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.

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.

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)

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.

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.

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.

Cerebellar tDCS does not modulate language processing performance in healthy individuals.

Clinical and neuroscientific studies have established that the cerebellum contributes to language processing. Yet most evidence is correlational and the exact role of the cerebellum remains unclear. The aim of this study was to investigate the role of the right cerebellum in language comprehension and production using non-invasive brain stimulation. In this double-blind, sham-controlled experiment, thirty-six healthy participants received anodal or sham transcranial direct current (tDCS) stimulation to the right cerebellum while performing a lexical decision, sentence comprehension, verbal fluency and a non-language control task. Active tDCS did not modulate performance in any of the tasks. Additional exploratory analyses suggest difficulty-specific performance modulation in the sentence comprehension and lexical decision task, with tDCS improving performance in easy trials of the sentence comprehension task and difficult trials in the lexical decision task. Overall, our findings provide no evidence for the involvement of the right posterior cerebellum in language processing. Further research is needed to dissociate the influence of task difficulty of the underlying cognitive processes.

A Brief History of Cerebellar Neurostimulation.

The first attempts at using electric stimulation to study human brain functions followed the experiments of Luigi Galvani and Giovanni Aldini on animal electricity during the eighteenth century. Since then, the cerebellum has been among the areas that have been studied by invasive and non-invasive forms of electrical and magnetic stimulation. During the nineteenth century, animal experiments were conducted to map the motor-related regions of cerebellar cortex by means of direct electric stimulation. As electric stimulation research on the cerebellum moved into the twentieth century, systematic research of electric cerebellar stimulation led to a better understanding of its effects and mechanism of action. In addition, the clinical potential of cerebellar stimulation in the treatment of motor diseases started to be explored. With the introduction of transcranial electric and magnetic stimulation, cerebellar research moved to non-invasive techniques. During the twenty-first century, following on groundbreaking research that linked the cerebellum to non-motor functions, non-invasive techniques have facilitated research into different aspects of cerebellar functioning. The present review provides a brief historical account of cerebellar neurostimulation and discusses current challenges and future direction in this field of research.

Electrode montage-dependent intracranial variability in electric fields induced by cerebellar transcranial direct current stimulation.

Transcranial direct current stimulation (tDCS) is an increasingly popular tool to investigate the involvement of the cerebellum in a variety of brain functions and pathologies. However, heterogeneity and small effect sizes remain a common issue. One potential cause may be interindividual variability of the electric fields induced by tDCS. Here, we compared electric field distributions and directions between two conventionally used electrode montages (i.e., one placing the return electrode over the ipsilateral buccinator muscle and one placing the return electrode [25 and 35 cm2 surface area, respectively] over the contralateral supraorbital area; Experiment 1) and six alternative montages (electrode size: 9 cm2; Experiment 2) targeting the right posterior cerebellar hemisphere at 2 mA. Interindividual and montage differences in the achieved maximum field strength, focality, and direction of current flow were evaluated in 20 head models and the effects of individual differences in scalp-cortex distance were examined. Results showed that while maximum field strength was comparable for all montages, focality was substantially improved for the alternative montages over inferior occipital positions. Our findings suggest that compared to several conventional montages extracerebellar electric fields are significantly reduced by placing smaller electrodes in closer vicinity of the targeted area.

Functional topography of anger and aggression in the human cerebellum.

New insights into the functional neuroanatomic correlates of emotions point toward the involvement of the cerebellum in anger and aggression. To identify cerebellar regions commonly activated in tasks examining the experience of anger and threat as well as exerting an aggressive response, two coordinate-based activation likelihood estimation meta-analyses reporting a total of 57 cerebellar activation foci from 819 participants were performed. For anger processing (18 studies), results showed significant clusters in the bilateral posterior cerebellum, overlapping with results from previous meta-analyses on emotion processing, and implying functional connectivity to cognitive, limbic, and social canonic networks in the cerebral cortex. By contrast, active aggression expression (10 studies) was associated with significant clusters in more anterior regions of the cerebellum, overlapping with cerebellar somatosensory and motor regions and displaying functional connectivity with the somatomotor and default mode network. This study not only strengthens the notion that the cerebellum is involved in emotion processing, but also provides the first quantitative evidence for distinct cerebellar functional activation patterns related to anger and aggression.

Failure to Improve Verbal Fluency with Transcranial Direct Current Stimulation.

