Disentangling pain and fatigue in chronic fatigue syndrome: a resting state connectivity study before and after cognitive behavioral therapy.

BACKGROUND: Fatigue is a central feature of myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), but many ME/CFS patients also report comorbid pain symptoms. It remains unclear whether these symptoms are related to similar or dissociable brain networks. This study used resting-state fMRI to disentangle networks associated with fatigue and pain symptoms in ME/CFS patients, and to link changes in those networks to clinical improvements following cognitive behavioral therapy (CBT). METHODS: Relationships between pain and fatigue symptoms and cortico-cortical connectivity were assessed within ME/CFS patients at baseline (N = 72) and after CBT (N = 33) and waiting list (WL, N = 18) and compared to healthy controls (HC, N = 29). The analyses focused on four networks previously associated with pain and/or fatigue, i.e. the fronto-parietal network (FPN), premotor network (PMN), somatomotor network (SMN), and default mode network (DMN). RESULTS: At baseline, variation in pain and fatigue symptoms related to partially dissociable brain networks. Fatigue was associated with higher SMN-PMN connectivity and lower SMN-DMN connectivity. Pain was associated with lower PMN-DMN connectivity. CBT improved SMN-DMN connectivity, compared to WL. Larger clinical improvements were associated with larger increases in frontal SMN-DMN connectivity. No CBT effects were observed for PMN-DMN or SMN-PMN connectivity. CONCLUSIONS: These results provide insight into the dissociable neural mechanisms underlying fatigue and pain symptoms in ME/CFS and how they are affected by CBT in successfully treated patients. Further investigation of how and in whom behavioral and biomedical treatments affect these networks is warranted to improve and individualize existing or new treatments for ME/CFS.

Clinical severity in Parkinson's disease is determined by decline in cortical compensation.

Dopaminergic dysfunction in the basal ganglia, particularly in the posterior putamen, is often viewed as the primary pathological mechanism behind motor slowing (i.e. bradykinesia) in Parkinson's disease. However, striatal dopamine loss fails to account for interindividual differences in motor phenotype and rate of decline, implying that the expression of motor symptoms depends on additional mechanisms, some of which may be compensatory in nature. Building on observations of increased motor-related activity in the parieto-premotor cortex of Parkinson patients, we tested the hypothesis that interindividual differences in clinical severity are determined by compensatory cortical mechanisms and not just by basal ganglia dysfunction. Using functional MRI, we measured variability in motor- and selection-related brain activity during a visuomotor task in 353 patients with Parkinson's disease (≤5 years disease duration) and 60 healthy controls. In this task, we manipulated action selection demand by varying the number of possible actions that individuals could choose from. Clinical variability was characterized in two ways. First, patients were categorized into three previously validated, discrete clinical subtypes that are hypothesized to reflect distinct routes of α-synuclein propagation: diffuse-malignant (n = 42), intermediate (n = 128) or mild motor-predominant (n = 150). Second, we used the scores of bradykinesia severity and cognitive performance across the entire sample as continuous measures. Patients showed motor slowing (longer response times) and reduced motor-related activity in the basal ganglia compared with controls. However, basal ganglia activity did not differ between clinical subtypes and was not associated with clinical scores. This indicates a limited role for striatal dysfunction in shaping interindividual differences in clinical severity. Consistent with our hypothesis, we observed enhanced action selection-related activity in the parieto-premotor cortex of patients with a mild-motor predominant subtype, both compared to patients with a diffuse-malignant subtype and controls. Furthermore, increased parieto-premotor activity was related to lower bradykinesia severity and better cognitive performance, which points to a compensatory role. We conclude that parieto-premotor compensation, rather than basal ganglia dysfunction, shapes interindividual variability in symptom severity in Parkinson's disease. Future interventions may focus on maintaining and enhancing compensatory cortical mechanisms, rather than only attempting to normalize basal ganglia dysfunction.

