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The side affects of addictive drugs (especially cocaine) will require "long-term adaptive changes in the receptors, neurotransmitters, and intracellular signalling transduction pathways".

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Research has been discussed in support of the idea that the cerebellum contributes to reward- and punishment-related predictive coding and plays a role in the regulation of bodily homeostasis which is proposed to be dysfunctional in depressive disorder.

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Medical Pictures Info - Health Definitions Photos | Health Definitions Photos

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The cerebellum is an area in the hindbrain which controls the movement and coordination, equilibrium, balance and muscle tone. The cerebellum is located just below the base of the skull, under the occipital lobes of cerebral cortex and above the brainstem. The cerebellum is similar to the cerebral cortex which comprises of white substance and a thin outer layer of gray matter. The cerebellum's folded outer layer has smaller, compact folds than the ones in cerebral cortex. There are hundreds of millions of neurons present in the cerebellum which are responsible for processing data. It moves the information to and fro between the areas of cerebral cortex and the body muscles which are involved with motor control.

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cerebellum | Medical Pictures Info - Health Definitions Photos

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The cerebellum is an area in the hindbrain which controls the movement and coordination, equilibrium, balance and muscle tone. The cerebellum is located just below the base of the skull, under the occipital lobes of cerebral cortex and above the brainstem.

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Abstract

Depressive disorder is associated with abnormalities in the processing of reward and punishment signals and disturbances in homeostatic regulation. These abnormalities are proposed to impair error minimization routines for reducing uncertainty. Several lines of research point towards a role of the cerebellum in reward- and punishment-related predictive coding and homeostatic regulatory function in depressive disorder. Available functional and anatomical evidence suggests that in addition to the cortico-limbic networks, the cerebellum is part of the dysfunctional brain circuit in depressive disorder as well. It is proposed that impaired cerebellar function contributes to abnormalities in predictive coding and homeostatic dysregulation in depressive disorder. Further research on the role of the cerebellum in depressive disorder may further extend our knowledge on the functional and neural mechanisms of depressive disorder and development of novel antidepressant treatments strategies targeting the cerebellum.

Keywords: Cerebellum, Depressive disorder, Homeostasis, Monitoring, Predictive coding, Punishment, Reward

Introduction

Psychological wellbeing to a significant extend depends on the individual's ability to deal with uncertainty [ 1]. Experience of uncertainty is inversely related to experiential feelings of control and results from actions that do not lead to the anticipated outcome. The mismatch between anticipated and actual outcome gives rise to a prediction error signal generated by the brain which is indicative for a disruption of internal bodily homeostasis [ 2]. Prediction error signals typically lead to a cascade of physiological and psychological processes that serve to re-establish equilibrium [ 3]. The idea of reducing uncertainty by optimizing predictability is known as the error minimization routine of predictive coding [ 2]. The error minimization routine is considered to form the basis of the organism's ability to construct and update internal models that allow for successful adaptation under changing conditions [ 2]. Feedback-related reward and punishment signals arguably play an important role in the formation of internal prediction models and in shaping context appropriate behavior [ 4]. The fact that depressive disorder is characterized by hypersensitivity to punishment and hyposensitivity to reward suggests that in patients, reward and punishment signals provide suboptimal input for the error minimization routine to work properly. Support for this idea comes from findings showing that patients suffering from depression show abnormal neural responses to unexpected outcomes as well as context updating in response to feedback [ 5]. Atypical physiological response patterns to stress and abnormal biorhythms in patients with mood disorders further hint at a dysregulation of the neural circuitry concerned with bodily homeostasis. The subjective experience of negative mood and lack of control may thus represent a phenomenological proxy for problems in homeostatic regulatory function [ 6].