Previous studies in healthy populations have provided equivocal evidence whether the application of anodal transcranial direct current stimulation (tDCS) over the left prefrontal cortex (PFC) can improve performance in verbal fluency tasks. In this double-blind, randomised within-participant study, we investigated whether anodal tDCS over the left PFC improves verbal fluency performance relative to sham tDCS. Forty eight healthy native German speakers performed two verbal fluency tasks after having received 20 min of anodal or sham tDCS over the left PFC. During stimulation, participants performed a picture naming task, which was expected to increase neuronal activity in the targeted region. We found no modulation of verbal fluency performance following anodal tDCS, with virtually identical overall scores across tDCS conditions. Furthermore, initiation time (i.e., time to produce the first correct utterance) was not affected by tDCS. As an unexpected finding, picture naming latencies were significantly longer during anodal compared to sham tDCS. Yet, changes in the naming task were not predictive of performance changes in the fluency task. Overall, the current study found no evidence that verbal fluency performance in healthy speakers could be improved by excitatory stimulation of the left PFC. We argue that previously observed positive effects could be false positives and should be interpreted with caution. The findings from the current study thus cast further doubt on the utility of tDCS in enhancing cognitive performance in the healthy (young) brain.

Perturbation of the right prefrontal cortex disrupts interference control.

Resolving cognitive interference is central for successful everyday cognition and behavior. The Stroop task is a classical measure of cognitive interference. In this task, participants have to resolve interference on a trial-by-trial basis and performance is also influenced by the trial history, as reflected in sequence effects. Previous neuroimaging studies have associated the left and right prefrontal cortex with successful performance in the Stroop task. Yet, the causal relevance of both regions for interference processing remains largely unclear. We probed the functional relevance of the left and right prefrontal cortex for interference control. In three sessions, 25 healthy participants received online repetitive transcranial magnetic stimulation (rTMS) over the left and right dorsolateral prefrontal cortex, and sham stimulation over the vertex. During each session, participants completed a verbal-response Stroop task. Relative to sham rTMS and rTMS over the left prefrontal cortex, rTMS over the right prefrontal cortex selectively disrupted the Stroop sequence effect (i.e., the congruency sequence effect; CSE). This effect was specific to sequential modulations of interference since rTMS did not affect the Stroop performance in the ongoing trial. Our results demonstrate the functional relevance of the right dorsolateral prefrontal cortex for the processing of interference control. This finding points towards process-specific lateralization within the prefrontal cortex. The observed process- and site-specific TMS effect provides new insights into the neurophysiological underpinnings of Stroop task performance and more general, the role of the prefrontal cortex in the processing of interference control.

Transient perturbation of the left temporal cortex evokes plasticity-related reconfiguration of the lexical network.

While much progress has been made in how brain organization supports language function, the language network's ability to adapt to immediate disturbances by means of reorganization remains unclear. The aim of this study was to examine acute reorganizational changes in brain activity related to conceptual and lexical retrieval in unimpaired language production following transient disruption of the left middle temporal gyrus (MTG). In a randomized single-blind within-subject experiment, we recorded the electroencephalogram from 16 healthy participants during a context-driven picture-naming task. Prior to the task, the left MTG was perturbed with real continuous theta-burst stimulation (cTBS) or sham stimulation. During the task, participants read lead-in sentences creating a constraining (e.g., "The farmer milks the") or nonconstraining context (e.g., "The farmer buys the"). The last word was shown as a picture that participants had to name (e.g., "cow"). Replicating behavioral studies, participants were overall faster in naming pictures following a constraining relative to a nonconstraining context, but this effect did not differ between real and sham cTBS. In contrast, real cTBS increased overall error rates compared to sham cTBS. In line with previous studies, we observed a decrease in alpha-beta (8-24 Hz) oscillatory power for constraining relative to nonconstraining contexts over left temporal-parietal cortex after participants received sham cTBS. However, following real cTBS, this decrease extended toward left prefrontal regions associated with both domain-general and domain-specific control mechanisms. Our findings provide evidence that immediately after perturbing the left MTG, the lexical-semantic network is able to quickly reconfigure, also recruiting domain-general regions.

Dissociating semantic and phonological contributions of the left inferior frontal gyrus to language production.