Developmental shift in testosterone influence on prefrontal emotion control.

A paradox of testosterone effects is seen in adolescents versus adults in social emotional approach-avoidance behavior. During adolescence, high testosterone levels are associated with increased anterior prefrontal (aPFC) involvement in emotion control, whereas during adulthood this neuro-endocrine relation is reversed. Rodent work shows that, during puberty, testosterone transitions from a neuro-developmental to a social-sexual activating hormone. In this study, we explored whether this functional transition is also present in human adolescents and young adults. Using a prospective longitudinal design, we investigated the role of testosterone on neural control of social emotional behavior during the transitions from middle to late adolescence and into young adulthood. Seventy-one individuals (tested at ages 14, 17, and 20 years) performed an fMRI-adapted approach-avoidance (AA) task involving automatic and controlled actions in response to social emotional stimuli. In line with predictions from animal models, the effect of testosterone on aPFC engagement decreased between middle and late adolescence, and shifted into an activational role by young adulthood-impeding neural control of emotions. This change in testosterone function was accompanied by increased testosterone-modulated amygdala reactivity. These findings qualify the testosterone-dependent maturation of the prefrontal-amygdala circuit supporting emotion control during the transition from middle adolescence into young adulthood.

Emotion regulation from an action-control perspective.

Despite increasing interest in emotional processes in cognitive science, theories on emotion regulation have remained rather isolated, predominantly focused on cognitive regulation strategies such as reappraisal. However, recent neurocognitive evidence suggests that early emotion regulation may involve sensorimotor control in addition to other emotion-regulation processes. We propose an action-oriented view of emotion regulation, in which feedforward predictions develop from action-selection mechanisms. Those can account for acute emotional-action control as well as more abstract instances of emotion regulation such as cognitive reappraisal. We argue the latter occurs in absence of overt motor output, yet in the presence of full-blown autonomic, visceral, and subjective changes. This provides an integrated framework with testable neuro-computational predictions and concrete starting points for intervention to improve emotion control in affective disorders.

Anxious individuals shift emotion control from lateral frontal pole to dorsolateral prefrontal cortex.

Anxious individuals consistently fail in controlling emotional behavior, leading to excessive avoidance, a trait that prevents learning through exposure. Although the origin of this failure is unclear, one candidate system involves control of emotional actions, coordinated through lateral frontopolar cortex (FPl) via amygdala and sensorimotor connections. Using structural, functional, and neurochemical evidence, we show how FPl-based emotional action control fails in highly-anxious individuals. Their FPl is overexcitable, as indexed by GABA/glutamate ratio at rest, and receives stronger amygdalofugal projections than non-anxious male participants. Yet, high-anxious individuals fail to recruit FPl during emotional action control, relying instead on dorsolateral and medial prefrontal areas. This functional anatomical shift is proportional to FPl excitability and amygdalofugal projections strength. The findings characterize circuit-level vulnerabilities in anxious individuals, showing that even mild emotional challenges can saturate FPl neural range, leading to a neural bottleneck in the control of emotional action tendencies.

The effect of context and reason on the neural correlates of intentions.

Many studies have identified networks in parietal and prefrontal cortex that are involved in intentional action. Yet, our understanding of the way these networks are involved in intentions is still very limited. In this study, we investigate two characteristics of these processes: context- and reason-dependence of the neural states associated with intentions. We ask whether these states depend on the context a person is in and the reasons they have for choosing an action. We used a combination of functional magnetic resonance imaging (fMRI) and multivariate decoding to directly assess the context- and reason-dependency of the neural states underlying intentions. We show that action intentions can be decoded from fMRI data based on a classifier trained in the same context and with the same reason, in line with previous decoding studies. Furthermore, we found that intentions can be decoded across different reasons for choosing an action. However, decoding across different contexts was not successful. We found anecdotal to moderate evidence against context-invariant information in all regions of interest and for all conditions but one. These results suggest that the neural states associated with intentions are modulated by the context of the action.

