The utility of measures of effort or performance validity tests within dementia populations has been called into question ( Rudman, Oyebode, Jones, & Bentham, 2011; Dean, Victor, Boone, Philpott, & Hess, 2009). Specifically, it has been shown that the relationship between emotional function and effort is poor and common measures of performance validity might not be valid in dementia ( Rudman et al., 2011).

Where a diagnosis of dementia is not immediately clear, such as with CL who had variable performance on performance validity testing and neuropsychological measures and who presented with mood disturbance and reduced effort throughout testing, performance validity test findings should be interpreted with caution ( Van Dyke, Millis, Axelrod, & Hanks, 2013). For a case like CL's, it is conceivable that a neuropsychologist with limited outside background medical information (such as was the case with CL) who starts with mood and performance validity testing, might terminate the examination due to the patient's questionable effort. While such situations might occur infrequently, they could negatively affect patient care. Thus in general, the use of performance validity testing in any population at increased risk of dementia (older adults) should be applied and interpreted with caution without neuroimaging to support one interpretation or another. Interpreting the results of CL's performance validity testing is thus of limited utility. It is possible but speculative that CL's variability in performance on performance validity testing and within cognitive domains is tied to her severe right hemisphere atrophy as well as her severe anterior temporal lobe atrophy.

Limitations

We recognize limitations with our study. MRI for CL was acquired at 1.5T while the normative group was acquired at 3T. Different sequence parameters were used, which could potentially introduce error into analyses; however, FreeSurfer is reliable across field strengths ( Han et al., 2006). Further, CL's clinical scan had comparable gray-white contrast and signal to noise to the control group (data not reported but derived in part from a FreeSurfer QA tool: https://surfer.nmr.mgh.harvard.edu/fswiki/QATools). All images were checked for segmentation quality; only CL had suboptimal segmentations due to significant temporal atrophy. Segmentation errors were fixed manually and then reprocessing occurred. Final segmentation was of excellent quality. For MRI with atypical atrophy or damage, automated segmentation tools will likely require manual intervention to yield valid results, a significant limitation for clinical use.

Manual segmentation or manual cleaning of automated segmentations would improve accuracy of hippocampal segmentations ( FreeSurfer overestimates hippocampal volumes, for example; refer to Tae, Kim, Lee, Nam, & Kim, 2008; Sánchez-Benavides et al., 2010) but manual segmentation is time-intensive and can require months of training to gain expertise. Time required for segmenting multiple brain regions, including portions of the cortex and selected subcortical regions, would be prohibitive for clinical use. Small, well-defined regions (e.g., caudate nucleus) can take 15-30 minutes for an expert rater to measure but larger or more complex brain regions require multiple hours per region. Manual methods also introduce human rater error. We recognize that we had a limited normative sample size (n = 20) but they were matched closely for sex, age, and education. The normative values we used, however, are similar to values recently reported in the literature ( Jiang et al., 2014; Long et al., 2012), although direct comparisons in thickness and volume can be limited by demographic differences between studies. We also did not investigate specific sub-regions of lobar cortex, which might clarify the pattern of atrophy further (e.g., anterior more than posterior).

Clinical Recommendations

Given the extent of CL's cognitive difficulties, it was recommended that her daily activities be supervised more closely by family or friends and then, as her abilities continue to decline, CL receive formal assistance. Closer monitoring of her home environment, medications, eating habits, and other self-care would benefit her overall health, especially in light of her unregulated hyperlipidemia. Given the extent of her deficits and brain atrophy, repeat neuropsychological assessment would not benefit her care.

Strengths and future directions

The strength of the current case report is our use of age and sex matched normative neuroimaging data to document the extent of CL's brain disease and asymmetrical atrophy and argue against pseudodementia and poor effort. Previous reports on poor effort in dementia have limited integration with neuroimaging. Normative imaging variables clarified the extent of her atrophy and helped support her diagnosis with dementia. At least one FDA-approved tool exists for quantifying brain volumes for clinical use (i.e., NeuroQuant, which is based on FreeSurfer segmentation algorithms and thus comparable to our methods; www.cortechslabs.com), but it is not used widely. There are, in contrast, many research tools available to reliably quantify brain volumes and lesion load but they have not yet transitioned to clinical applications. Marketed software for clinical requires FDA approval given the definitions of "medical devices" in Section 201(h) of the Federal Food, Drug & Cosmetic Act (FD&C; 21 U.S.C. 301). Some argue that this will also be the case for computerized neuropsychological assessment systems in the future ( Bauer et al., 2012).

With this case report, we offer a glimpse of the possibilities and challenges for integrating neuropsychology and standardized neuroimaging for differential diagnosis classification. Integration, however, requires careful consideration to age, sex, education, comorbidities, MRI field strength and acquisition parameters, as well as other potentially salient factors that might alter brain-behavioral inferences. The same rigor used to derive psychological assessment tools and normative values must be applied to creating neuroimaging normative values. Neuropsychologists with sub-specialty interests in neuroimaging appear uniquely positioned to initiate the integration of normative-based assessment and normative-based neuroimaging for clinical care.

