Consensus Paper: Cerebellum and Reward.

Cerebellum is a key-structure for the modulation of motor, cognitive, social and affective functions, contributing to automatic behaviours through interactions with the cerebral cortex, basal ganglia and spinal cord. The predictive mechanisms used by the cerebellum cover not only sensorimotor functions but also reward-related tasks. Cerebellar circuits appear to encode temporal difference error and reward prediction error. From a chemical standpoint, cerebellar catecholamines modulate the rate of cerebellar-based cognitive learning, and mediate cerebellar contributions during complex behaviours. Reward processing and its associated emotions are tuned by the cerebellum which operates as a controller of adaptive homeostatic processes based on interoceptive and exteroceptive inputs. Lobules VI-VII/areas of the vermis are candidate regions for the cortico-subcortical signaling pathways associated with loss aversion and reward sensitivity, together with other nodes of the limbic circuitry. There is growing evidence that the cerebellum works as a hub of regional dysconnectivity across all mood states and that mental disorders involve the cerebellar circuitry, including mood and addiction disorders, and impaired eating behaviors where the cerebellum might be involved in longer time scales of prediction as compared to motor operations. Cerebellar patients exhibit aberrant social behaviour, showing aberrant impulsivity/compulsivity. The cerebellum is a master-piece of reward mechanisms, together with the striatum, ventral tegmental area (VTA) and prefrontal cortex (PFC). Critically, studies on reward processing reinforce our view that a fundamental role of the cerebellum is to construct internal models, perform predictions on the impact of future behaviour and compare what is predicted and what actually occurs.

The Evolution of the Optimization of Cognitive and Social Functions in the Cerebellum and Thereby the Rise of Homo sapiens Through Cumulative Culture.

The evolution of the prominent role of the cerebellum in the development of composite tools, and cumulative culture, leading to the rise of Homo sapiens is examined. Following Stout and Hecht's (2017) detailed description of stone-tool making, eight key repetitive involvements of the cerebellum are highlighted. These key cerebellar learning involvements include the following: (1) optimization of cognitive-social control, (2) prediction (3) focus of attention, (4) automaticity of smoothness, appropriateness, and speed of movement and cognition, (5) refined movement and social cognition, (6) learns models of extended practice, (7) learns models of Theory of Mind (ToM) of teachers, (8) is predominant in acquisition of novel behavior and cognition that accrues from the blending of cerebellar models sent to conscious working memory in the cerebral cortex. Within this context, the evolution of generalization and blending of cerebellar internal models toward optimization of social-cognitive learning is described. It is concluded that (1) repetition of movement and social cognition involving the optimization of internal models in the cerebellum during stone-tool making was the key selection factor toward social-cognitive and technological advancement, (2) observational learning during stone-tool making was the basis for both technological and social-cognitive evolution and, through an optimizing positive feedback loop between the cerebellum and cerebral cortex, the development of cumulative culture occurred, and (3) the generalization and blending of cerebellar internal models related to the unconscious forward control of the optimization of imagined future states in working memory was the most important brain adaptation leading to intertwined advances in stone-tool technology, cognitive-social processes behind cumulative culture (including the emergence of language and art) and, thereby, with the rise of Homo sapiens.

Opsoclonus-Myoclonus-Ataxia Syndrome Due to Covid-19.

Opsoclonus-myoclonus syndrome (OMS) as a rare neurological encephalopathic entity associated with non-specific infections or cancer processes has been repeatedly described in the setting of SARS-CoV-2 infection. We report a case of a 53-year-old man with SARS-CoV-2 infection, who developed clinical features of opsoclonus-myoclonus ataxia syndrome including cognitive impairments with a prolonged course of disease. Of particular note, cerebrospinal fluid (CSF) analysis revealed the production of myelin oligodendrocyte glycoprotein (MOG) antibodies, suggesting an underlying neuroimmunological mechanism associated with infection with the novel SARS-CoV-2 virus.

Introduction into the Role of the Cerebellum in Emotion.

The cerebellum is well known for its contribution to motor performance, but less for its involvement to cognitive and affective processing. The growing interest of clinical and neuroscientific research has resulted in a fascinating focus on the cerebellar mechanisms of emotion. Advances in functional neuroimaging and noninvasive stimulation protocols have successively delineated circumscribed cerebellar areas with its functional and topographic connections to the conventionally predominating cerebral cortex in basic as well as high order emotion processing. This encompasses all information processing stages which include perception and attention, and the evaluation and integration of emotion cues to the trajectories in motor, cognitive, and affective behavior. Not surprisingly, research has identified the cerebellum being part of the brain's network associated with art, morality, and social cognition. This book will provide an overview of the details of these intriguing issues, supporting a contemporary understanding of the fundamental as well as specific features of cerebellar functions within emotion processes.

The Neurophysiology of the Cerebellum in Emotion.

Neuroscientific investigation of the detailed neurophysiology of emotion processing is a rapidly progressing field, which has opened discussion on key findings regarding the timing characteristics of the neuronal networks involved. Study designs incorporating quantitative electroencephalography (EEG) and event-related potentials (ERP) have mapped neuronal representations at various stages of emotion processing, identifying early and late stages corresponding to cerebral activity in attention and in appraisal of emotion. Interestingly, in addition to confirming aspects of cerebral cortex involvement, these investigations have also implicated the cerebellum in emotion processing. This has led to research aimed at distinguishing the contributions of cerebellar and cerebral networks and how these may interrelate. With respect to underlying neurophysiological mechanisms, ERP studies confirm that the cerebellum is involved in both early and late stages of processing of salient emotion cues, and also in capturing emotions in facial expressions. Topological analyses indicate direct connections between the vermis, Crus I, and Crus II areas of the cerebellum and the cerebral area of lateral prefrontal cortex. This suggests a broad evolutionary development of large-scale cerebral networks in emotion. In this chapter, we highlight findings to date of neurophysiological activity related to cerebellar participation in emotion processing. The neurophysiological findings, which by inference represent underlying neural activity, emphasize an integrative role of the cerebellum in emotion.

The Cerebellum and Beauty: The Impact of the Cerebellum in Art Experience and Creativity.

There is growing interest in the cerebellum's contributions to higher order functions of the human brain. When considering specific activities of the human cerebellum related to art, we differentiate two broad areas. Neural activity within different locations of the cerebellum is involved in art perception and in artistic creativity. The cerebellum plays an underappreciated role in neuroaesthetics, including the perception and evaluation of art objects, their appreciation and affective aesthetic experience. Certain areas of the cerebellum presumably are of particular relevance, incorporating cognitive and affective issues within large-scaled neural networks in perceiving and appraising artworks. For art creativity, many investigations report cerebellar implementations. Important areas in these domains are evolutionary younger parts of the cerebellar hemispheres, in particular the lobule VII with its Crus I and II, influencing crucial networks such as the Default Mode Network in optimizing creativity. These structures help guide pattern recognition and in art appreciation as they may play a role in predicting ongoing neural network activities through a crucial frontoparietal axis. In this chapter, we consider how our current neuroscientific understanding of cerebellar functions point to a likely role of the cerebellum in art appreciation and creativity.

Current and Future Perspectives of the Cerebellum in Affective Neuroscience.

The importance of the cerebellum in basic as well as higher order domains of affect processing in the brain has been vividly elaborated and specified by the contributions collected in this book. Indeed, according to increasingly precise research findings in functional neuroimaging and functional neurophysiology, individually delineable areas of the cerebellum play a role in virtually all process levels of the responsible networks of emotion perception, attribution, and experience via a variety of reciprocal connections to the limbic system and distinct areas of the parietal, temporal, and prefrontal cortex. The works in this book identify alternative perspectives in neuroscience research that offer new directions in future investigations. Important aspects will be to pin down the precise cerebellar processes in multiple sensory integration and allocation in cognitive and affective evaluation, and also cognitive-affective as well as motor behavioral responses. In this context, imaging and electrophysiological techniques will highlight the spatial and temporal, and thus the topographic and topological, specificities of the cerebellar areas to the respective networks. In the final chapter, questions and suggestions for future neuroscientific investigations are identified, from whose developments several fields of neurological and psychological disciplines could benefit in order to open up therapeutic avenues for people with cerebellar disorders.

Clinical and neurophysiological patterns of impairments to emotion attention and empathy in multiple sclerosis.