A neurocognitive theory of flexible emotion control: The role of the lateral frontal pole in emotion regulation.

Emotion regulation is essential to survive in a world full of challenges with rapidly changing contextual demands. The ability to flexibly shift between different emotional control strategies is critical to successfully deal with these demands. Recently, decision neuroscience has shown the importance of monitoring alternative control strategies. However, this insight has not been incorporated into current neurocognitive models of emotional control. Here, we integrate insights from decision and affective sciences into a novel viewpoint on emotion control, the Flexible Emotion Control Theory (FECT). This theory explains how an individual can flexibly change emotion-regulatory behavior to adapt to varying goals and contextual demands. Crucially, FECT proposes that rapid switching between alternative emotional control strategies requires concurrent evaluation of current as well as alternative (unchosen) options. The neural implementation of FECT relies on the involvement of distinct prefrontal structures, including the lateral frontal pole (FPl) and its connections with other cortical (prefrontal, parietal, motor) and subcortical systems. This novel account of emotion control integrates insights from decision sciences, clinical research, as well as meta-analytic evidence for the consistent FPl involvement during emotional control when monitoring of alternative emotional control strategies is required. Moreover, it provides novel, neurocognitively grounded starting points for interventions to improve emotion control in affective disorders, such as anxiety and aggression.

Cerebral Adaptation Associated with Peripheral Nerve Recovery in Neuralgic Amyotrophy: A Randomized Controlled Trial.

BACKGROUND: Neuralgic amyotrophy (NA) is a common peripheral nerve disorder caused by auto-immune inflammation of nerves in the brachial plexus territory, characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Recent work has confirmed that NA patients with residual motor dysfunction have abnormal cerebral sensorimotor representations of their affected upper extremity. OBJECTIVE: To determine whether abnormal cerebral sensorimotor representations associated with NA can be altered by specialized, multidisciplinary outpatient rehabilitation focused on relearning motor control. METHODS: 27 NA patients with residual lateralized symptoms in the right upper extremity participated in a randomized controlled trial, comparing 17 weeks of multidisciplinary rehabilitation (n = 16) to usual care (n = 11). We used task-based functional MRI and a hand laterality judgment task, which involves motor imagery and is sensitive to altered cerebral sensorimotor representations of the upper extremity. RESULTS: Change in task performance and related brain activity did not differ significantly between the multidisciplinary rehabilitation and usual care groups, whereas the multidisciplinary rehabilitation group showed significantly greater clinical improvement on the Shoulder Rating Questionnaire. Both groups, however, showed a significant improvement in task performance from baseline to follow-up, and significantly increased activity in visuomotor occipito-parietal brain areas, both specific to their affected upper extremity. CONCLUSIONS: Abnormal cerebral sensorimotor representations of the upper extremity after peripheral nerve damage in NA can recover toward normality. As adaptations occurred in visuomotor brain areas, multidisciplinary rehabilitation after peripheral nerve damage may be further optimized by applying visuomotor strategies. This study is registered at ClinicalTrials.gov (NCT03441347).

The CABB dataset: A multimodal corpus of communicative interactions for behavioural and neural analyses.