While the involvement of the left inferior frontal gyrus (IFG) in language production is undisputed, the role of specific subregions at different representational levels remains unclear. Some studies suggest a division of anterior and posterior regions for semantic and phonological processing, respectively. Crucially, evidence thus far only comes from correlative neuroimaging studies, but the functional relevance of the involvement of these subregions during a given task remains elusive. We applied repetitive transcranial magnetic stimulation (rTMS) over anterior and posterior IFG (aIFG/pIFG), and vertex as a control site, while participants performed a category member and a rhyme generation task. We found a functional-anatomical double dissociation between tasks and subregions. Naming latencies were significantly delayed in the semantic task when rTMS was applied to aIFG (relative to pIFG and vertex). In contrast, we observed a facilitation of naming latencies in the phonological task when rTMS was applied to pIFG (relative to aIFG and vertex). The results provide first causal evidence for the notion that anterior portions of the IFG are selectively recruited for semantic processing while posterior regions are functionally specific for phonological processing during word production. These findings shed light on the functional parcellation of the left IFG in language production.

Putting focus on transcranial direct current stimulation in language production studies.

Previous language production studies targeting the inferior frontal and superior temporal gyrus using anodal tDCS have provided mixed results. Part of this heterogeneity may be explained by limited target region focality of conventionally used electrode montages. We examined the focality of conventionally and alternative electrode montages. Electrical field distributions of anodal tDCS targeting IFG and pSTG were simulated in conventional setups (anodal electrode over left IFG/pSTG, reference electrode over right supraorbital region) and an alternative electrode montage in four different brains. Conventional montages showed maximum field strengths outside of the target regions. Results from alternative electrode montages showed that focality of tDCS could be improved by adjustments in electrode placement. Heterogeneity of findings of language production studies deploying conventional montages may in part be explained by diffuse electrical field distributions. Alternative montages may improve focality and provide more unequivocal results.

Non-invasive brain stimulation to investigate language production in healthy speakers: A meta-analysis.

Non-invasive brain stimulation (NIBS) has become a common method to study the interrelations between the brain and language functioning. This meta-analysis examined the efficacy of transcranial magnetic stimulation (TMS) and direct current stimulation (tDCS) in the study of language production in healthy volunteers. Forty-five effect sizes from 30 studies which investigated the effects of NIBS on picture naming or verbal fluency in healthy participants were meta-analysed. Further sub-analyses investigated potential influences of stimulation type, control, target site, task, online vs. offline application, and current density of the target electrode. Random effects modelling showed a small, but reliable effect of NIBS on language production. Subsequent analyses indicated larger weighted mean effect sizes for TMS as compared to tDCS studies. No statistical differences for the other sub-analyses were observed. We conclude that NIBS is a useful method for neuroscientific studies on language production in healthy volunteers.

The Role of Left Dorsolateral Prefrontal Cortex in Language Processing.

In addition to the role of left frontotemporal areas in language processing, there is increasing evidence that language comprehension and production require cognitive control and working memory resources involving the left dorsolateral prefrontal cortex (DLPFC). The aim of this study was to investigate the role of the left DLPFC in both language comprehension and production. In a double-blind, sham-controlled crossover experiment, thirty-two participants received cathodal or sham transcranial direct current stimulation (tDCS) to the left DLPFC while performing a language comprehension and a language production task. Results showed that cathodal tDCS increases reaction times in the language comprehension task, but decreases naming latencies in the language production task. However, additional analyses revealed that the polarity of tDCS effects was highly correlated across tasks, implying differential individual susceptibility to the effect of tDCS within participants. Overall, our findings demonstrate that left DLPFC is part of the complex cortical network associated with language processing.

Words we do not say-Context effects on the phonological activation of lexical alternatives in speech production.

There is compelling evidence that context strongly influences our choice of words (e.g., whether we refer to a particular animal with the basic-level name "bird" or the subordinate-level name "duck"). However, little is known about whether the context already affects the degree to which the alternative words are activated. In this study, we explored the effect of a preceding linguistic context on the phonological activation of alternative picture names. In Experiments 1 to 3, the context was established by a request produced by an imaginary interlocutor. These requests either constrained the naming response to the subordinate level on pragmatic grounds (e.g., "name the bird!") or not (e.g., "name the object!"). In Experiment 4, the context was established by the speaker's own previous naming response. Participants named the pictures with their subordinate-level names and the phonological activation of the basic-level names was assessed with distractor words phonologically related versus unrelated to that name (e.g., "birch" vs. "lamp"). In all experiments, we consistently found that distractor words phonologically related to the basic-level name interfered with the naming response more strongly than unrelated distractor words. Moreover, this effect was of comparable size for nonconstraining and constraining contexts indicating that the alternative name was phonologically activated and competed for selection, even when it was not an appropriate lexical option. Our results suggest that the speech production system is limited in its ability of flexibly adjusting and fine-tuning the lexical activation patterns of words (among which to choose from) as a function of pragmatic constraints. (PsycINFO Database Record