Cerebellum and Predictive Coding

Central to predictive coding is the idea of the brain operating as a system which constructs experience-based inferential internal models of the world [ 2, 7]. While the role of the cerebellum in the context of adaptive control and predictive coding is established for the sensorimotor domain [ 8], current evidence indicates that this function extends to the non-motor domain as well [ 9]. Endocranial analyses of fossil humans demonstrate that in the course of evolution, expansion of the cerebral volume was paralleled by a quantitatively similar increase of cerebellar volume [ 10]. These volumetric increases have been attributed to growing social and cultural complexity [ 10]. While the cerebellum in modern man accounts for approximately 10 % of the total brain volume, this structure contains more than half of all neurons present in the human brain. These anatomical facts suggest that the cerebellum is a strong computational structure and plays a more prominent role in human behavior than previously thought [ 11]. This assumption is further strengthened by the reciprocal anatomical projections of the cerebellum to cortical and limbic areas. The posterior cerebellar hemispheres are connected to the cerebral cortex via the deep cerebellar nuclei and thalamus. Primate anatomical and human functional neuroimaging studies have shown that Crus I and II of the posterior cerebellar hemisphere are connected via the dentate nuclei to the association areas of the parietal and frontal cortex [ 12]. The anterior part of the cerebellum is linked to the subcortical punishment and reward structures of the brain, including the amygdala and striatum [ 9]. Furthermore, assuming a role for the cerebellum in the brain's homeostatic functioning, the monosynaptic reciprocal connections to the hypothalamus are particularly notable [ 13]. The hypothalamus has a central role in governing metabolic, autonomic, and endocrine processes to maintain internal bodily homeostasis [ 6]. In addition, afferent connections from the cortical and limbic areas via the pontine nuclei located in the brainstem provide a closed circuit of cerebello-cortical and cerebello-limbic loops [ 14]. In fact, damage to the cerebellum can lead to dysfunctions in executive functioning, emotional instability, and mood [ 9]. Abnormal cerebellar activity associated with the processing of emotional relevant information in patients with depressive disorder has been confirmed in a meta-analysis of functional neuroimaging studies [ 15]. In addition, reduced cerebellar volumes in patients suffering from depressive disorder lend further support for cerebellar involvement in negative mood states [ 16]. These findings are in line with results showing an inverse parametric association between cerebellar volumes and neurotic personality traits in a non-clinical sample of volunteers [ 17]. The link between cerebellar volume and neuroticism hints at a possible role of the cerebellum in the vulnerability to experience negative affect and mood disorders. However, the associative nature of the study does not allow inferences on the directionality of the correlation. More direct evidence for cerebellar involvement in non-motor functions and mood comes from non-invasive brain stimulation studies in healthy volunteers [ 18]. Disruptive transcranial magnetic stimulation (TMS) applied to the cerebellum increases self-reports of negative mood as a result of impaired emotion regulation, while administering facilitatory TMS to the cerebellum increases positive mood and attentional biases for appetitive stimuli [ 18]. Recordings of distinct anterior scalp-recorded theta (4-7 Hz) oscillations following excitation of the human cerebellum with single-pulse TMS indicate the existence of a functional link between the cerebellum and the cerebral cortex [ 19]. Interestingly, theta oscillations are part of the cortico-limbic routines implicated in error monitoring and context updating. In further support, electric stimulation of the deep cerebellar nuclei elicits distinct theta oscillations located in limbic subdivisions of the prefrontal cortex in awake, behaving rats [ 20]. Taken together, these findings confirm the existence of reciprocal communication pathways between the cerebellum and cortico-limbic brain regions and provide a functional neuroanatomical basis for reward and punishment-related predictive coding and mood regulation (Fig. ).

Cerebellar Predictive Coding and Depressive Disorder

Major depressive disorder is associated with volume reductions in the frontal cortex, hippocampus, and striatum [ 21]. In addition, abnormal patterns of activity in the frontal cortex, striatum, globus pallidus, amygdala, and cerebellum have been observed [ 15]. These meta-analytic results support the view that depressive disorder involves abnormalities in the reward-punishment-related limbic circuits paralleled by dysfunctional brain structures implicated in top-down regulation. Further evidence for compromised regulation capacity and top-down regulation in depressive disorder was demonstrated in a recent meta-analysis which found lower functional connectivity between frontal and limbic structures [ 22]. The same study also showed that depressed patients had lower connectivity between parietal and frontoparietal regions involved in attending to the external environment but hyperconnectivity in the default network associated with internal self-referential thoughts and feelings [ 22]. Furthermore, the cerebellum was hypoconnected to the parietal cortex, a finding which concurs with the proposed cerebellar role in reality monitoring and predictive coding.

In agreement with conventional motor theories that conceptualize the cerebellum as a learning machine, three computational primitives for understanding the relations between homeostasis, predictive coding, and depressive disorder are important [ 10, 14]. Firstly, an internal forward model that is able to predict/anticipate the consequences of behavior. Secondly, an internal feedback model that is able to compare and detect mismatches between predicted and actual outcomes. Thirdly, an error minimization routine that actively modifies the internal forward and feedback models enabling more accurate predictions of the environment. From this viewpoint, behavioral adaptive responses involve the cerebellum performing Bayesian probability modeling that uses reward and punishment signals as inputs to update the priors to minimize uncertainty and regain bodily homeostasis [ 2]. Results from functional neuroimaging studies show that cerebellar activity correlates with error monitoring and probabilistic inferences in decision-making and context updating [ 23].

According to the uniform cerebellar transform function, the homogenous microstructure of the cerebellum allows for the processing of multimodal input signals originating from the rich cerebellar connections with cortical and limbic parts of the brain [ 9]. Anxiety and depression can be viewed as phenomenological manifestations of disrupted bodily homeostasis and uncertainty that prompts the cerebellum to update the priors of the internal model to minimize prediction errors. The conceptual framework predicts that in line with the universal cerebellar transform function, neuroticism and mood disorders are associated with problems in updating the internal model. Problems with updating the priors of the internal model will affect the prediction error minimization routine and contribute to feelings of uncertainty and loss of control. This view builds upon the central idea that the cerebellum is important for synchronizing cortical cognitive and limbic motivational information processing streams to fit contextual demands. In addition, the latter also gives a possible mechanistic account for why abnormalities in the cerebellar transform function could result in disorganized thought and feelings [ 9]. Abnormalities in cerebellar predictive coding may offer a theoretical framework to explain at least in part why anxiety and depression are associated with subjective reports of experiencing loss of control and feelings of helplessness. Finally, the present framework may provide a starting point for developing novel non-invasive brain stimulation protocols for the treatment of depressive disorder by targeting the cerebellum [ 18].