We present a dataset of behavioural and fMRI observations acquired in the context of humans involved in multimodal referential communication. The dataset contains audio/video and motion-tracking recordings of face-to-face, task-based communicative interactions in Dutch, as well as behavioural and neural correlates of participants' representations of dialogue referents. Seventy-one pairs of unacquainted participants performed two interleaved interactional tasks in which they described and located 16 novel geometrical objects (i.e., Fribbles) yielding spontaneous interactions of about one hour. We share high-quality video (from three cameras), audio (from head-mounted microphones), and motion-tracking (Kinect) data, as well as speech transcripts of the interactions. Before and after engaging in the face-to-face communicative interactions, participants' individual representations of the 16 Fribbles were estimated. Behaviourally, participants provided a written description (one to three words) for each Fribble and positioned them along 29 independent conceptual dimensions (e.g., rounded, human, audible). Neurally, fMRI signal evoked by each Fribble was measured during a one-back working-memory task. To enable functional hyperalignment across participants, the dataset also includes fMRI measurements obtained during visual presentation of eight animated movies (35 min total). We present analyses for the various types of data demonstrating their quality and consistency with earlier research. Besides high-resolution multimodal interactional data, this dataset includes different correlates of communicative referents, obtained before and after face-to-face dialogue, allowing for novel investigations into the relation between communicative behaviours and the representational space shared by communicators. This unique combination of data can be used for research in neuroscience, psychology, linguistics, and beyond.

Get to grips with motivation: Slipping and gripping movements are biased by approach-avoidance context.

People are better at approaching appetitive cues signaling reward and avoiding aversive cues signaling punishment than vice versa. This action bias has previously been shown in approach-avoidance tasks involving arm movements in response to appetitive or aversive cues. It is not known whether appetitive or aversive stimuli also bias more distal dexterous actions, such as gripping and slipping, in a similar manner. To test this hypothesis, we designed a novel task involving grip force control (gripping and slipping) to probe gripping-related approach and avoidance behavior. 32 male volunteers, aged 18-40 years, were instructed to either grip ("approach") or slip ("avoid") a grip-force device with their right thumb and index finger at the sight of positive or negative images. In one version of this pincer grip task, participants were responding to graspable objects and in another version of the task they were responding to happy or angry faces. Bayesian repeated measures Analysis of variance revealed extreme evidence for an interaction between response type and cue valence (Bayes factor = 296). Participants were faster to respond in affect-congruent conditions ("approach appetitive," "avoid aversive") than in affect-incongruent conditions ("approach aversive," "avoid appetitive"). This bias toward faster response times for affect-congruent conditions was present regardless of whether it was a graspable object or a face signaling valence. Since our results mirror the approach and avoidance effects previously observed for arm movements, we conclude that a tendency favoring affectively congruent cue-response mappings is an inherent feature of motor control and thus also includes precision grip.

Cerebellar transcranial direct current stimulation modulates timing but not acquisition of conditioned eyeblink responses in SCA3 patients.

BACKGROUND: Delay eyeblink conditioning is an extensively studied motor learning paradigm that critically depends on the integrity of the cerebellum. In healthy individuals, modulation of cerebellar excitability using transcranial direct current stimulation (tDCS) has been reported to alter the acquisition and/or timing of conditioned eyeblink responses (CRs). It remains unknown whether such effects can also be elicited in patients with cerebellar disorders. OBJECTIVE: To investigate if repeated sessions of cerebellar tDCS modify acquisition and/or timing of CRs in patients with spinocerebellar ataxia type 3 (SCA3) and to evaluate possible associations between disease severity measures and eyeblink conditioning parameters. METHODS: Delay eyeblink conditioning was examined in 20 mildly to moderately affected individuals with SCA3 and 31 healthy controls. After the baseline assessment, patients were randomly assigned to receive ten sessions of cerebellar anodal tDCS or sham tDCS (i.e., five days per week for two consecutive weeks). Patients and investigators were blinded to treatment allocation. The same eyeblink conditioning protocol was administered directly after the last tDCS session. The Scale for the Assessment and Rating of Ataxia (SARA), cerebellar cognitive affective syndrome scale (CCAS-S), and disease duration were used as clinical measures of disease severity. RESULTS: At baseline, SCA3 patients exhibited significantly fewer CRs than healthy controls. Acquisition was inversely associated with the number of failed CCAS-S test items but not with SARA score. Onset and peak latencies of CRs were longer in SCA3 patients and correlated with disease duration. Repeated sessions of cerebellar anodal tDCS did not affect CR acquisition, but had a significant treatment effect on both timing parameters. While a shift of CRs toward the conditioned stimulus was observed in the sham group (i.e., timing became more similar to that of healthy controls, presumably reflecting the effect of a second eyeblink conditioning session), anodal tDCS induced a shift of CRs in the opposite direction (i.e., toward the unconditioned stimulus). CONCLUSION: Our findings provide evidence that cerebellar tDCS is capable of modifying cerebellar function in SCA3 patients. Future studies should assess whether this intervention similarly modulates temporal processing in other degenerative ataxias.

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.

Phase-locked transcranial electrical brain stimulation for tremor suppression in dystonic tremor syndromes.

OBJECTIVE: To establish the causal role of the cerebellum and motor cortex in dystonic tremor syndromes, and explore the therapeutic efficacy of phase-locked transcranial alternating current stimulation (TACS). METHODS: We applied phase-locked TACS over the ipsilateral cerebellum (N = 14) and contralateral motor cortex (N = 17) in dystonic tremor syndrome patients, while patients assumed a tremor-evoking posture. We measured tremor power using accelerometery during 30 s stimulation periods at 10 different phase-lags (36-degrees increments) between tremor and TACS for each target. Post-hoc, TACS-effects were related to a key clinical feature: the jerkiness (regularity) of tremor. RESULTS: Cerebellar TACS modulated tremor amplitude in a phase-dependent manner, such that tremor amplitude was suppressed or enhanced at opposite sides of the phase-cycle. This effect was specific for patients with non-jerky (sinusoidal) tremor (n = 10), but absent in patients with jerky (irregular) tremor (n = 4). Phase-locked stimulation over the motor cortex did not modulate tremor amplitude. CONCLUSIONS: This study indicates that the cerebellum plays a causal role in the generation of (non-jerky) dystonic tremor syndrome. Our findings suggest pathophysiologic heterogeneity between patients with dystonic tremor syndrome, which mirrors clinical variability. SIGNIFICANCE: We show tremor phenotype dependent involvement of the cerebellum in dystonic tremor syndrome. Tremor phenotype may thus guide optimal intervention targets.

Visuomotor processing is altered after peripheral nerve damage in neuralgic amyotrophy.

Neuralgic amyotrophy is a common peripheral nerve disorder caused by autoimmune inflammation of the brachial plexus, clinically characterized by acute pain and weakness of the shoulder muscles, followed by motor impairment. Despite recovery of the peripheral nerves, patients often have residual motor dysfunction of the upper extremity, leading to persistent pain related to altered biomechanics of the shoulder region. Building on clinical signs that suggest a role for cerebral mechanisms in these residual complaints, here we show and characterize cerebral alterations following neuralgic amyotrophy. Neuralgic amyotrophy patients often develop alternative motor strategies, which suggests that (mal)adaptations may occur in somatomotor and/or visuomotor brain areas. Here, we tested where changes in cerebral sensorimotor representations occur in neuralgic amyotrophy, while controlling for altered motor execution due to peripheral neuropathy. We additionally explore the relation between potential cerebral alterations in neuralgic amyotrophy and clinical symptoms. During functional MRI scanning, 39 neuralgic amyotrophy patients with persistent, lateralized symptoms in the right upper extremity and 23 matched healthy participants solved a hand laterality judgement task that can activate sensorimotor representations of the upper extremity, across somatomotor and visuomotor brain areas. Behavioural and cerebral responses confirmed the involvement of embodied, sensorimotor processes across groups. Compared with healthy participants, neuralgic amyotrophy patients were slower in hand laterality judgement and had decreased cerebral activity specific to their affected limb in two higher-order visual brain regions: the right extrastriate cortex and the parieto-occipital sulcus. Exploratory analyses revealed that across patients, extrastriate activity specific to the affected limb decreased as persistent pain increased, and affected limb-related parieto-occipital activity decreased as imagery performance of the affected limb became slower. These findings suggest that maladaptive cerebral plasticity in visuomotor areas involved in sensorimotor integration plays a role in residual motor dysfunction and subsequent persistent pain in neuralgic amyotrophy. Rehabilitation interventions that apply visuomotor strategies to improve sensorimotor integration may help to treat neuralgic amyotrophy patients.