Patients suffering from multiple sclerosis experience various cognitive and affective impairments, resulting in a negative impact on social behavior and personal independence to differing degrees. According to these often clinically subtle but conflicting cognitive-affective impairments, recordings of these socially relevant issues are still of demand to stratifying clinical and social support in a sophisticated way. Therefore, we studied specific cognitive and affective capacities in eleven patients with a predominant relapsing-remitting type of multiple sclerosis by applying paradigms of event-related potentials and a well-selected neuropsychological test protocol. Thus far, distinct cognitive disturbances of executive and attentional domains and the Wechsler Memory Test's four memory indices were found in multiple sclerosis patients. Concerning affective domains, patients showed discrete impairments of affect discrimination and affected naming as proved by specific testing (Tuebinger Affect Battery). Neurophysiologically, event-related potentials recordings in multiple sclerosis patients, were associated with decreased implicit emotion processing to cues of different emotion arousal at the early processing stage depending on attentional capacities and alterations of implicit emotion modulation at late processing stages. These clinical neurophysiological and neuropsychological data were correlated in part to quantitative magnetic resonance imaging brain lesions. Summarizing our data, our data indicate certain neurocognitive and neuroaffective dysfunctions in patients with multiple sclerosis, thus highlighting the validity of sensitive recording of less apparent neurologic disturbances in multiple sclerosis for optimizing the individual care management in patients.

The Cerebellar Cognitive Affective/Schmahmann Syndrome: a Task Force Paper.

Sporadically advocated over the last two centuries, a cerebellar role in cognition and affect has been rigorously established in the past few decades. In the clinical domain, such progress is epitomized by the "cerebellar cognitive affective syndrome" ("CCAS") or "Schmahmann syndrome." Introduced in the late 1990s, CCAS reflects a constellation of cerebellar-induced sequelae, comprising deficits in executive function, visuospatial cognition, emotion-affect, and language, over and above speech. The CCAS thus offers excellent grounds to investigate the functional topography of the cerebellum, and, ultimately, illustrate the precise mechanisms by which the cerebellum modulates cognition and affect. The primary objective of this task force paper is thus to stimulate further research in this area. After providing an up-to-date overview of the fundamental findings on cerebellar neurocognition, the paper substantiates the concept of CCAS with recent evidence from different scientific angles, promotes awareness of the CCAS as a clinical entity, and examines our current insight into the therapeutic options available. The paper finally identifies topics of divergence and outstanding questions for further research.

Comparison of visual and auditory emotion recognition in patients with cerebellar and Parkinson´s disease.

Widespread cortical-subcortical networks are involved in the recognition and discrimination of emotional contents of facial and vocal expression, whereby the cerebellum and basal ganglia are two subcortical regions implicated in these networks with limited evidence to their specific contributions. To investigate this we compared patients with circumscribed cerebellar lesions and patients with Parkinson's disease (PD) on an approved test battery. We studied two groups with subcortical disease, focal cerebellar infarction (n = 22) and PD (n = 22), and a neurological control group with focal supratentorial ischemia (SI) (n = 16) were. Assessments were according to inpatient protocols for neuropsychological routine evaluation, including tests of memory, executive function and attention. Participants completed the Tuebingen Affect Battery, a recognized measure of recognition and discrimination of facial and vocal expression of emotion. As a result, cerebellar lesions were associated with greater impairment than PD and SI in recognition and discrimination of cues of both facial and vocal expressions of differing basic emotions. No confounding effect of other cognitive domains, particularly executive function and attention, was found. Taken together, our findings suggest a specific contribution of the cerebellum to cerebral networks that process facial and vocal emotion expression, related to rapid decisions regulating appropriate behavioral responses in social environments.

Neural correlates of impaired emotional face recognition in cerebellar lesions.

Clinical and neuroimaging data indicate a cerebellar contribution to emotional processing, which may account for affective-behavioral disturbances in patients with cerebellar lesions. We studied the neurophysiology of cerebellar involvement in recognition of emotional facial expression. Participants comprised eight patients with discrete ischemic cerebellar lesions and eight control patients without any cerebrovascular stroke. Event-related potentials (ERP) were used to measure responses to faces from the Karolinska Directed Emotional Faces Database (KDEF), interspersed in a stream of images with salient contents. Images of faces augmented N170 in both groups, but increased late positive potential (LPP) only in control patients without brain lesions. Dipole analysis revealed altered activation patterns for negative emotions in patients with cerebellar lesions, including activation of the left inferior prefrontal area to images of faces showing fear, contralateral to controls. Correlation analysis indicated that lesions of cerebellar area Crus I contribute to ERP deviations. Overall, our results implicate the cerebellum in integrating emotional information at different higher order stages, suggesting distinct cerebellar contributions to the proposed large-scale cerebral network of emotional face recognition.

Age-related increase of VGF-expression in T lymphocytes.

VGF is a protein expressed by neurons and processed into several peptides. It plays a role in energy homeostasis and promotes growth and survival. Recently, VGF mRNA was detected in peripheral leukocytes. Since it is known that aging is associated with a decrease in the development and function of neuronal as well as immune cells, we addressed the question whether a peripheral expression of VGF by CD3+ T cells and CD56+ NK cells is correlated with age. Therefore, the frequency of VGF+CD3+ and VGF+CD56+ cells was determined in mentally healthy volunteers aged between 22 and 88. We found an age-dependent increase in the number of VGF+CD3+ T cells that correlated with HbA1c and the body mass index (BMI). VGF-expression by NK cells was age-independent. Blockade of VGF reduced proliferation and secretion of cytokines such as IL-2, IL-17A, IL-1ß, IL-10 and TNF by CD3+ T cells and PBMCs. Rapamycin-mediated T cell blockade significantly reduced the frequency of VGF-expressing T cells. We conclude that VGF contributes to survival and function of peripheral T cells. The age-dependent increase in VGF-expression could serve as mechanism that counterregulates the decrease in functionality of T lymphocytes.

Consensus paper: Language and the cerebellum: an ongoing enigma.

In less than three decades, the concept "cerebellar neurocognition" has evolved from a mere afterthought to an entirely new and multifaceted area of neuroscientific research. A close interplay between three main strands of contemporary neuroscience induced a substantial modification of the traditional view of the cerebellum as a mere coordinator of autonomic and somatic motor functions. Indeed, the wealth of current evidence derived from detailed neuroanatomical investigations, functional neuroimaging studies with healthy subjects and patients and in-depth neuropsychological assessment of patients with cerebellar disorders shows that the cerebellum has a cardinal role to play in affective regulation, cognitive processing, and linguistic function. Although considerable progress has been made in models of cerebellar function, controversy remains regarding the exact role of the "linguistic cerebellum" in a broad variety of nonmotor language processes. This consensus paper brings together a range of different viewpoints and opinions regarding the contribution of the cerebellum to language function. Recent developments and insights in the nonmotor modulatory role of the cerebellum in language and some related disorders will be discussed. The role of the cerebellum in speech and language perception, in motor speech planning including apraxia of speech, in verbal working memory, in phonological and semantic verbal fluency, in syntax processing, in the dynamics of language production, in reading and in writing will be addressed. In addition, the functional topography of the linguistic cerebellum and the contribution of the deep nuclei to linguistic function will be briefly discussed. As such, a framework for debate and discussion will be offered in this consensus paper.

Altered EEG lagged coherence during rest in obsessive-compulsive disorder.

OBJECTIVE: Functional magnetic resonance imaging (fMRI) studies found alterations of functional connectivity in obsessive compulsive disorder (OCD). However, there is little knowledge about region of interest (ROI) based electroencephalogram (EEG) connectivity, i.e. lagged non-linear and linear coherence in OCD. Goal of this study was to compare these EEG measures during rest and at different vigilance stages between patients and healthy controls (HC). METHODS: A 15 min resting-state EEG was recorded in 30 unmedicated patients and 30 matched HC. Intracortical lagged non-linear coherence of the main EEG-frequency bands within a set of frontal ROIs and within the default mode network (DMN) were computed and compared using intracortical exact low resolution electromagnetic tomography (eLORETA) software. RESULTS: Lagged non-linear but not linear coherence was significantly decreased for patients in comparison to HC for the beta 2 frequency between frontal brain areas but not within the DMN. When analysing separate EEG-vigilance stages, only high vigilance stages yielded decreased frontal phase synchronisation at beta and theta frequencies. CONCLUSIONS: The results underline an altered neuronal communication within frontal brain areas during rest in OCD. SIGNIFICANCE: These findings encourage further research on connectivity measures as possible biomarkers for physiological homogeneous subgroups.

EEG-vigilance regulation during the resting state in obsessive-compulsive disorder.

OBJECTIVE: Obsessive compulsive disorder (OCD) has been associated with disturbed sleep-wake cycles and cortical hypermetabolism. However, it still remains unclear whether OCD is associated with a dysregulation of vigilance (i.e. "brain arousal"). VIGALL (Vigilance Algorithm Leipzig) is an EEG-based tool to assess vigilance dynamics. Aim of this study is to test the hypothesis that during resting state less declines to lower vigilance stages are found in unmedicated patients with OCD (n=30) compared to healthy controls (HCs, n=30). METHODS: Fifteen minutes of resting EEG were recorded; preceding sleep duration, nicotine/caffeine consumption and severity of OCD and depressive symptoms were assessed. RESULTS: Significant differences of EEG-vigilance were found for the factor "group" (OCD vs. HC), factor "time" and interaction "group×time" in a repeated measures ANOVA with increased EEG-vigilance in OCD patients. OCD patients showed significantly fewer transitions between EEG-vigilance stages. CONCLUSIONS: In line with findings of disturbed sleep regulation, OCD is associated with altered EEG-vigilance regulation with a failure of declining toward low vigilance stages during rest. SIGNIFICANCE: These results encourage the use of EEG-vigilance regulation for determining subgroups for e.g. studying treatment response and suggest awareness for possible vigilance effects in neuroimaging studies of OCD.

Stress, depression and antidepressant treatment options in patients suffering from multiple sclerosis.

Stress constitutes a risk factor for diseases where the immune system plays a significant role. Stress is recognized as a possible trigger for flare ups during the course of multiple sclerosis (MS). The disclosure to the patient of the diagnosis of MS, the commencement of immunomodulatory therapy, and the unpredictability and vagaries of disease progression are all sources of stress. Biological stress systems such as the hypothalamic-pituitary-adrenal system and the sympathetic nervous system may influence the pathogenesis and the disease course of MS. The ability to cope with stress may also be impaired, mediated for example by cognitive deficits or loss of abilities and resources as disease progresses or by the high prevalence of concurrent mood disturbances such as depression and chronic fatigue. Psychiatric comorbidities of MS disease or therapy as well as impairments of coping strategies are underrecognized in clinical practice. Treatment plans for depression among MS patients, as the most common psychiatric comorbidity, should be individualized with integrated approaches. Antidepressants are effective for the treatment of depression in MS patients although further clinical research into the neurobiological and psychological bases of depressive disorders in MS patients is clearly needed. In therapy, coping strategies can be enhanced through multidisciplinary assessment of the various challenges and restrictions imposed by the disease and assisting and supporting the patient in addressing these. Exercise, as a form of positive stress (eustress), also has a role in therapy.

The 5-HT1A-receptor agonist flibanserin reduces drug-induced dyskinesia in RGS9-deficient mice.

Drug-induced dyskinesia is a major complication of dopamine replacement therapy in advanced Parkinson's disease consisting of dystonia, chorea and athetosis. Agonists at 5-HT1A-receptors attenuate levodopa-induced motor complications in non-human primates. Mice with increased dopamine D2 receptor (DRD2) signalling due to the lack of expression of the regulator of G-protein signalling 9 (RGS9) also develop dyskinesia following levodopa treatment. We investigated whether the 5-HT1A-receptor agonist flibanserin compared with buspirone reduces motor abnormalities induced by levodopa or quinelorane, a selective dopamine D2-receptor agonist. Following dopamine depletion via reserpine, 40 mice (20 wild-type and 20 RGS9 knock-out) were treated with flibanserin or buspirone in combination with levodopa or quinelorane. Motor behaviour was analysed using open field analysis. RGS9 knock-out mice displayed significantly more drug-induced dystonia (p < 0.04; t test) than wild type. In quinelorane-treated wild-type mice flibanserin as well as buspirone significantly reduced dystonia (p < 0.05). In RGS9 knock-out animals again both reduced quinelorane-induced dystonia. However, flibanserin was significantly more effective (p = 0.003). Following reserpine pretreatment and administration of levodopa wild-type and RGS 9 knock-out mice showed mild to moderate dystonia. Surprisingly, 10 mg/kg buspirone increased dystonia in both animal groups, whereas it was decreased by 10 mg/kg flibanserin. However, compared with levodopa alone only the increase of dystonia by buspirone was significant (p < 0.04). Flibanserin showed promising antidyskinetic effects in a model of drug-induced dyskinesia. Our data underline the possible benefit of 5-HT1A agonists in drug-induced dyskinesia.