In conclusion, research has been discussed in support of the idea that the cerebellum contributes to reward- and punishment-related predictive coding and plays a role in the regulation of bodily homeostasis which is proposed to be dysfunctional in depressive disorder.

Conflict of Interest

The author declares that he has no conflict of interest.

References

16. Escalona PR, Early B, McDonald WM. Reduction of cerebellar volume in major depression: a controlled magnetic resonance imaging study. Depression. 1993;1:156-8. doi: 10.1002/depr.3050010307. [[ CrossRef] Google Scholar]

18. Schutter DJ. Handbook of the cerebellum and cerebellar disorders. New York: Springer; 2013. Human cerebellum in motivation and emotion; pp. 1771-82. [ Google Scholar]

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A Cerebellar Framework for Predictive Coding and Homeostatic Regulation in Depressive Disorder

# data[].attributes.attachment_link.description
Depressive disorder is associated with abnormalities in the processing of reward and punishment signals and disturbances in homeostatic regulation. These abnormalities are proposed to impair error minimization routines for reducing uncertainty. Several lines of research point towards a role of the cerebellum in reward- and punishment-related predictive coding and homeostatic regulatory function in depressive disorder.

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Located at the back part of the brain, which is lower than the occipital and temporal lobes, and within the posterior cranial fossa

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https://teachmeanatomy.info/neuroanatomy/structures/cerebellum/#:~:text=The%20cerebellum%20is%20located%20at,within%20the%20posterior%20cranial%20fossa.

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Acquires information from sensory systems, the spinal cord, etc. then controls motor movements

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Organizes voluntary movements like posture, balance coordination, and speech, while maintaining smooth and balanced muscular activity

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https://www.healthline.com/human-body-maps/cerebellum#2

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It is smaller than the cerebrum but contains more significant nerve cells. And takes account for about ten percent of the brains total size.

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The cerebellum consists of two hemispheres which are connected by the vermis, a narrow midline area. Like other structures in the central nervous system, the cerebellum consists of grey matter and white matter:

Grey matter - located on the surface of the cerebellum. It is tightly folded, forming the cerebellar cortex.

White matter - located underneath the cerebellar cortex. Embedded in the white matter are the four cerebellar nuclei (the dentate, emboliform, globose, and fastigi nuclei).

There are three ways that the cerebellum can be subdivided - anatomical lobes, zones and functional divisions

There are three anatomical lobes that can be distinguished in the cerebellum; the anterior lobe, the posterior lobe and the flocculonodular lobe. These lobes are divided by two fissures - the primary fissure and posterolateral fissure.

There are three cerebellar zones. In the midline of the cerebellum is the vermis. Either side of the vermis is the intermediate zone. Lateral to the intermediate zone are the lateral hemispheres. There is no difference in gross structure between the lateral hemispheres and intermediate zones

The cerebellum can also be divided by function. There are three functional areas of the cerebellum - the cerebrocerebellum, the spinocerebellum and the vestibulocerebellum.

Cerebrocerebellum - the largest division, formed by the lateral hemispheres. It is involved in planning movements and motor learning. It receives inputs from the cerebral cortex and pontine nuclei, and sends outputs to the thalamus and red nucleus. This area also regulates coordination of muscle activation and is important in visually guided movements.

Spinocerebellum - comprised of the vermis and intermediate zone of the cerebellar hemispheres. It is involved in regulating body movements by allowing for error correction. It also receives proprioceptive information.

Vestibulocerebellum - the functional equivalent to the flocculonodular lobe. It is involved in controlling balance and ocular reflexes, mainly fixation on a target. It receives inputs from the vestibular system, and sends outputs back to the vestibular nuclei.

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The cerebellum consists of two hemispheres which are connected by the vermis, a narrow midline area. Like other structures in the central nervous system, the cerebellum consists of grey matter and white matter: Grey matter - located on the surface of the cerebellum. It is tightly folded, forming the cerebellar cortex.

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Head injury or having a stroke can lead to damage to the cerebellum in the brain, which can cause  uncoordinated movement to the body.

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Cerebellum Facts, Function, Location, and Disorders

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The cerebellum is located at the base of your skull where your head meets your neck. The function of the cerebellum is primarily focused on movement and balance. It also plays a role in cognitive functions like language and attention.

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Abstract

Increasing evidence has involved the cerebellum in functions beyond the sphere of motor control. In the present article, we review evidence that involves the cerebellum in addictive behaviour. We aimed on molecular and cellular targets in the cerebellum where addictive drugs can act and induce mechanisms of neuroplasticity that may contribute to the development of an addictive pattern of behaviour. Also, we analyzed the behavioural consequences of repetitive drug administration that result from activity-dependent changes in the efficacy of cerebellar synapses. Revised research involves the cerebellum in drug-induced long-term memory, drug-induced sensitization and the perseverative behavioural phenotype. Results agree to relevant participation of the cerebellum in the functional systems underlying drug addiction. The molecular and cellular actions of addictive drugs in the cerebellum involve long-term adaptative changes in receptors, neurotransmitters and intracellular signalling transduction pathways that may lead to the re-organization of cerebellar microzones and in turn to functional networks where the cerebellum is an important nodal structure. We propose that drug induced activity-dependent synaptic changes in the cerebellum are crucial to the transition from a pattern of recreational drug taking to the compulsive behavioural phenotype. Functional and structural modifications produced by drugs in the cerebellum may enhance the susceptibility of fronto-cerebellar circuitry to be changed by repeated drug exposure. As a part of this functional reorganization, drug-induced cerebellar hyper-responsiveness appears to be central to reducing the influence of executive control of the prefrontal cortex on behaviour and aiding the transition to an automatic mode of control.

