Neurodevelopmental trajectories of cerebellar grey matter associated with verbal abilities in males with autism spectrum disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental condition frequently associated with structural cerebellar abnormalities. Whether cerebellar grey matter volumes (GMV) are linked to verbal impairments remains controversial. Here, the association between cerebellar GMV and verbal abilities in ASD was examined across the lifespan. Lobular segmentation of the cerebellum was performed on structural MRI scans from the ABIDE I dataset in male individuals with ASD (N=144, age: 8.5-64.0 years) and neurotypical controls (N=188; age: 8.0-56.2 years). Stepwise linear mixed effects modeling including group (ASD vs. neurotypical controls), lobule-wise GMV, and age was performed to identify cerebellar lobules which best predicted verbal abilities as measured by verbal IQ (VIQ). An age-specific association between VIQ and GMV of bilateral Crus II was found in ASD relative to neurotypical controls. In children with ASD, higher VIQ was associated with larger GMV of left Crus II but smaller GMV of right Crus II. By contrast, in adults with ASD, higher VIQ was associated with smaller GMV of left Crus II and larger GMV of right Crus II. These findings indicate that relative to the contralateral hemisphere, an initial reliance on the language-nonspecific left cerebellar hemisphere is offset by more typical right-lateralization in adulthood.

Electrophysiological correlates of (mis)judging social information.

Social information can be used to optimize decision-making. However, the simultaneous presentation of multiple sources of advice can lead to a distinction bias in judging the validity of the information. While the involvement of event-related potential (ERP) components in social information processing has been studied, how they are modulated by (mis)judging an advisor's information validity remains unknown. In two experiments participants performed a decision-making task with highly accurate or inaccurate cues. Each experiment consisted of an initial, learning, and test phase. During the learning phase, three advice cues were simultaneously presented and the validity of them had to be assessed. The effect of different cue constellations on ERPs was investigated. In the subsequent test phase, the willingness to follow or oppose an advice cue was tested. Results demonstrated the distinction bias with participants over or underestimating the accuracy of the most uncertain cues. The P2 amplitude was significantly increased during cue presentation when advisors were in disagreement as compared to when all were in agreement, regardless of cue validity. Further, a larger P3 amplitude during outcome presentation was found when advisors were in disagreement and increased with more informative cues. As such, the most uncertain cues were related to the smallest P3 amplitude. The findings hint at the possible role of P3 in judging and learning the predictability of social cues. This study provides novel insights into the role of P2 and P3 components during the judgment of social information validity.

Doubling down on dual systems: A cerebellum-amygdala route towards action- and outcome-based social and affective behavior.

The amygdala and cerebellum are both evolutionary preserved brain structures containing cortical as well as subcortical properties. For decades, the amygdala has been considered the fear-center of the brain, but recent advances have shown that the amygdala acts as a critical hub between cortical and subcortical systems and shapes social and affective behaviors beyond fear. Likewise, the cerebellum is a dedicated control unit that fine-tunes motor behavior to fit contextual requirements. There is however increasing evidence that the cerebellum strongly influences subcortical as well as cortical processes beyond the motor domain. These insights broadened the view on the cerebellum's functions to also include social and affective behavior. Here we explore how the amygdala and cerebellum might interact in shaping social and affective behaviors based on their roles in threat reactivity and reinforcement learning. A novel mechanistic neural framework of cerebellum-amygdala interactions will be presented which provides testable hypotheses for future social and affective neuroscientific research in humans.

Cerebellar Asymmetry of Motivational Direction: Anger-Dependent Effects of Cerebellar Transcranial Direct Current Stimulation on Aggression in Healthy Volunteers.