The diagnostic value of clinical EEG in detecting abnormal synchronicity in panic disorder.

Electroencephalographic (EEG) findings repeatedly reported abnormal synchronous or even epileptiform discharges in panic disorder. Although less frequently occurring in patients with panic disorder, these deviant EEG features during panic attacks were also observed in intracranial EEG. For this purpose, our article reviews the consideration of abnormal synchronous neuronal activity in different neurocircuits, particularly limbic, as a suggested condition of panic attacks. Therapeutic approaches of anticonvulsants have shown reductions of symptoms and frequency of attacks in numerous patients suffering from panic disorder, supporting the presumption of underlying abnormal synchronous neuronal activity. Thus, scalp EEG recordings are still recommended for discovering indications of abnormal synchronous neuronal activity in panic patients.

[The risk for myocarditis of clozapine and other atypical antipsychotics: case report and study of the literature]. / Das Myokarditisrisiko einer Clozapin-Therapie und bei anderen atypischen Antipsychotika.

OBJECTIVE: Clozapine is considered as a strong psychopharmaceutic agent in symptom control of psychotic disturbances. However, possible side effects to hematologic, metabolic and cardiologic systems are still entailing a defensive application in psychiatric praxis. METHODS: A patient suffering from schizoaffective disorder clinically developed symptoms of cardial disturbances under the psychopharmacotherapy of Clozapine. Specific laboratory analysis and technical procedures were applied, clarifying the background of this serious event. RESULTS: ECG and specific myocardial enzymes (CK, Troponine-I) requesting an acute myocardial infarction were negative. Specific laboratory analysis revealed positive inflammation markers with elevated C-reactive protein and interleukin-6. Additionally, there was increasing of TNF-alpha and C3 as well as an eosinophilia at differential blood cell count. Echocardiography found an unspecific dyskinesia of the left ventricle, but contrast-enhanced cardial MRI showed structural intramyocardial inhomogeneities suggesting a myocarditis. CONCLUSIONS: In spite of the striking psycho-pharmacotherapeutic benefit, Clozapine may be associated with serious cardial events. We discuss these cardiological problems in association to a Clozapine therapy in regard to its clinical relevance in treatment of psychotic disturbances.

Evidence of neurotoxicity of ecstasy: sustained effects on electroencephalographic activity in polydrug users.

OBJECTIVE: According to previous EEG reports of indicative disturbances in Alpha and Beta activities, a systematic search for distinct EEG abnormalities in a broader population of Ecstasy users may especially corroborate the presumed specific neurotoxicity of Ecstasy in humans. METHODS: 105 poly-drug consumers with former Ecstasy use and 41 persons with comparable drug history without Ecstasy use, and 11 drug naives were investigated for EEG features. Conventional EEG derivations of 19 electrodes according to the 10-20-system were conducted. Besides standard EEG bands, quantitative EEG analyses of 1-Hz-subdivided power ranges of Alpha, Theta and Beta bands have been considered. RESULTS: Ecstasy users with medium and high cumulative Ecstasy doses revealed an increase in Theta and lower Alpha activities, significant increases in Beta activities, and a reduction of background activity. Ecstasy users with low cumulative Ecstasy doses showed a significant Alpha activity at 11 Hz. Interestingly, the spectral power of low frequencies in medium and high Ecstasy users was already significantly increased in the early phase of EEG recording. Statistical analyses suggested the main effect of Ecstasy to EEG results. CONCLUSIONS: Our data from a major sample of Ecstasy users support previous data revealing alterations of EEG frequency spectrum due rather to neurotoxic effects of Ecstasy on serotonergic systems in more detail. Accordingly, our data may be in line with the observation of attentional and memory impairments in Ecstasy users with moderate to high misuse. Despite the methodological problem of polydrug use also in our approach, our EEG results may be indicative of the neuropathophysiological background of the reported memory and attentional deficits in Ecstasy abusers. Overall, our findings may suggest the usefulness of EEG in diagnostic approaches in assessing neurotoxic sequela of this common drug abuse.