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national center for biotechnology information

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Why should we keep the cerebellum in mind when thinking about addiction? - PubMed

# data[].attributes.attachment_link.description
Increasing evidence has involved the cerebellum in functions beyond the sphere of motor control. In the present article, we review evidence that involves the cerebellum in addictive behaviour. We aimed on molecular and cellular targets in the cerebellum where addictive drugs can act and induce mecha ...

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Once homeostasis is disrupted, it alters the components for memory, the rewarding system, and motivation are therefore increased, which leads to the cognitive control being destroyed.

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Abstract

Although cerebellar alterations have been consistently noted in the addiction literature, the pathophysiology of this link remains unclear. The cerebellum is commonly classified as a motor structure, but human functional neuroimaging along with clinical observations in cerebellar stroke patients and anatomical tract tracing in non-human primates suggest its involvement in cognitive and affective processing. A comprehensive literature search on the role of the cerebellum in addiction was performed. This review article (1) considers the potential role of the cerebellum in addiction, (2) summarizes the cerebellar structural alterations linked to addiction, (3) presents the functional neuroimaging evidence linking the cerebellum with addiction, and (4) proposes a model for addiction that underscores the role of the cerebellum. The data implicate the cerebellum as an intermediary between motor and reward, motivation and cognitive control systems, as all are relevant etiologic factors in addiction. Furthermore, consideration of these findings could contribute to deeper and more sophisticated insights into normal reward and motivational function. The goal of this review is to spread awareness of cerebellar involvement in addictive processes, and to suggest a preliminary model for its potential role.

Keywords: PET, MRI, craving, opioids, cocaine, marijuana, alcohol

1. Introduction

Over the past two decades, a convergence of clinical ( Manto, 2012; Phillips et al., 1987) and basic research investigations of addictive substances ( Kühn et al., 2012; Miquel et al., 2009; Strick et al., 2009; Sullivan et al., 2000; Volkow et al., 1997) have implicated the cerebellum in addiction. Though cerebellar findings are frequent in such studies, they are often marginalized, as the structure is not typically thought of as having a key role in addiction. In more extreme cases, the cerebellum is not even captured in some neuroimaging studies, eliminating it entirely from scientific consideration. With the availability of freely available cerebellar spatial registration software ( Diedrichsen et al., 2011; Diedrichsen et al., 2010), improved acquisition parameters designed to capture the whole brain ( Uğurbil et al., 2013), and cerebellar neuroimaging atlases ( Diedrichsen et al., 2009; Diedrichsen, 2006), few barriers remain to consider significant imaging effects often found in this structure. This paper will review the structural and functional neuroimaging literature that implicates the cerebellum in addiction, and will discuss these findings in the context of contemporary theories of affective and cognitive cerebellar function. Although the cerebellum has received little attention in the context of addiction, this review turns the focus towards the cerebellum to highlight its potential involvement. A model for addiction will be presented, that features the cerebellum as a key modulator of behavior.

The role the cerebellum may play in addiction may be inferred from its involvement in non-motor function, which has been extensively reviewed ( Ramnani, 2012; Schmahmann, 2004; Stoodley, 2012; Strick et al., 2009). In brief, the cerebellum receives extensive afferent input from the pontine nuclei, which receive input from prefrontal and association cortices in the cerebrum. Lesions to the posterior cerebellar hemispheres can lead to cerebellar cognitive affective syndrome, which features higher-level deficits beyond motor planning and execution. Resting state neuroimaging has shown that the cerebellum contains a variety of functional networks associated with many parts of the neocortex, beyond motor areas. fMRI studies have shown that the cerebellum also activates with a variety of functions, even those unassociated with a motor component. Cerebellar mechanisms of addictive drug action have been previously reviewed in the context of molecular and cellular investigations ( Miquel et al., 2009). Collectively, the evidence suggests that the cerebellum may be intertwined with brain processes related to addiction, such as reward, motivational drive, saliency, inhibitory control, and insight. As summarized here, morphological and functional studies on human subjects with compulsive drug abuse indicate that the cerebellum is prominently involved in addiction.