It has recently been theorized that the frontal asymmetry of approach- and avoidance-related motivation is mirrored in the posterolateral cerebellum. Accordingly, left-to-right dominant cerebellar activity is associated with avoidance-related motivation, whereas right-to-left dominant cerebellar activity is associated with approach-related motivation. The aim of this study was to examine the cerebellar asymmetry of motivational direction in approach-related behavior in the context of aggression. In this randomized double-blind sham-controlled crossover study, thirty healthy right-handed adult volunteers received 2 mA active or sham left cathodal-right anodal transcranial direct current stimulation (tDCS) to the cerebellum on two separate occasions while engaging in the Point Subtraction Aggression Paradigm (PSAP) task to measure aggressive behavior. Self-reported state anger was assessed before, halfway and immediately after the task, and heart rate and heart rate variability (HRV) were measured during the task. No main effects of tDCS on aggressive behavior, heart rate and HRV were found. Higher state anger before and during the PSAP task was associated with increased aggressive behavior in the active compared to sham tDCS condition. Aggressive behavior was positively correlated with heart rate during active tDCS, while an inverse association was observed during sham tDCS. Results provide support for the cerebellar asymmetry of motivational direction in approach-related behavior and illustrate the importance of affective state-dependency in tDCS-related effects.

Cognitive Complaints and Their Impact on Daily Life in Patients with Degenerative Cerebellar Disorders.

Cognitive and affective sequelae of cerebellar disease are receiving increased attention, but their actual rate of occurrence remains unclear. Complaints may have a significant impact on patients, affecting social behavior and psychological well-being. This study aims to explore the extent of subjective cognitive and affective symptoms in patients with degenerative ataxias in the Netherlands. An explorative study was set up in a heterogeneous group of degenerative ataxia patients. Self-reported cognition was evaluated in terms of executive functioning and affect (Dysexecutive Questionnaire/DEX), and memory/attention (Cognitive Failures Questionnaire/CFQ). The Daily Living Questionnaire (DLQ) was administered to quantify the impact on daily life. Furthermore, informants completed questionnaires to obtain insight into patients' self-awareness and social cognition (Observable Social Cognition Rating Scale/OSCARS). This study shows that subjective complaints in the domains of (1) executive functioning and/or (2) memory and attention were reported by 29% of all patients (n = 24/84). In addition, more difficulties in daily life in terms of language/comprehension and community/participation were reported, and this was more common for patients with cognitive complaints than those without. Discrepancies between patients and informants about executive functioning were present in both directions. Deficits in social cognition were not identified at the group level, but more social-cognitive problems were observed in patients with more executive problems rated by informants. Taken together, our findings indicate that cognitive complaints are common in patients with degenerative cerebellar disorders and have an impact on daily life functioning. These results may help to increase awareness of cognitive symptoms and their impact in patients with cerebellar ataxia, their significant others, and professional caregivers.

Mind matters: A narrative review on affective state-dependency in non-invasive brain stimulation

Variability in findings related to non-invasive brain stimulation (NIBS) have increasingly been described as a result of differences in neurophysiological state. Additionally, there is some evidence suggesting that individual differences in psychological states may correlate with the magnitude and directionality of effects of NIBS on the neural and behavioural level. In this narrative review, it is proposed that the assessment of baseline affective states can quantify non-reductive properties which are not readily accessible to neuroscientific methods. Particularly, affective-related states are theorized to correlate with physiological, behavioural and phenomenological effects of NIBS. While further systematic research is needed, baseline psychological states are suggested to provide a complementary cost-effective source of information for understanding variability in NIBS outcomes. Implementing measures of psychological state may potentially contribute to increasing the sensitivity and specificity of results in experimental and clinical NIBS studies. (AU)

Interindividual differences in posterior fossa morphometry affect cerebellar tDCS-induced electric field strength.