Hierarchical Integration of Communicative and Spatial Perspective-Taking Demands in Sensorimotor Control of Referential Pointing.

Recognized as a simple communicative behavior, referential pointing is cognitively complex because it invites a communicator to consider an addressee's knowledge. Although we know referential pointing is affected by addressees' physical location, it remains unclear whether and how communicators' inferences about addressees' mental representation of the interaction space influence sensorimotor control of referential pointing. The communicative perspective-taking task requires a communicator to point at one out of multiple referents either to instruct an addressee which one should be selected (communicative, COM) or to predict which one the addressee will select (non-communicative, NCOM), based on either which referents can be seen (Level-1 perspective-taking, PT1) or how the referents were perceived (Level-2 perspective-taking, PT2) by the addressee. Communicators took longer to initiate the movements in PT2 than PT1 trials, and they held their pointing fingers for longer at the referent in COM than NCOM trials. The novel findings of this study pertain to trajectory control of the pointing movements. Increasing both communicative and perspective-taking demands led to longer pointing trajectories, with an under-additive interaction between those two experimental factors. This finding suggests that participants generate communicative behaviors that are as informative as required rather than overly exaggerated displays, by integrating communicative and perspective-taking information hierarchically during sensorimotor control. This observation has consequences for models of human communication. It implies that the format of communicative and perspective-taking knowledge needs to be commensurate with the movement dynamics controlled by the sensorimotor system.

Cerebello-thalamic activity drives an abnormal motor network into dystonic tremor.

Dystonic tremor syndromes are highly burdensome and treatment is often inadequate. This is partly due to poor understanding of the underlying pathophysiology. Several lines of research suggest involvement of the cerebello-thalamo-cortical circuit and the basal ganglia in dystonic tremor syndromes, but their role is unclear. Here we aimed to investigate the contribution of the cerebello-thalamo-cortical circuit and the basal ganglia to the pathophysiology of dystonic tremor syndrome, by directly linking tremor fluctuations to cerebral activity during scanning. In 27 patients with dystonic tremor syndrome (dystonic tremor: n = 23; tremor associated with dystonia: n = 4), we used concurrent accelerometery and functional MRI during a posture holding task that evoked tremor, alternated with rest. Using multiple regression analyses, we separated tremor-related activity from brain activity related to (voluntary) posture holding. Using dynamic causal modelling, we tested for altered effective connectivity between tremor-related brain regions as a function of tremor amplitude fluctuations. Finally, we compared grey matter volume between patients (n = 27) and matched controls (n = 27). We found tremor-related activity in sensorimotor regions of the bilateral cerebellum, contralateral posterior and anterior ventral lateral nuclei of the thalamus (VLp and VLa), contralateral primary motor cortex (hand area), contralateral pallidum, and the bilateral frontal cortex (laterality with respect to the tremor). Grey matter volume was increased in patients compared to controls in the portion of contralateral thalamus also showing tremor-related activity, as well as in bilateral medial and left lateral primary motor cortex, where no tremor-related activity was present. Effective connectivity analyses showed that inter-regional coupling in the cerebello-thalamic pathway, as well as the thalamic self-connection, were strengthened as a function of increasing tremor power. These findings indicate that the pathophysiology of dystonic tremor syndromes involves functional and structural changes in the cerebello-thalamo-cortical circuit and pallidum. Deficient input from the cerebellum towards the thalamo-cortical circuit, together with hypertrophy of the thalamus, may play a key role in the generation of dystonic tremor syndrome.