2. Gross cerebellar anatomy

In the human, the cerebellum consists of two hemispheres connected by a midline structure, the vermis (). These hemispheres are divided into lobules, with the primary fissure defining anterior and posterior lobes. The lobule immediately anterior to the horizontal fissure is identified as crus I, with crus II on the opposite side of the fissure. Like the cerebral cortex, the cerebellum has an outer cortical layer made up of gray matter, and with an inner layer of white matter scaffolding. The white matter tracts appear like stalks of broccoli, with the highly convoluted cortical gray matter extruding as if they were leaves, leading to the term cerebellar folia. The cerebellar peduncles form a thick trunk of white matter that connects the cerebellum to the brainstem. The cerebellar cortex has a highly conserved lattice structure consisting of three layers (Molecular, Purkinje cell, and Granular layers) with different cytoarchitectural features. Purkinje cells are inhibitory neurons that project to the deep cerebellar neurons, and regulate their efferent signals output to the brainstem and cerebral cortex. Currently, standard neuroimaging methods are able to differentiate gray and white matter macrostructure, and can define the paths of white matter tracts.

The cerebellum receives input through two major brainstem afferent relays, the inferior olive and the pontine nuclei, through the climbing fibers and mossy fiber pathways respectively (). The climbing fiber pathway enters the cerebellum through the inferior cerebellar peduncle, and the mossy fiber pathway enters through the middle cerebellar peduncle. Both pathways convey projections from the cerebral cortex to the cerebellum, with the pontine nuclei receiving a larger proportion of input from non-motor cortical regions (please see ( Schmahmann, 1996) for detailed review), but also showing reciprocal connections with the basal ganglia ( Bostan & Strick, 2010).

3. Cerebellar mechanisms related to addiction

Cerebellar function has traditionally been ascribed to motor coordination, including postural control, eye movements, motor learning, and time keeping associated with motor tasks. In this capacity, the cerebellum receives sensory inputs from the spinal cord and integrates them with cortical inputs to execute complex motor tasks ( Courchesne & Allen, 1997; Doyon et al., 2003; Ito, 2006; Ivry, 1997). Dysmetria, a symptom of cerebellar dysfunction, reflects an inability to execute intended motor tasks due to a lack of sensory-motor coordination. The cerebellum's role in motor learning, as studied in the context of classical conditioning, has also been extended to include reinforcement learning and the establishment of motivational behavior ( Bauer et al., 2011; Swain et al., 2011; Thoma et al., 2008).

The cerebellum has been hypothesized to have a single generalizable function ( D'Angelo & Casali, 2012; Ito, 2006; Schmahmann, 2004), given its strikingly uniform arrangement of neurons. This singular function has been theorized to be modulation, which would extend to different domains based on the variety of functional inputs the cerebellum receives. This theory suggests that the cerebellum could optimize performance by modulating behavior according to context, acting as an oscillation dampener. For example, the cerebellum may modulate emotional processes by integrating positive and negative affective inputs in the same way that it modulates fine motor control by integrating sensory inputs. Different parts of the cerebellum receive inputs from different parts of the brain, leading to a functional topography within the cerebellum that may reflect compartmentalization of modulatory processes ( Stoodley & Schmahmann, 2009). For example, depending on the location, cerebellar lesions can result not only in movement disorders such as ataxia and dysmetria, but also disrupted affect and cognitive ability ( Schmahmann & Sherman, 1998; Schmahmann, 1991; Schmahmann, 2004). Similarly, cerebellar abnormalities are observed in patients with obsessive-compulsive disorder and attention deficit hyperactivity disorder ( Seidman et al., 2011; Zarei et al., 2011). Given their relationship with cerebellar abnormalities, comorbidities between these disorders and substances of abuse may produce interactions that manifest in the cerebellum.

The cerebellar areas Crus I, Lobule VI, and VIIb are associated with functional resting state networks (RSNs) that are related to executive and associative processing in the cerebral cortex ( Buckner et al., 2011). RSNs represent coherent signal fluctuations that are measured across different networks at rest that imply functional relationships between brain regions (). In a dataset of 1000 healthy subjects, Buckner and colleagues identified functional connectivity between the cerebellum and 7 major RSNs in the cerebrum. Crus I, Lobule VI, and VIIb were all correlated with brain regions related to cognitive control, such as the dorsolateral prefrontal cortex and the dorsomedial prefrontal cortex. Functional correlations between these areas in the cerebellum and the prefrontal cortex have also been observed in other functional connectivity studies using fewer subjects ( Habas et al., 2009; Krienen & Buckner, 2009; O'Reilly et al., 2010; Sang et al., 2012), which complements anatomical tracer studies in non-human primates that show reciprocal connections between these areas ( Kelly & Strick, 2003; Middleton & Strick, 1994, 2001). Furthermore, both Crus I and Lobule VI were correlated with an RSN that included the anterior insula and anterior cingulate cortex, structures related to stimulus salience ( Habas et al., 2009; Mouraux et al., 2011) and, in the case of the insula, interoception ( Craig, 2009). The cerebellum may play an influential modulatory role in reward/saliency, as it also shares reciprocal connections with dopaminergic systems in the basal ganglia ( Bostan & Strick, 2010). The functional correlations between these cerebellar areas with cerebral structures related to executive control, drug craving, response selection, and salience ( Goldstein & Volkow, 2002, 2011; Habas et al., 2009; Volkow et al., 2010) further highlight the cerebellum's potential role in addiction.

Addiction includes a breakdown in motivational homeostasis, a disruption in reward and aversive processing and their modulation ( Koob, 1996). Recent functional neuroimaging findings indicate that the cerebellum may modulate motivational processing ( Moulton et al., 2011). In healthy volunteers, aversive heat and unpleasant pictures activated overlapping areas in the cerebellum, specifically in Crus I, Lobule VI, and VIIb. This functional overlap between different unpleasant sensory modalities suggests that the cerebellum contains specific regions in encoding generalized aversive process. In this case, cerebellar activation of these areas was interpreted as reflecting aversion rather than stimulus salience, as a control analysis of pleasant pictures did not replicate activation observed with unpleasant pictures. Not only were these areas commonly activated by aversive stimuli, but their activity coincided with decreased activity in brain areas related to emotional and motivational processing, including the hypothalamus, the subgenual anterior cingulate cortex, and the parahippocampal gyrus. This response pattern suggests that the cerebellum could modulate the flow of aversive information and motivational processing (), complementing clinical observations of disrupted affective and cognitive processing in stroke patients ( Schmahmann & Sherman, 1998; Schmahmann, 1991; Schmahmann, 2004).

Interestingly, prescription opioid-dependent patients have decreased functional connectivity at rest between reward structures and the cerebellum, including Crus I ( Upadhyay et al., 2010). In opioid dependent patients, cerebellar functional connectivity with the nucleus accumbens and the amygdala decreased relative to age-gender matched controls. This change in functional correlation suggests that these reward regions are decoupled from cerebellar activation, indicating that opioid dependent patients have disrupted communication between these regions.

4. Addiction and neuroimaging measures of cerebellar structure

The primary neuroimaging techniques to assess changes in cerebellar structure in vivo in humans are magnetic resonance imaging (MRI) based methods, such as volumetric MRI, and diffusion tensor imaging (DTI). Volumetric MRI is a morphometric approach that uses 3D T1-weighted images to measure changes in the volume of specific anatomical structures, either in terms of total volume, grey matter, or white matter. One type of method to analyze volumetric MRI is voxel-based morphometry (VBM), a method that compares grey or white matter volume between brain states (e.g. addicted vs. healthy) based on MRI signal intensity in a voxel-by-voxel manner. Another volumetric method measures cortical thickness, a gray matter measure of the distance between the pial surface and the underlying white matter, calculated using computationally rendered 3D brain surfaces based on T1-weighted images. Though a refined measure, cortical thickness has not been practically applied to the cerebellum, primarily due to the lack of adequate spatial resolution to capture the exquisite complexity of cerebellar folia. In addition to measures of brain volume, MRI can be used to measure the axonal organization of white matter tracts with DTI. DTI acquisitions measure the directional diffusion of water, which is highly directional in proximity to white matter tracts. The hydrophobic phospholipid bilayer of the myelin sheath restricts the flow of water perpendicular to axonal processes, which results in anisotropic diffusion. DTI can be used to calculate measures of diffusion, such as fractional anisotropy (FA), which reflects white matter integrity or structure.

Volumetric MRI studies have documented that users of addictive substances tend to have smaller cerebellums (). Previous studies that have used whole-brain neuroimaging to identify addiction-related circuits have, with few exceptions, downplayed findings in the cerebellum in favor of better-understood motivational pathways. In the context of structural changes, significant decreases in gray matter in the cerebellum have been detected with long-term exposure to cocaine ( Barrós-Loscertales et al., 2011; Sim et al., 2007), heroin ( Lin et al., 2012; Walhovd et al., 2007), nicotine ( Brody et al., 2004; Gallinat et al., 2006; Kühn et al., 2012), and alcohol ( Chanraud et al., 2007; Chanraud et al., 2010; Mechtcheriakov et al., 2007; Shear et al., 1996; Sullivan et al., 2000; Sullivan et al., 2010). These gray matter decreases occur in the cerebellar cortices, but have not been linked to specific cerebellar cell groups given the spatial resolution limitations of MRI. A few studies have proposed that these cerebellar deficits could relate to motor deficits ( Sullivan et al., 2000; Sullivan et al., 2010), executive function deficits ( Chanraud et al., 2007; Lin et al., 2012; Sim et al., 2007; Sullivan et al., 2000), or dysfunctional processing of drug-related cues ( Kühn et al., 2012). The structural differences in the posterior cerebellum are reoccurring across volumetric MRI studies, suggesting that (1) the cerebellum either reduces in volume as a consequence of chronic drug use, or (2) small cerebellums are a risk factor in the development drug addictions.

Table 1

4.1 Cocaine exposure

Cocaine is a crystalline tropane alkaloid derived from the coca plant, and acts as a serotonin-norepinephrine-dopamine reuptake inhibitor. Both serotonin receptors and norepinephrine receptors are expressed in the cerebellum. A VBM study on cocaine use and brain structure ( Sim et al., 2007) suggests that drug use impacts specific regions within the cerebellum. This study compared gray and white matter in 40 cocaine abusers and 41 matched healthy controls, and found that abusers had significantly reduced gray matter in Lobule VI, Crus I, and Crus II. The finding of reduced gray matter in Lobule VI in cocaine abusers was also corroborated recently in another VBM study ( Barrós-Loscertales et al., 2011). Lobule VI, Crus I, and Crus II are located in the posterior cerebellar hemispheres, which have been related to modulation of affect and cognition in clinical studies on cerebellar stroke ( Schmahmann & Sherman, 1998).