OBJECTIVE: Clinical, behavioural, and neurophysiological effects of cerebellar transcranial direct current stimulation (tDCS) are highly variable and difficult to predict. We aimed to examine associations between cerebellar tDCS-induced electric field strength, morphometric posterior fossa parameters, and skin-cerebellum distance. As a secondary objective, field characteristics were compared between cephalic and extracephalic electrode configurations. METHODS: Electric field simulations of midline cerebellar tDCS (7 × 5 cm electrodes, current intensities of 2 mA) were performed on MRI-based head models from 37 healthy adults using buccinator, frontopolar, and lower neck reference electrodes. Average field strengths were determined in eight regions of interest (ROIs) covering the anterior and posterior vermis and cerebellar hemispheres. Besides skin-cerebellum distance, various angles were measured between posterior fossa structures. Multivariable linear regression models were used to identify predictors of field strength in different ROIs. RESULTS: Skin-cerebellum distance and "pons angle" were independently associated with field strength in the anterior and posterior vermis. "Cerebellar angle" and skin-cerebellum distance affected field strength in anterior and posterior regions of the right cerebellar hemisphere. Field strengths in all examined cerebellar areas were highest in the frontopolar and lowest in the lower neck montage, while the opposite was found for field focality. The lower neck montage induced considerably less spreading toward anterior cerebellar regions compared with the buccinator and frontopolar montages, which resulted in a more evenly distributed field within the cerebellum. CONCLUSION: In addition to skin-cerebellum distance, interindividual differences in posterior fossa morphometry, specifically pons and cerebellar angle, explain part of the variability in cerebellar tDCS-induced electric field strength. Furthermore, when targeting the midline cerebellum with tDCS, an extracephalic reference electrode is associated with lower field strengths and higher field focality than cephalic montages. SIGNIFICANCE: This study identifies two novel subject-specific anatomical factors that partly determine cerebellar tDCS-induced electric field strength and reveals differences in field characteristics between electrode montages.

The human cerebellum in reward anticipation and outcome processing: An activation likelihood estimation meta-analysis.

The cerebellum generates internal prediction models and actively compares anticipated and actual outcomes in order to reach a desired end state. In this process, reward can serve as a reinforcer that shapes internal prediction models, enabling context-appropriate behavior. While the involvement of the cerebellum in reward processing has been established in animals, there is no detailed account of which cerebellar regions are involved in reward anticipation and outcome processing in humans. To this end, an activation likelihood estimation meta-analysis of functional neuroimaging studies was performed to investigate cerebellar functional activity patterns associated with reward anticipation and outcome processing in healthy adults. Results showed that reward anticipation (k = 31) was associated with regional activity in the bilateral anterior lobe, bilateral lobule VI, left Crus I and the posterior vermis, while reward outcome (k = 16) was associated with regional activity in the declive and left lobule VI. These findings demonstrate distinct involvement of the cerebellum in reward anticipation and outcome processing as part of a predictive coding routine.

Moral Thinking and Empathy in Cognitive Behavioral Therapy for Children and Adolescents with Conduct Problems: A Narrative Review.

Cognitive behavioral therapy (CBT) for conduct problems in children and adolescents aims to decrease behaviors which may be considered moral transgressions (e.g., aggressive and antisocial behavior) and to increase behaviors that benefit others (e.g., helping, comforting). However, the moral aspects underlying these behaviors have received relatively little attention. In view of increasing the effectiveness of CBT for conduct problems, insights into morality and empathy based on studies from developmental psychology and cognitive neuroscience are reviewed and integrated into a previously proposed model of social problem-solving (Matthys & Schutter, Clin Child Fam Psychol Rev 25:552-572, 2022). Specifically, this narrative review discusses developmental psychology studies on normative beliefs in support of aggression and antisocial behavior, clarification of goals, and empathy. These studies are complemented by cognitive neuroscience research on harm perception and moral thinking, harm perception and empathy, others' beliefs and intentions, and response outcome learning and decision-making. A functional integration of moral thinking and empathy into social problem-solving in group CBT may contribute to the acceptance of morality-related issues by children and adolescents with conduct problems.

Mind matters: A narrative review on affective state-dependency in non-invasive brain stimulation.

Variability in findings related to non-invasive brain stimulation (NIBS) have increasingly been described as a result of differences in neurophysiological state. Additionally, there is some evidence suggesting that individual differences in psychological states may correlate with the magnitude and directionality of effects of NIBS on the neural and behavioural level. In this narrative review, it is proposed that the assessment of baseline affective states can quantify non-reductive properties which are not readily accessible to neuroscientific methods. Particularly, affective-related states are theorized to correlate with physiological, behavioural and phenomenological effects of NIBS. While further systematic research is needed, baseline psychological states are suggested to provide a complementary cost-effective source of information for understanding variability in NIBS outcomes. Implementing measures of psychological state may potentially contribute to increasing the sensitivity and specificity of results in experimental and clinical NIBS studies.