​

Acknowledgements

Supported in part by NINDS K23 NS60660; NINDS R01 NS082386; NINR R01 NR014181

References

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# data[].attributes.attachment_link.title
Integrating Neuropsychology and Brain Imaging for a Referral of Possible Pseudodementia: A Case Report

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We present the case of "CL," a 65 year-old, right-handed, Caucasian female referred for a neuropsychological evaluation of memory difficulties and depression with the rule out of pseudodementia. Mood measures showed elevated depression and apathy symptoms. The neuropsychological profile showed variable effort, intact comprehension but compromised confrontation naming and verbal memory deficits.

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Utilizing neuropsychological measures to predict vocational outcome in a head trauma population

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Utilizing neuropsychological measures to predict vocational outcome in a head trauma population

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Looks at people who have suffered from head trauma and the authors use neuropsychological testing to see how successful they are in vocational training.
It is relevant to the course work as it tests the accuracy of neuropsychological assessments when looking at vocational assessments

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The present study examined the ability of traditional neuropsychological measures to predict successful vocational training in a severely neurologically impaired population. Eighty head trauma patients were evaluated prior to pre-vocational training which involved cognitive remediation and psychosocially-based intervention. Subjects were approximately 2 years post-injury. Results showed that of the total population studies, 73-8% participated in vocational evaluations, 23-8% did not, and 2-4% of the sample returned to work or college. Neuropsychological assessments were over 77% accurate in predicting whether subjects would successfully complete this vocational evaluation. The most significant predictors were reading comprehension, immediate and delayed verbal memory, level of depression, and dysphasic symptomatology. Issues relating to generalizability of cognitive retraining to the vocational evaluation and/or vocational training setting are discussed. Future considerations for both clinical practice and research include the use of ecologically valid measures.

# data[].attributes.attachment_link.title
Utilizing neuropsychological measures to predict vocational outcome in a head trauma population

# data[].attributes.attachment_link.description
The present study examined the ability of traditional neuropsychological measures to predict successful vocational training in a severely neurologically impaired population. Eighty head trauma patients were evaluated prior to pre-vocational training which involved cognitive remediation and psychosocially-based intervention. Subjects were approximately 2 years post-injury.

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Cognition: An Overview of Neuroimaging Techniques

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Cognition: An Overview of Neuroimaging Techniques

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This paper outlines the usefulness of using different neuroimaging techniques, including the importance of using two different types in conjunction with each other. This allows for a wider scope of the brain to be researched, e.g. using MEG and EEG scans simultaneously as one technique may cover more than the other.

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The advent of neuroimaging techniques for use in humans has led to an explosion of research on the neural basis of cognitive processes in humans during the past decade. Brain imaging methods include both anatomical techniques, which create a snapshot of brain structure, and functional techniques, which create a series of dynamic snapshots that reflect ongoing brain activity. Functional techniques contribute most directly to our understanding of the workings of the human brain because they enable us to identify the neural circuitry underlying specific cognitive processes.

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February 2017 · QJM: An International Journal of Medicine

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(PDF) Cognition: An Overview of Neuroimaging Techniques

# data[].attributes.attachment_link.description
The advent of neuroimaging techniques for use in humans has led to an explosion of research on the neural basis of cognitive processes in humans during the past decade. Brain imaging methods include both anatomical techniques, which create a snapshot of brain structure, and functional techniques, which create a series of dynamic snapshots that reflect ongoing brain activity.

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Functional Brain Imaging in Neuropsychology over the past 25 years

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Functional Brain Imaging in Neuropsychology over the past 25 years

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Relevance: This paper highlights how neuroimaging has contributed to neuropsychological research. It also includes limitations and ideas for future development.

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Abstract

Keywords: functional neuroimaging, functional MRI, neuropsychology, neurocognition

Introduction

The study of brain function in health or disease requires integration of behavioral and neurophysiologic data. Over the last several decades we have seen that this can be achieved through the use of dimensionally-defined neurobehavioral probes ( R. C. Gur, Erwin, & Gur, 1992) while simultaneously imaging the brain ( Buchsbaum et al., 1990; R. E. Gur et al., 1983; Weinberger, Berman, & Zec, 1986). Functional neuroimaging techniques include electromagnetic methods, such as event-related potentials (ERP) and magneto-encephalography (MEG), both of which are reviewed elsewhere in this Special Edition, and hemodynamic techniques (e.g. functional magnetic resonance imaging (fMRI)). The latter rely on the ability to track the effects of neural activity on the energy needs of brain tissue by measuring components of the metabolic chain, such as glucose and oxygen consumption rates that alter cerebral blood flow (CBF). Many neuroimaging techniques have been applied-and continue to be applied-over the last 25 years to study neuropsychological domains. These include the Xenon-133 technique for measuring CBF ( R. Anderson, 1996); single photon emission computed tomography (SPECT) for studying CBF and neuroreceptors ( Mariani et al., 2010); magnetic resonance spectroscopy (MRS) ( Ende, 2015); positron emission tomography (PET) for assessing metabolism, CBF, and neuroreceptor functioning ( Cabeza & Nyberg, 1997, 2000) and fMRI. As fMRI is the most commonly used technique we will dedicate most of this article to the advances made using fMRI over the past 25 years.

A brief history of neuroimaging in neuropsychology

Neuropsychology began at a time when brain functioning could only be inferred from the study of individuals with severe head injury (for review( Bennett, et al., 2016)). Remarkably, this clinico-pathological approach, which started with a single case report (Broca 1861), yielded substantial progress in the identification and understanding of the role of the cerebral cortex in sensation, perception, language, memory, reasoning and volition ( Chaillou, 1863; Jackson & Owen, 1863; Wernicke, 1874). Neuropsychologists have contributed standardized measures of behavioral domains, which could be linked to clinico-pathological findings, and constructed "batteries" that are being used for diagnosis and treatment assessments across the range of neuropsychiatric disorders.

However, the clinico-pathological approach has several theoretical and practical limitations. Methodologic constraints relate difficulties in controlling variability on both banks of the brain-behavior bridge. Brain lesions are not always reliably localized and are seldom in precisely the same location, pre-morbid data are usually sparse, comorbid conditions nearly always exist, samples vary demographically, and all these can affect neuropsychological performance profile. Most importantly, this methodology limits the investigator to documenting effects of naturally-occurring phenomena, unable to experimentally manipulate neuropsychological domains of interest and test their effects on brain function. A practical constraint of this methodology is that it depends on the availability of patients with documented lesions.

The possibility of studying brain-behavior relation by measuring regional brain activity in healthy people while performing experimentally-controlled cognitive tasks only came to the horizon in about 1975. Two teams, both led by psychologists, developed a non-invasive method that allowed precisely that ( Obrist, Thompson, Wang, & Wilkinson, 1975; Risberg, Ali, Wilson, Wills, & Halsey, 1975). The method involved inhalation of trace amounts of a radioactive gas, 133-Xenon, mixed with room air. The uptake of the tracer by the brain was recorded by collimated crystal detectors, and its clearance could be used to calculate CBF in the fast-clearing (gray matter) compartment in physiologic units (e.g., ml/100g/min). Initial studies were performed on small samples with uncontrolled task conditions, but by 1980 well-powered studies demonstrated statistically significant task effects on CBF, with verbal tasks showing greater left hemispheric activation and in spatial tasks greater right-hemispheric activation associated with better performance (e.g., ( R. C. Gur & Reivich, 1980)). Subsequent studies showed sensitivity of these measures to sex and handedness differences ( R. C. Gur et al., 1982), as well as age effects ( R. C. Gur, Gur, Obrist, Skolnick, & Reivich, 1987) and effects of brain damage ( R. C. Gur et al., 1987) and psychopathology ( R. E. Gur et al., 1985). For example, they uncovered a substantial sex difference in the rates of cerebral blood flow (), with females having higher values throughout the cortex. The non-invasive 133-Xenon inhalation method became a relatively widespread clinical and research tool and investigators began to map brain systems and relate brain function to major behavioral domains ( Anderson 1996).

Progress in functional neuroimaging was accelerated considerably with the introduction of positron emission tomography (PET), which uses radioactive tracers that allow 3-dimensional quantitation of parameters related to regional brain metabolic activity ( Greenberg et al., 1981; M. E. Phelps, Kuhl, & Mazziota, 1981). Beyond mitigating the main limitation of the 2-dimensional 133-Xenon clearance technique, which could only give information on cortical regions with a time resolution of about 16 minutes, PET proved to be versatile and eventually allowed repeated measurement of cerebral blood flow with time resolution of 2 to 3 minutes. Initial PET studies, however, were restricted to fluorine-18 labeled deoxyglucose, which has a half-life of about 110 minutes, so repeated measures were not feasible within the same day. First applications of PET with cognitive tasks were in single cases, and (to our knowledge) the first demonstration of statistical effects of cognitive tasks on regional brain metabolism had 4 participants receiving a verbal (analogies) and 4 receiving a spatial (line orientation) task ( R. C. Gur et al., 1983). Within the limitations of these sample sizes, however, the early functional neuroimaging studies did go beyond merely demonstrating hypothesized effects. They taught us, for example, that even narrowly defined neuropsychological domains recruit a network of co-activated regions (). An advantage of these early studies was that they provided quantitative measures related to energy metabolism in physiologic units (e.g., ml/100g of tissue/minute). For example, in the study examining hemispheric effects on metabolism, it was possible to establish that absolute rates of glucose metabolism were higher for the verbal than for the spatial task across regions of interest (see ). Further studies have shown that, within such networks, nodes can be identified that relate specifically to aspects of that domain (). The measures of local glucose metabolism took long to acquire, but they turned out to be stable under a standardized "resting state" condition ( Gusnard & Raichle, 2001) enough to reveal sex differences ( R. C. Gur, Mozley, Mozley, & Resnick, 1995) and age related effects ( Duara et al., 1983).

Subsequent developments in PET allowed for more rapid measurement of brain activation using injection of water labeled with the fast-decaying (half-life of 2 minutes) oxygen-15 ligand. This method allowed repeated measurement of cerebral blood flow within minutes, so multiple tasks could be included in the same session ( P. T. Fox et al., 1986). There was increased sophistication in image analysis ( P. T. Fox, Mintun, Reiman, & Raichle, 1988) and data sharing, and more emphasis on making tasks better psychometrically validated ( R. C. Gur, et al., 1992; R. C. Gur & Reivich, 1980; Posner & DiGirolamo, 2000). Brain mapping in three-dimensions began in earnest, with the ability to examine subcortical regions as they interact with cortical activation in relation to a range of cognitive and, later on, emotion processing tasks.

A major limitation of PET is the exposure of research participants to ionizing radiation. This exposure limits acceptable sample sizes of healthy volunteers, limits the number of tasks that can be given and eliminates from consideration any study of healthy people younger than 18. All these limitations on functional neuroimaging evaporated with the introduction of functional MRI. Indeed, functional neuroimaging using magnetic resonance imaging has outpaced, if not entirely replaced, all other techniques, although PET continues to be a solid method used in some subfields. Over the past 25 years the increase in the number of fMRI studies assessing some aspect of brain function is approximately 5-fold (); a trajectory that is expected to continue. In what follows, we will focus upon the influence of fMRI studies on neuropsychology.

The basics of fMRI

Functional magnetic resonance imaging (fMRI) has several variants, all based on changes in the magnetic properties of blood affected by its degree of oxygenation. The energy demands of activated neurons, which require glucose and oxygen carried by arterial blood, induce local increases in cerebral blood flow and this blood is highly oxygenated since it reaches the brain straight from the lungs. Scan sequences that are sensitive to blood oxygenation level-dependent (BOLD) contrast are applied in rapid succession during task performance and at baseline, and differences between blocks of activation-contrasts between active and control conditions-can be used to map human brain function ( Bandettini, Wong, Hinks, Tikofsky, & Hyde, 1992; Kwong et al., 1992; Ogawa, Lee, Kay, & Tank, 1990). This approach has yielded reliable activation maps ( G. G. Brown et al., 2011) and was further refined to permit event-related measures. An important variant of fMRI, arterial spin-labeling (ASL) based measurement of cerebral perfusion, even allows for quantitative measures of CBF in physiologic units.

Technological advances influencing fMRI during the past 25 years

Much of the improvement in fMRI over the last 25 years was fueled by technological advances ( Shah, Anderson, Lee, & Wiggins, 2010). The first human fMRI studies ( Bandettini, et al., 1992; Kwong, et al., 1992) were achieved using 1.5Tesla MRI scanners and single or few channel head coils or surface coils. While 1.5T scanners continue to be used, 3T scanners have become the norm within the past 10 years. These scanners are more powerful and offer improved speed and quality of data acquisition. The signal-to-noise ratio is greatly improved, which has a direct impact on the ability to acquire high-quality BOLD-fMRI. In addition, significant advances in receiver coils have improved spatial resolution and acquisition speed. Now 7T MRI ( Moser, 2010) is becoming more common and offers the potential for additional gains in sensitivity and specificity. Unfortunately, stronger magnets also lead to more prominent susceptibility artifacts that can negatively impact fMRI contrasts. Care must be taken at high and ultra-high fields to ensure that acquisition parameters take advantage of the improved speed and quality while mitigating potential artifact.

fMRI's role in brain mapping

A complementary finding to the involvement of some regions in multiple tasks was the observation that some regions become consistently activated during a resting "default mode" state, and these same regions become "deactivated" by nearly any task ( Gusnard & Raichle, 2001; Raichle & Snyder, 2007). The idea of a "default mode network", a network of regions that become active when there is no task, has inspired search for more domain-specific networks, and this search has been facilitated by examining correlations among regions in the pattern of activation across time-series (e.g. PPI analyses ( O'Reilly, Woolrich, Behrens, Smith, & Johansen-Berg, 2012)). Such "connectivity" analyses were applied to examine interactions among regions, and more recently to document co-activated networks in resting state functional connectivity analyses. This topic is covered in more detail below.

Developmental studies with fMRI

Functional neuroimaging approaches are also helping to elucidate sex differences in adolescent brain activation patterns. ASL-based fMRI showed, in a sample of 951 human youths aged 8 -22 years from the Philadelphia Neurodevelopmental Cohort (PNC), marked sex differences across development ( Satterthwaite, Shinohara, et al., 2014). Both sexes show decline of CBF between age 8 and adolescence, but whereas in males the decline in CBF continues into the third decade, in females the decline stops with pubescence and CBF values increase into adulthood. Thus, adult females have higher CBF, as was found with the 133-xenon method ( Gur, 1982) and with PET oxygen-15 labeled water ( Ragland, Coleman, Gur, Glahn, & Gur, 2000).

Finally, the incorporation of activation tasks into large-scale genomic neuroimaging studies has allowed rapid accumulation of information on how neurobehavioral systems emerge and mature. For example, the PNC study used a fractal n-back fMRI paradigm to investigate brain responses to working memory load ( Satterthwaite et al., 2013). Performance was associated both with executive network activation and with deactivation of the default mode network. Patterns of brain activation mediated the observed age-related improvements in working memory performance. Such results delineate a process of functional maturation of the executive system that emphasizes improved ability to transition among brain states as the hallmark of functional brain maturation. Most importantly, additional large scale efforts are underway (e.g. Human Connectome Project Lifespan Babies & Children; The Developing Human Connectome Project) that aim to make major scientific progress by linking together imaging, clinical, behavioral, and genetic information over thousands of individuals.

Clinical neuropsychology and fMRI

Clinically, the potential is immeasurable for fMRI to become part and parcel of the clinical practice of neuropsychology. Currently, clinical fMRI has two main applications: 1) the generation of noninvasive biomarkers of brain function for the classification and monitoring of neurological and psychiatric patients, and 2) pre-surgical planning for surgery that may affect motor, language and memory areas ( Beisteiner, 2013). The sections above focused on the first application (e.g. fMRI in development and rsfMRI in AD). The second clinical application requires reliable data in individual patients ( Lee et al., 2016). For example, fMRI is currently being used clinically with the help of neuropsychologists for presurgical planning ( Pillai, 2010) localization of focal epilepsy ( Duncan, Winston, Koepp, & Ourselin, 2016), and identifying covert awareness ( Fernandez-Espejo, Norton, & Owen, 2014). Moreover, rsfMRI, has been successfully implemented in the localization of sensorimotor cortex in patients with epilepsy ( Bettus et al., 2010; Mitchell et al., 2013) and brain tumors ( Kokkonen et al., 2009; Yezhuvath, Lewis-Amezcua, Varghese, Xiao, & Lu, 2009). For example, Bettus et al. ( Bettus, et al., 2010), used rsfMRI to localize seizure focus in 22 patients with mesial temporal lobe epilepsy (MTLE). Significant increases in connectivity patterns were found in the contralateral hemisphere in patients with MTLE, with sensitivity of 64% and a specificity of 91%. Importantly, the rsfMRI results indicated that the most disconnected regions of the brain were aspects of the hippocampus and entorhinal cortex. Bettus et al. argue that alterations in the rsfMRI signal were the most specific marker of epileptogenic zone localization and demonstrate that rsfMRI can be successfully implemented in a single individual.

Yet, the use of fMRI has not been widely adopted in most clinical settings ( Rosen & Savoy, 2012). There are several reasons for this slow pace of adapting fMRI to neuropsychological practice. Patient compliance, performance monitoring, detecting subtle neuroplastic changes, measuring compensatory brain activation ( Beisteiner, 2013) and the reliability of fMRI ( Griffanti, et al., 2016) are a few specific challenges (see Limitations of fMRI section). Admittedly, fMRI signal change is small and sophisticated statistical analyses are needed to separate signal from noise ( Jezzard & Buxton, 2006; Price, Crinion, & Friston, 2006). Unfortunately, there is the need for complex statistical analysis, which itself may create a barrier in the clinical setting. However, we should not let the conservative nature of clinical practice and the lack of sufficient training in functional neuroimaging be a deterrent to expanding the clinical application of fMRI. By incorporating training in fMRI design and analysis in to the regimen of clinical neuropsychologists, we believe these barriers can be overcome.

Incorporation of network analysis in neuropsychology

This approach has been useful in measuring plasticity of cognitive systems during cognitive training ( Guerra-Carrillo, Mackey, & Bunge, 2014), studying developmental and age-related changes in neural networks ( Gu et al., 2015; Stevens, Pearlson, & Calhoun, 2009; Supekar, Musen, & Menon, 2009) and in differentiating individuals with neurological and neuropsychiatric disorders from healthy individuals ( M. D. Fox & Greicius, 2010; Greicius). Improvement in cognitive performance is a cornerstone of neuropsychology and recent rsfMRI studies find that repeated experience with reasoning problems alter connectivity of the brain ( Mackey, Singley, & Bunge, 2013). Specifically, training over a three-month period altered functional connectivity in the frontoparietal and parietal-striatal brain systems. Most importantly, these changes in brain connectivity were associated with improvements on standardized testing ( Mackey, et al., 2013). Such a result suggest that neuropsychological approaches can have a direct and meaningful impact on individualized rsfMRI brain patterns.

Within a developmental context, a recent study by Gu et al. ( Gu, et al., 2015) quantified the formation of network modules in the PNC youths and demonstrated that the brain's functional network organization, as defined by the balance of within- vs. between-module connectivity, changes in youth through a process of modular evolution that is governed by the specific cognitive roles of each system. Moreover, individual variability in these roles was correlated with cognitive performance. In a subsequent analysis of the PNC data, a hypergraph representation of resting-state functional MRI data revealed three distinct classes of subnetworks (hyperedges): clusters, bridges, and stars. These classes respectively represented homogeneously connected, bipartite, and focal architectures. Cluster hyperedges resembled previously-identified functional modules of the brain such as default mode, somatomotor, visual, and salience systems. In contrast, star hyperedges, which represent highly localized subnetworks centered on a small set of regions, were distributed across the entire cortex. Finally, bridge hyperedges linked clusters and stars in a core-periphery organization. Notably, developmental changes within hyperedges were ordered in a similar core-periphery fashion, with the greatest developmental effects occurring in networked hyperedges within the functional core. These results reveal a novel decomposition of the network organization of human brain, and suggest that dynamic maturation of network modules in youth may be a critical driver for the development of cognition ( Gu et al., 2016).

Finally, with respect to clinical diagnostics, changes in resting state connectivity patterns from the hippocampus, a hub of the default mode network, can be used to reliability identify patients with Alzheimer's disease as compared to healthy older adults ( Supekar, Menon, Rubin, Musen, & Greicius, 2008). Moreover, the use of multivariate modeling of resting state fMRI data can further improve diagnostic classification ( Koch et al., 2012). Resting state fMRI has also been used to identify many neuropsychiatric disorders including schizophrenia ( Bassett, Nelson, Mueller, Camchong, & Lim, 2012; Shen, Wang, Liu, & Hu, 2010), depression ( Craddock, Holtzheimer, Hu, & Mayberg, 2009), autism ( J. S. Anderson et al., 2011), ADHD ( Yu-Feng et al., 2007). In summary, rsfMRI is a novel functional MRI tool that appears to have significant potential to allow us a more nuanced understanding the organization, development and degeneration of the brain and cognition.

Limitations of fMRI

While much has been learned using fMRI over the last 25 years, there are arguments about the role that fMRI has had in furthering our understanding of the brain ( Coltheart, 2006; Henson, 2006; Passingham, 2013), especially since the translation of research findings to clinical practice has been limited ( Rosen & Savoy, 2012). While we believe that the evidence above supports the utility of fMRI, we acknowledge that it has limitations and caveats that are often conveniently ignored. Assessing brain function using fMRI is a complex endeavor and both physical (e.g. vasculature) and multiple methodological constraints. Lack of methodological rigor in fMRI is the most important and urgently addressable limitation ( Poldrack, 2012). Traditional fMRI studies often have small samples, inflated effects sizes, fail to systematically perform quality control prior to statistical analysis (e.g. head motion), use imprecise experimental design and use limited or flawed statistical procedures. Therefore, reported effects are often not replicated. Notably, other fields have had similar concerns ( Ioannidis & Trikalinos, 2005). Issues of statistical rigor in functional neuroimaging are comprehensively covered in several articles ( Poldrack, 2012; Vul, Harris, Winkielman, & Pashler, 2009; Yarkoni, Poldrack, Van Essen, & Wager, 2010), in particular limitations of commonly employed statistical approaches in fMRI have been unveiled ( Eklund, Nichols, & Knutsson, 2016).

The small samples used in typical functional neuroimaging studies (6-20 participants/group) has generated lines of studies that are significantly underpowered ( Vul, et al., 2009; Yarkoni, 2009; Yarkoni, et al., 2010). The use of small samples leads to both Type II error-the failure to detect real effects-and Type I error -inflation of effect sizes ( Yarkoni, 2009). Small samples with stringent significance thresholds may only allow for the detection of extremely large effects ( Braver, Cole, & Yarkoni, 2010; Wager, Hernandez, Jonides, & Lindquist, 2007; Yarkoni, 2009). It is likely that many effect size estimates based upon single fMRI studies are inappropriately high. However, efforts to combine results across studies through meta-analytic approaches ( Eickhoff, et al., 2012; P. T. Fox, et al., 1999) appear to provide some consensus and more realistic effects size estimates across the literature ( Minzenberg, et al., 2009). Importantly, studies with larger sample sizes are becoming increasingly common ( Hasan et al., 2008; Satterthwaite, Elliott, et al., 2014)

Because of the weak BOLD signal, fMRI data quality is paramount to accurately attributing brain function to neuropsychological constructs. Neuroimaging data confounds, in particular head motion, are highly pertinent ( Friston, Holmes, Poline, Price, & Frith, 1996; Liu, Zhu, & Zhong, 2015; Power, Barnes, Snyder, Schlaggar, & Petersen, 2012; Reuter et al., 2015; D. R. Roalf et al., 2016; Yoshida, Oishi, Faria, & Mori), especially in children and adolescents ( Satterthwaite et al., 2012). For example, the confounding influence of head motion on resting-state functional connectivity has received substantial attention ( Power, et al., 2012; Satterthwaite, et al., 2012; Van Dijk, Sabuncu, & Buckner, 2012), and indicates that over-interpretation of the data can occur if motion is not systematically addressed. While generally accepted standards are lacking, significant progress is being made. Data quality including signal-to-noise and motion should be explicitly reported and accounted for in any BOLD-fMRI comparison between groups or across individuals. Such effects are of importance for longitudinal or neurodevelopmental studies, where age and motion are highly correlated (children move their heads more than adults). A failure to account for the effects of data quality may result in inflated estimates from the BOLD signal.

While many of the methodological limitations noted above can be overcome, specific limitations of vasculature will continue to be a challenge for fMRI studies. The BOLD effect represents a vital tool to chart brain function, yet it does not measure neural activity directly; rather, it reflects changes in blood oxygenation resulting from the relative balance between cerebral oxygen metabolism and oxygen supply ( Shah, et al., 2010; Yacoub, Harel, & Shmuel, 2015). Specifically, the BOLD signal is sensitive to changes in a variety of essential neurophysiological properties related to energy metabolism-cerebral metabolic rate of oxygen, cerebral blood flow and cerebral blood volume-all of which change with neural processing. As such, the BOLD effect is only an indirect measurement of one consequence of neural activity. Furthermore, its time resolution is limited to the hemodynamic response, which evolves over seconds. Probing behaviors that evolve over shorter time durations is difficult with fMRI. Yet, concerted multimodal efforts will rely heavily upon fMRI for localization of neural circuits. For example, approaches that combine the spatial localization of fMRI with the neuromodulation capability of transcranial magnetic stimulation are promising avenues within the field of neuropsychology. Accordingly, we touch upon several exciting future directions.

The future of functional neuroimaging

Despite the significant challenges noted above, recent developments offer promise for functional neuroimaging methods. First and foremost, improving methodological rigor, replication and incorporating advanced statistical methodologies (e.g. pattern analysis, machine learning, etc.) will improve the specificity and utility of fMRI within specific neuropsychological domains ( Poldrack, 2012)

Multimodal neuroimaging is already available and its influence in clinical and research practice will be considerable. The use of sophisticated MRI techniques to localize structure (e.g. diffusion weighted MRI) along with function (e.g. fMRI) will open new ways to understanding how brain structural and functional architectures interact ( Sotiras et al., 2017). In addition, combining functional techniques such as PET and fMRI will allow simultaneous acquisition of multifunctional data, including tracer uptake, fMRI, and magnetic resonance spectroscopy ( Jadvar & Colletti, 2014; Pichler, Judenhofer, & Pfannenberg, 2008). This combination technique is of particular interest in diagnostic imaging of dementia where PET tracers for amyloid beta and tau ( Klunk et al., 2004; Rowe et al., 2008; J. Shin, Lee, Kim, Kim, & Cho, 2008) provide precise localization of neuropathological insult, while MRI can measure both brain structure and function. This multimodal approach will likely yield detailed information about the cascade of events that leads to neurodevelopment and neurodegeneration. Finally, the advent of Big Data initiatives offers opportunities for unparalleled discovery ( Van Horn & Toga, 2014), which should be leveraged by neuropsychologists. The collection and combination of large neuroimaging datasets with complementary neuropsychological performance data will allow for highly reliable, generalizable efforts to better understand the brain. Finally, the integration of neuroimaging data with genetics will enable the examination of the effects of pleiotropy, epistasis, and gene-by environment interactions ( Meyer-Lindenberg, 2012).

Finally, we acknowledge that traditional neuropsychological test batteries are well validated, used in diverse populations and applied clinically to assess brain dysfunction (Benton; Kaplan, 1990; Kolb & Whishaw, 1996; Ropper & Brown, 2005). However, many of these neuropsychological batteries are based on lesion studies and do not incorporate advances in functional neuroimaging, which capitalize on cognitive neuroscience approaches to examine brain circuitry (e.g., ( D'Esposito, Kayser, & Chen, 2009; Davidson, Jackson, & Kalin, 2000; R. C. Gur, et al., 1992; R. C. Gur & Reivich, 1980; Panksepp, 1998; Posner & DiGirolamo, 2000)). Most current neuropsychological testing is done with paper and pencil tests that take hours to administer and as many hours to score and interpret. They result in lengthy reports that describe a range of deficits without much reference to brain systems that could be implicated. Advances in human brain mapping over the past 25 years generated tasks that are solidly validated in functional neuroimaging studies and can be used to measure individual differences efficiently. For example, a set of tasks has been validated using functional neuroimaging and compiled into a computerized neurocognitive battery (CNB), which provides, within one hour of testing, measures of accuracy and speed on 14 tests that cover the domains of executive functions, episodic memory, complex cognition, social cognition and sensorimotor speed and can be administered inside the scanner ( R. C. Gur et al., 2001; R. C. Gur et al., 2010).

The integration of neuroimaging into the standard practice of clinical neuropsychology faces obstacles and raises important questions concerning incremental validity, utility (access and costs), ecological validity, and the robustness of findings from the neuroimaging literature. There are also professional issues, such as credentialing and interdisciplinary boundaries. How would neuropsychologists doing clinical brain imaging relate to colleagues in neuroradiology? How much training in conventional neuroradiology would be needed by neuropsychologists relying on imaging findings? Notably, whether neuroimaging findings add incremental validity to conventional neuropsychological assessment, can usefully complement conventional assessments or should replace such assessments is an open question rather than settled science.

Notwithstanding these considerations, we can envision a clinical neuropsychologist of the future who relies less on the paper forms of neuropsychological tests and more on computerized tests that are based on modern cognitive neuroscience and validated with structural and functional neuroimaging. That clinical neuropsychologist will know how to follow the clinical interview and testing with an fMRI session, supervised by the neuropsychologist, in which a computerized battery of tests will be administered to the patient in the scanner. The readout will include information on aberrations in brain parameters and networks related to behavioral deficits, which will be aided by images and graphs to be interpreted by our future clinical neuropsychologist. The tools are available to get there, we need a new generation of clinical neuropsychologists with the training to take the plunge. Ultimately, the burden relies upon those neuropsychologists who are neuroimagers to make our results and the applied value of neuroimaging studies clearer and more accessible to all neuropsychologists.

Conclusion

Functional neuroimaging has evolved in the past three decades from a set of esoteric methods applicable to small samples in highly specialized centers to ubiquitously available, sophisticated, safe and noninvasive methods that provide multimodal parameters of brain structure and function and that can be applied in multiple settings on large-scale samples. Functional neuroimaging studies to date have expanded and broadened the scope of our understanding of how brain generates and regulates behavior, but arguably we have just scratched the surface. The challenge for neuroscience is to find ways to integrate multimodal information into a coherent model that describes normative brain-behavior links and their aberration with neuropsychiatric disorders. The challenge for neuropsychology is to take its place in the front seat of this effort, by increasing the methodological rigor of functional neuroimaging studies and improving their relevance to behavioral domains of interest. Clinical neuropsychology faces the greatest challenge, that of abandoning cherished assessment procedures - that are based on older methodology and are cumbersome to administer and evaluate - in favor of rapid, computerized assessments that are based on modern cognitive neuroscience and can be more precisely linked to the functioning of specific brain systems. The future of seeing clinical neuropsychologists involved in the implementation and interpretation of routine fMRI evaluations of patients could just be around the corner.

​

Acknowledgments

Funding Sources: This work was supported by the National Institute of Mental Health grants K01MH102609 to DRR; R01to RCG and the Dowshen Program for Neuroscience at the University of Pennsylvania

Footnotes
Financial Disclosures/Conflicts of Interest:
David R. Roalf PhD reports no potential conflicts of interest or financial disclosures related to this work.

Ruben C. Gur PhD receives royalties from the Brain Resource Centre.

¹ Until then the available methods were variants of the Kety-Schmidt technique (Kety and Schmidt, 1945), which required catheterization of the carotid artery and jugular vein, not practical for a psychological laboratory studies.

²It should be noted that while Jarl Risberg described himself as a Neuropsychologist, Walter Obrist was considered by colleagues as a physiologist and was initially quite skeptical that his method had any applications to psychology. When Obrist arrived at University X (masked for review) he was approached by a colleague and knocked on his door asking to use the method to look at CBF changed during cognitive activity. Obrist looked at his watch, told his new colleague to sit down, and informed him that he has 15 minutes, which are likely the last 15 minutes they'll spend together. He proceeded to explain why there is no physiological reason for changes in CBF caused by mere cognitive activity. The brain gets constant supply of highly oxygenated blood, there are known mechanisms of autoregulation, and the metabolic demands of thoughts are unlikely sufficient to cause detectible local changes in cerebral blood flow. His hope for the method was to distinguish between comatose patients who will regain consciousness and those who will not. Years later, after they became close collaborators, Obrist "confessed" to his colleague that his PhD too was in Psychology.

³Lest the reader think that those investigators were lazy, consider that each participant had to be flown (in a twin-engine Cessna) from SiteA (masked for review) to Brookhaven National Labs, each received a venous and an arterial catheter, and the normative "Cognitive slots" took second seat to scanning clinical cases. Furthermore, there was no image analysis software to speak of (except for reconstruction) and all regions of interest had to be expert-drawn.

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Functional Brain Imaging in Neuropsychology over the past 25 years

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Keywords: functional neuroimaging, functional MRI, neuropsychology, neurocognition The study of brain function in health or disease requires integration of behavioral and neurophysiologic data. Over the last several decades we have seen that this can be achieved through the use of dimensionally-defined neurobehavioral probes ( R. C.

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Combined lesion-deficit and fMRI approaches in single-case studies: unique contributions to cognitive neuroscience

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Combined lesion-deficit and fMRI approaches in single-case studies: unique contributions to cognitive neuroscience

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Why relevant for this coursework? This paper may highlight some of the benefits of fMRI to feed into your essay. Note that although lesion studies are not central to your coursework, there may be information here in this paper that could be useful to develop your argument.

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Highlights

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The number of published neuroscience papers on single-case studies is declining.

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Combining lesion-deficit case studies and functional imaging yields valuable insights.

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These insights go beyond those obtained by lesion-deficit or functional imaging alone.

Although lesion-deficit case studies are foundational in cognitive neuroscience, published papers presenting single lesion cases are declining. In this review, we argue that there is a valuable place for single-case lesion-deficit research, especially when combined with functional neuroimaging methods, such as functional magnetic resonance imaging (fMRI). To support this, we present a summary of notable findings from single-case combined lesion-deficit and fMRI studies published in recent years (2017-2020). These studies show the unique value that this combined approach brings to the understanding of complex functions, brain-level connectivity, and plasticity and recovery. We encourage researchers to consider combining lesion-deficit and functional imaging methods in the analysis of single cases, as this approach affords unique opportunities to address challenging unanswered questions about brain-behavior relationships.

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# data[].attributes.attachment_link.title
Combined lesion-deficit and fMRI approaches in single-case studies: unique contributions to cognitive neuroscience

# data[].attributes.attachment_link.description
The number of published neuroscience papers on single-case studies is declining. * Combining lesion-deficit case studies and functional imaging yields valuable insights. * These insights go beyond those obtained by lesion-deficit or functional imaging alone. Although lesion-deficit case studies are foundational in cognitive neuroscience, published papers presenting single lesion cases are declining.