4.2 Opioid exposure

Opioids such as heroin act on opioid receptors in the brain, of which mu- and kappa-varieties are present in the human cerebellum ( Schadrack et al., 1999). Regarding the impact of opiates on structure, the volume of cerebellar cortex is significantly reduced in children who were exposed to heroin in utero ( Walhovd et al., 2007). In this study, gray matter differences were evaluated in 14 exposed vs. 14 control children using a region of interest analysis. When accounting for age, gestational age, and gender, cerebellar white matter and cerebellar cortex showed a significant loss in gray matter, along with the accumbens, putamen, pallidum, amygdala, and cerebral cortex overall. Though these structural changes were reported as the main findings, the only significant effect was in the cerebellar cortex when intracranial volume was included as a factor. Considering that intracranial volume is highly variable in children of different ages, this serves to highlight the vulnerability of the cerebellum to heroin exposure during prenatal development.

A recent DTI study in ex-heroin users reported a reduction in mean FA in the cerebellum ( Bora et al., 2012). Using DTI, 30 ex-heroin users on either methadone or buprenorphine maintenance medication were compared with 29 age-gender matched healthy controls. Bora et al. found lower FA, degraded white matter integrity, in the superior and middle cerebellar peduncles. These cerebellar peduncles serve as major pathways for afferent and efferent neural information flow between the cerebellum and the midbrain, including the pons. The implication that these white matter tracts are degraded with a history of heroin abuse suggests that addiction is related to a disruption in cerebellar processing and connectivity with other brain regions.

4.3 Nicotine exposure

Nicotine is a parasympathomimetic alkaloid, which acts as a nicotinic acetylcholine receptor agonist. In the cerebellum, these receptors control the release of the neurotransmitters glutamate, gamma-aminobutryic acid (GABA), and norepinephrine. VBM studies in cigarette smokers vs. healthy controls have demonstrated reduced gray matter in the posterior cerebellar hemispheres, specifically in Lobule VI ( Brody et al., 2004; Gallinat et al., 2006) and Crus I ( Kühn et al., 2012). Gray matter volume in Crus I was also found to be correlated negatively to the magnitude of nicotine dependence ( Kühn et al., 2012). The effect of nicotine on cerebellar structure has recently been reviewed in detail ( Gallinat et al., 2006).

4.6 Premorbid Cerebellar Volume and Addiction

Recent structural evidence indicates that abnormal cerebellar volume may reflect genetic risk to addiction. Fifty siblings of stimulant-dependent individuals compared with fifty unrelated healthy controls had more cerebellar gray matter ( Ersche et al., 2012). These siblings were not users of addictive substances, yet they showed significant differences in the posterior cerebellar hemispheres compared to healthy volunteers. This suggests that the cerebellar abnormalities may identify individuals genetically at risk to develop dependence. However, stimulant-dependent individuals themselves showed no significant differences with controls in the cerebellum. In either case, the data from this study indicate that cerebellar structure may influence the potential to develop addiction. This has also been suggested with alcoholism ( Benegal et al., 2007; Hill et al., 2011; Tessner & Hill, 2010), where individuals at high risk for developing alcohol dependence have altered cerebellar gray matter volume relative to controls. Cerebellar indications are also observed in neurological assessments of patients with substance dependence to cocaine and heroin as well ( Manto, 2012).

5. Addiction and neuroimaging measures of cerebellar function

The neuroimaging techniques frequently used to measure functional activation are positron emission tomography (PET) and functional MRI (fMRI). PET relies on radiolabelled tracers to localize measures of brain activity. Examples of such tracers include radiolabelled water to measure regional cerebral blood flow (rCBF), and fluorodeoxyglucose (FDG) to measure glucose metabolism. Instead of radioactive tracers, fMRI uses the magnetic properties of oxygenated as compared to deoxygenated hemoglobin to track neural activity. This indirect measure is also referred to as the blood oxygen level dependent (BOLD) signal. Both of these techniques have measured physiological responses in the cerebellum in response to drugs of abuse or drug cues.

6. A model for cerebellar systems in addiction

Given the supporting evidence, the cerebellum's role as a modulator can be readily adapted to existing models of addiction. In the context of neuroimaging, a major conceptual model for addiction is the i-RISA (Impaired Response Inhibition and Salience Attribution) model ( Goldstein & Volkow, 2002, 2011), also described as a four-circuit model ( Volkow et al., 2003; Volkow et al., 2010). Briefly, the model consists of four inter-connected circuits relating to memory, reward/saliency, executive control, and motivation/drive. The response to a reward is mediated by the interactions of these four components.

In the addicted brain, the homeostatic balance is drastically altered, such that the components for memory, reward/saliency, and motivation/drive are amplified, and cognitive control is diminished. Different brain regions have been assigned to each circuit, such as the dorsolateral prefrontal cortex for control and the nucleus accumbens for reward. With the cerebellum's postulated function as a multimodal modulator of cognition, affect, and aversion, the cerebellum is optimally configured to regulate brain processes directly involved in addiction (). This cerebellar model for addiction proposes that the cerebellum plays an influential role in maintaining the homeostatic balance of the four circuits. In the addicted brain, structural gray matter deficits in Lobule VI, VIIb, Crus I, Crus II, and the vermis implicate changes in the cerebellum's ability to interact and communicate with brain regions related to the four circuits.

These brain regions receive inputs from the deep cerebellar nuclei, the main output channels of the cerebellum. From the cerebellar cortex, the dentate and fastigial nuclei receive inputs from the lateral hemisphere and vermis, respectively. Within the dentate nuclei, separate cerebellar output channels have been identified that project to areas related to cognitive (BA 9 and 46 in the dorsolateral prefrontal cortices), skeletomotor (motor and premotor cortices), and oculomotor function (frontal eye fields) ( Middleton & Strick, 2000; Strick et al., 2009). The fastigial nuclei have an output channel that relates to limbic processing, with projections to the hippocampus, amygdala, and the cingulate cortex ( Strick et al., 2009). However, not all of the output channels through the deep cerebellar nuclei have been mapped.

In addiction, decreased inhibition of brain regions such as the hypothalamus, subgenual anterior cingulate, and parahippocampal gyrus would result in a net excitatory effect in brain circuits related to reward/salience, motivational drive, and memory, as well as stress and interoception. Likewise, the reciprocal pathways between brain circuits related to executive control would be disrupted, interfering with the ability of the prefrontal cortex to inhibit unwanted drug seeking behavior. Addiction has conventionally been assumed to impair the cerebellum, but the notion that the cerebellum may serve a more active role has not been thoroughly examined. This model is meant to inspire hypotheses to test the assertion that the cerebellum may or may not have a generative role in addictive processes.

To our knowledge, no prospective lesion or developmental studies in humans have been published to address the potential causal role of the cerebellum in addiction. However, animal models for motivational behavior suggest that lesions to the dentate deep cerebellar nuclei impair the development of reinforcement learning ( Bauer et al., 2011; Thoma et al., 2008). In the human studies presented here, the posterior hemispheres tend to be affected, suggesting that abnormalities in this region are a vulnerability factor for addiction. However, given that only a handful of studies exist for each substance, we were unable to perform a quantitative neuroimaging meta-analysis to investigate whether cause and effect varies across substances.

7. Conclusions

The cerebellum is potentially a key modulator that impacts and is impacted by addiction. Specific structures in the posterior cerebellar hemispheres, such as hemispheric lobule VI and Crus I, are particularly salient as contributing factors. Despite its relatively low profile in the literature, evidence of the cerebellum's involvement in addiction continues to accumulate. While neuroimaging has revealed the cerebellum to be unexpectedly related to addiction, further investigations are needed to directly assess its physiological relevance.

The coalescence of preclinical, neuroimaging, and clinical data suggests that cerebellar alterations both predispose and may play a key role in the course of addictive disorder. The existing models of addiction do not take into account the potential involvement of the cerebellum, yet it may be involved in the opponent vs. proponent effects of addictive drugs, along with incentive sensitization, and aberrant learning mechanisms ( Berridge & Robinson, 2003; Hyman et al., 2006).

If confirmed in clinical studies, our insights could have important implications for prevention and treatment of substance use disorders and behavioral addictions, such as pathological gambling and internet addiction. Specifically, if cerebellar vulnerability factors for addiction could be defined, they might be used to target susceptible individuals for early interventions. On the other hand, abnormalities arising in the context of ongoing addictive disorder may be used for diagnostic purposes and/or for a choice of a proper therapeutic agent in conjunction with monitoring of therapeutic response. The proposed model may also provide important leads for recognition and treatment of reward deficiency syndrome typical of patients with other disorders where cerebellar abnormalities were also noted, including depression, schizophrenia, and post-traumatic stress disorder.

Acknowledgements

This work was supported by the National Institutes of Health (National Institute on Drug Abuse Grant K01DA024289 to E.A.M; National Institute of Neurological Disorders and Stroke Grant K24NS064050 to D.B.; National Institute on Drug Abuse Grants R01DA023579 and R21DA034954 to R.Z.G.).

Footnotes

Conflict of Interest Statement: The authors claim no conflicts of interest.

Author contribution EM and DB conceptualized the review. EM drafted the manuscript. DB, RZ, IE, and LB provided critical revision of the manuscript for important intellectual content. All authors critically reviewed content and approved final version for publication.

References

Manto M. Toxic agents causing cerebellar ataxias. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology. Vol. 103. 2012. pp. 201-213. [[PubMed] Google Scholar]

# data[].attributes.attachment_link.title
The Cerebellum and Addiction: Insights Gained from Neuroimaging Research

# data[].attributes.attachment_link.description
Although cerebellar alterations have been consistently noted in the addiction literature, the pathophysiology of this link remains unclear. The cerebellum is commonly classified as a motor structure, but human functional neuroimaging along with clinical observations in cerebellar stroke patients and anatomical tract tracing in non-human primates suggest its involvement in cognitive and affective processing.