Cerebellar Grey Matter Volumes in Reactive Aggression and Impulsivity in Healthy Volunteers.

Several lines of evidence point towards the involvement of the cerebellum in reactive aggression. In addition to the posterior cerebellar hemisphere, the vermis has been suggested to play a prominent role in impulse regulation. In the present study, we set out to further examine the relationships between cerebellar grey matter volumes, aggression, and impulsivity in 201 healthy volunteers. 3 T structural magnetic resonance imaging scans were acquired to investigate grey matter volumes of the cerebellar vermis and the anterior and posterior lobules. Aggression was assessed with the Buss-Perry Aggression Questionnaire and impulsivity was measured with the Barratt Impulsiveness Scale-11. Results showed that impulsivity was positively associated with grey matter volumes of the cerebellar vermis and inversely correlated with grey matter volumes of the right posterior lobule. In addition, smaller volumes of the right posterior lobules were associated with higher physical aggression. Exploratory analyses indicated that for the right hemisphere, this association was driven by grey matter volumes of lobules VIIb and VIIIa. Our findings provide correlational evidence in healthy volunteers for the involvement of the cerebellar vermis and posterior lobules in a cortico-limbic-cerebellar circuit of aggression.

Effects of Multisession Transcranial Direct Current Stimulation on Stress Regulation and Emotional Working Memory: A Randomized Controlled Trial in Healthy Military Personnel.

OBJECTIVES: Top-down stress regulation, important for military operational performance and mental health, involves emotional working memory and the dorsolateral prefrontal cortex (DLPFC). Multisession transcranial direct current stimulation (tDCS) applied over the DLPFC during working memory training has been shown to improve working memory performance. This study tested the hypothesis that combined tDCS with working memory training also improves top-down stress regulation. However, tDCS response differs between individuals. Resting-state electrophysiological brain activity was post hoc explored as a possible predictor of tDCS response. The predictive value of the ratio between slow-wave theta oscillations and fast-wave beta oscillations (theta/beta ratio) was examined, together with the previously identified tDCS response predictors age, education, and baseline working memory performance. MATERIALS AND METHODS: Healthy military service members (n = 79) underwent three sessions of real or sham tDCS over the right DLPFC (anode: F4, cathode: behind C2) at 2 mA for 20 minutes during emotional working memory training (N-back task). At baseline and within a week after the tDCS training sessions, stress regulation was assessed by fear-potentiated startle responses and subjective fear in a threat-of-shock paradigm with instructed emotional downregulation. Results were analyzed in generalized linear mixed-effects models. RESULTS: Threat-of-shock responses and emotional working memory performance showed no significant group-level effects of the real vs sham tDCS training intervention (p > 0.07). In contrast, when considering baseline theta/beta ratios or the other tDCS response predictors, exploratory results showed a trait-dependent beneficial effect of tDCS on emotional working memory training performance during the first session (p < 0.01). CONCLUSIONS: No evidence was found for effectivity of the tDCS training intervention to improve stress regulation in healthy military personnel. The emotional working memory training results emphasize the importance of studying the effects of tDCS in relation to individual differences. CLINICAL TRIAL REGISTRATION: This study was preregistered on September 16, 2019, at the Netherlands Trial Register (www.trialregister.nl) with ID: NL8028.

A Comparative Perspective on the Cerebello-Cerebral System and Its Link to Cognition.