Aerobic Exercise Alters Brain Function and Structure in Parkinson's Disease: A Randomized Controlled Trial.

OBJECTIVE: Randomized clinical trials have shown that aerobic exercise attenuates motor symptom progression in Parkinson's disease, but the underlying neural mechanisms are unclear. Here, we investigated how aerobic exercise influences disease-related functional and structural changes in the corticostriatal sensorimotor network, which is involved in the emergence of motor deficits in Parkinson's disease. Additionally, we explored effects of aerobic exercise on tissue integrity of the substantia nigra, and on behavioral and cerebral indices of cognitive control. METHODS: The Park-in-Shape trial is a single-center, double-blind randomized controlled trial in 130 Parkinson's disease patients who were randomly assigned (1:1 ratio) to aerobic exercise (stationary home trainer) or stretching (active control) interventions (duration = 6 months). An unselected subset from this trial (exercise, n = 25; stretching, n = 31) underwent resting-state functional and structural magnetic resonance imaging (MRI), and an oculomotor cognitive control task (pro- and antisaccades), at baseline and at 6-month follow-up. RESULTS: Aerobic exercise, but not stretching, led to increased functional connectivity of the anterior putamen with the sensorimotor cortex relative to the posterior putamen. Behaviorally, aerobic exercise also improved cognitive control. Furthermore, aerobic exercise increased functional connectivity in the right frontoparietal network, proportionally to fitness improvements, and it reduced global brain atrophy. INTERPRETATION: MRI, clinical, and behavioral results converge toward the conclusion that aerobic exercise stabilizes disease progression in the corticostriatal sensorimotor network and enhances cognitive performance. ANN NEUROL 2022;91:203-216.

The Anticipatory and Task-Driven Nature of Visual Perception.

Humans have a remarkable capacity to arrange and rearrange perceptual input according to different categorizations. This begs the question whether the categorization is exclusively a higher visual or amodal process, or whether categorization processes influence early visual areas as well. To investigate this we scanned healthy participants in a magnetic resonance imaging scanner during a conceptual decision task in which participants had to answer questions about upcoming images of animals. Early visual cortices (V1 and V2) contained information about the current visual input, about the granularity of the forthcoming categorical decision, as well as perceptual expectations about the upcoming visual stimulus. The middle temporal gyrus, the anterior temporal lobe, and the inferior frontal gyrus were also involved in the categorization process, constituting an attention and control network that modulates perceptual processing. These findings provide further evidence that early visual processes are driven by conceptual expectations and task demands.

Constructing Others' Beliefs from One's Own Using Medial Frontal Cortex.

Many daily choices are based on one's own knowledge. However, when predicting other people's behavior, we need to consider the differences between our knowledge and other people's presumed knowledge. Social agents need a mechanism to use privileged information for their own behavior but exclude it from predictions of others. Using fMRI, we investigated the neural implementation of such social and personal predictions in healthy human volunteers of both sexes by manipulating privileged and shared information. The medial frontal cortex appeared to have an important role in flexibly making decisions using privileged information for oneself or predicting others' behavior. Specifically, we show that ventromedial PFC tracked the state of the world independent of the type of decision (personal, social), whereas dorsomedial regions adjusted their frame of reference to the use of privileged or shared information. Sampling privileged evidence not available to another person also relied on specific interactions between temporoparietal junction area and frontal pole.SIGNIFICANCE STATEMENT What we know about the minds of others and how we use that information is crucial to understanding social interaction. Mentalizing, or reading the minds of others, is argued to be particularly well developed in the human and crucially affected in some disorders. However, the intractable nature of human interactions makes it very difficult to study these processes. Here, we present a way to objectively quantify the information people have about others and to investigate how their brain deals with this information. This shows that people use similar areas in the brain related to nonsocial decision-making when making decisions in social situations and modify this information processing by the knowledge about others use these to modify their information processing according to the knowledge of others.