The longstanding idea that the cerebral cortex is the main neural correlate of human cognition can be elaborated by comparative analyses along the vertebrate phylogenetic tree that support the view that the cerebello-cerebral system is suited to support non-motor functions more generally. In humans, diverse accounts have illustrated cerebellar involvement in cognitive functions. Although the neocortex, and its transmodal association cortices such as the prefrontal cortex, have become disproportionately large over primate evolution specifically, human neocortical volume does not appear to be exceptional relative to the variability within primates. Rather, several lines of evidence indicate that the exceptional volumetric increase of the lateral cerebellum in conjunction with its connectivity with the cerebral cortical system may be linked to non-motor functions and mental operation in primates. This idea is supported by diverging cerebello-cerebral adaptations that potentially coevolve with cognitive abilities across other vertebrates such as dolphins, parrots, and elephants. Modular adaptations upon the vertebrate cerebello-cerebral system may thus help better understand the neuroevolutionary trajectory of the primate brain and its relation to cognition in humans. Lateral cerebellar lobules crura I-II and their reciprocal connections to the cerebral cortical association areas appear to have substantially expanded in great apes, and humans. This, along with the notable increase in the ventral portions of the dentate nucleus and a shift to increased relative prefrontal-cerebellar connectivity, suggests that modular cerebellar adaptations support cognitive functions in humans. In sum, we show how comparative neuroscience provides new avenues to broaden our understanding of cerebellar and cerebello-cerebral functions in the context of cognition.

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.

Non-invasive Brain Stimulation of the Cerebellum in Emotion.

Transcranial magnetic and direct current stimulation are non-invasive brain stimulation techniques that are used to investigate cerebellar functions in healthy and clinical populations. These approaches allow transient modulation of neural excitability of the human cerebellar cortex to directly examine phenomenological, behavioral, and physiological aspects of motivation and emotion. While cerebellar neurostimulation in the field of social and affective neuroscience is still in its initial phase, empirical evidence confirms the direct involvement of the cerebellum in motivation and emotion. Non-invasive stimulation of the cerebellum provides a unique experimental approach to study the relation between the cerebellum and emotions in humans.

The Cerebellum and Disorders of Emotion.

Neuropsychological and experimental brain research have provided independent lines of evidence in support of cerebellar involvement in disorders of emotion. Medial cerebellar structures and their connections to the limbic system are involved in visceral aspects and the generation of emotions, whereas the posterolateral cerebello-thalamo-cortical loops are implicated in emotion regulation and subjective sense of control. Disturbances within these cerebellar-centred circuits are proposed to underlie homeostatic dysregulation and suboptimal predictive coding that provide a transdiagnostic mechanism by which the cerebellum may contribute to the vulnerability and persistence of mental disorders.

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.

Assessing corticospinal excitability and reaching hand choice during whole body motion.

Behavioral studies have shown that humans account for inertial acceleration in their decisions of hand choice when reaching during body motion. Physiologically, it is unclear at what stage of movement preparation information about body motion is integrated with the process of hand selection. Here, we addressed this question by applying transcranial magnetic stimulation over left motor cortex (M1) of human participants who performed a preferential reach task while they were sinusoidally translated on a linear motion platform. If M1 only represents a read-out of the final hand choice, we expect the body motion not to affect the motor-evoked potential (MEP) amplitude. If body motion biases the hand selection process before target onset, we expect corticospinal excitability to be influenced by the phase of the motion, with larger MEP amplitudes for phases that show a bias to using the right hand. Behavioral results replicate our earlier findings of a sinusoidal modulation of hand choice bias with motion phase. MEP amplitudes also show a sinusoidal modulation with motion phase, suggesting that body motion influences corticospinal excitability, which may ultimately reflect changes of hand preference. The modulation being present before target onset suggests that competition between hands is represented throughout the corticospinal tract. Its phase relationship with the motion profile indicates that other processes after target onset take up time until the hand selection process has been completely resolved, and the reach is initiated.NEW & NOTEWORTHY Full body-motion biases decisions of hand choice. We examined the signatures of this bias in hand preference in corticospinal excitability before a reach target was presented. Our results show that behavior and corticospinal excitability modulate depending on the state of the body in motion. This suggests that information about body motion penetrates deeply within the motor system.

Cerebellar Transcranial Direct Current Stimulation in Spinocerebellar Ataxia Type 3: a Randomized, Double-Blind, Sham-Controlled Trial.

Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement.