Cortico-basal Ganglia-thalamo-cortical Research Articles

The role of the dorsal anterior cingulate cortex in obsessive-compulsive disorder

Despite extensive research efforts, the pathophysiology of obsessive-compulsive disorder (OCD) is still largely unknown. The dorsal anterior cingulate cortex (dACC) plays an important role in cognitive control and is therefore hypothesized to contribute to the pathogenesis of OCD. In this review, we aim to gain a wider understanding of the specific functions of the dACC and its role in the pathophysiology of OCD. The dACC is part of the cortico-basal ganglia-thalamo-cortical loop, where it forms connections between sensory input streams, cognitive and affective processing regions, and structures that regulate behaviour. This position facilitates a broad function for the dACC in multiple domains, which center on goal-directed behaviour and reward-based learning. When presented with a certain threatening stimulus, the dACC instructs downstream structures to select actions to respond to this particular stimulus, based on previous experiences We hypothesize that hyperactivity of the dACC may impair goal-directed behaviour in OCD patients which in turn may lead to obsessive-compulsive symptoms by creating an over-reliance on threatening stimuli and inadequate selection of neutralizing actions. The working mechanisms of cognitive behavioural therapy, serotonergic medication, repetitive transcranial magnetic stimulation and deep brain stimulation in OCD may be in part explained by the normalization of the activity of the dACC within the cortico-basal ganglia-thalamo-cortical (CBGTC) loop.

Dynamic reorganization of the cortico-basal ganglia-thalamo-cortical network during task learning.

SummaryAdaptive behavior is coordinated by neuronal networks that are distributed across multiple brain regions such as in the cortico-basal ganglia-thalamo-cortical (CBGTC) network. Here, we ask how cross-regional interactions within such mesoscale circuits reorganize when an animal learns a new task. We apply multi-fiber photometry to chronically record simultaneous activity in 12 or 48 brain regions of mice trained in a tactile discrimination task. With improving task performance, most regions shift their peak activity from the time of reward-related action to the reward-predicting stimulus. By estimating cross-regional interactions using transfer entropy, we reveal that functional networks encompassing basal ganglia, thalamus, neocortex, and hippocampus grow and stabilize upon learning, especially at stimulus presentation time. The internal globus pallidus, ventromedial thalamus, and several regions in the frontal cortex emerge as salient hub regions. Our results highlight the learning-related dynamic reorganization that brain networks undergo when task-appropriate mesoscale network dynamics are established for goal-oriented behavior.

A cortico-basal ganglia-thalamo-cortical channel underlying short-term memory

Persistent activity underlying short-term memory encodes sensory information or instructs specific future movement and, consequently, has a crucial role in cognition. Despite extensive study, how the same set of neurons respond differentially to form selective persistent activity remains unknown. Here, we report that the cortico-basal ganglia-thalamo-cortical (CBTC) circuit supports the formation of selective persistent activity in mice. Optogenetic activation or inactivation of the basal ganglia output nucleus substantia nigra pars reticulata (SNr)-to-thalamus pathway biased future licking choice, without affecting licking execution. This perturbation differentially affected persistent activity in the frontal cortex and selectively modulated neural trajectory that encodes one choice but not the other. Recording showed that SNr neurons had selective persistent activity distributed across SNr, but with a hotspot in the mediolateral region. Optogenetic inactivation of the frontal cortex also differentially affected persistent activity in the SNr. Together, these results reveal a CBTC channel functioning to produce selective persistent activity underlying short-term memory.

Mechanisms of Network Interactions for Flexible Cortico-Basal Ganglia-Mediated Action Control.

In humans, finely tuned γ synchronization (60–90 Hz) rapidly appears at movement onset in a motor control network involving primary motor cortex, the basal ganglia and motor thalamus. Yet the functional consequences of brief movement-related synchronization are still unclear. Distinct synchronization phenomena have also been linked to different forms of motor inhibition, including relaxing antagonist muscles, rapid movement interruption and stabilizing network dynamics for sustained contractions. Here, I will introduce detailed hypotheses about how intrasite and intersite synchronization could interact with firing rate changes in different parts of the network to enable flexible action control. The here proposed cause-and-effect relationships shine a spotlight on potential key mechanisms of cortico-basal ganglia-thalamo-cortical (CBGTC) communication. Confirming or revising these hypotheses will be critical in understanding the neuronal basis of flexible movement initiation, invigoration and inhibition. Ultimately, the study of more complex cognitive phenomena will also become more tractable once we understand the neuronal mechanisms underlying behavioral readouts.

Dissociation between two aspects of procedural learning in Tourette syndrome: Enhanced statistical and impaired sequence learning

ABSTRACT Tourette syndrome (TS) is a childhood-onset neurodevelopmental disorder that primarily affects the cortico-basal ganglia-thalamo-cortical (CBGTC) circuitry and is characterized by motor and vocal tics. Previous studies have found enhancement in procedural memory, which depends on the CBGTC circuitry and plays an important role in the learning and processing of numerous motor, social, and cognitive skills and habits. Based on these studies, procedural hyperfunctioning in TS has been proposed. However, the neurocognitive mechanism underlying such hyperfunctioning is poorly understood. Here, we investigated how two aspects of procedural learning, namely 1) frequency-based statistical learning and 2) order-based sequence learning, are affected in TS. Twenty-one children with TS between the ages of ten and fifteen as well as 21 typically developing controls were tested on a probabilistic sequence learning task that enables the parallel assessment of these two aspects. We found that children with TS showed enhanced sensitivity to statistical information but impaired sequence learning compared to typically developing children. The deconstruction of procedural memory suggests that procedural hyperfunctioning in TS may be supported by enhanced sensitivity to statistical information. These results can provide a potential path for improving therapy methods and skill-oriented educational programs for TS.

Cortico-Striatal Oscillations Are Correlated to Motor Activity Levels in Both Physiological and Parkinsonian Conditions.

Oscillatory neural activity in the cortico-basal ganglia-thalamocortical (CBGTC) loop is associated with the motor state of a subject, but also with the availability of modulatory neurotransmitters. For example, increased low-frequency oscillations in Parkinson’s disease (PD) are related to decreased levels of dopamine and have been proposed as biomarkers to adapt and optimize therapeutic interventions, such as deep brain stimulation. Using neural oscillations as biomarkers require differentiating between changes in oscillatory patterns associated with parkinsonism vs. those related to a subject’s motor state. To address this point, we studied the correlation between neural oscillatory activity in the motor cortex and striatum and varying degrees of motor activity under normal and parkinsonian conditions. Using rats with bilateral or unilateral 6-hydroxydopamine lesions as PD models, we correlated the motion index (MI)—a measure based on the physical acceleration of the head of rats—to the local field potential (LFP) oscillatory power in the 1–80 Hz range. In motor cortices and striata, we observed a robust correlation between the motion index and the oscillatory power in two main broad frequency ranges: a low-frequency range [5.0–26.5 Hz] was negatively correlated to motor activity, whereas a high-frequency range [35.0–79.9 Hz] was positively correlated. We observed these correlations in both normal and parkinsonian conditions. In addition to these general changes in broad-band power, we observed a more restricted narrow-band oscillation [25–40 Hz] in dopamine-denervated hemispheres. This oscillation, which seems to be selective to the parkinsonian state, showed a linear frequency dependence on the concurrent motor activity level. We conclude that, independently of the parkinsonian condition, changes in broad-band oscillatory activities of cortico-basal ganglia networks (including changes in the relative power of low- and high-frequency bands) are closely correlated to ongoing motions, most likely reflecting he operations of these neural circuits to control motor activity. Hence, biomarkers based on neural oscillations should focus on specific features, such as narrow frequency bands, to allow differentiation between parkinsonian states and physiological movement-dependent circuit modulation.

The Pathophysiology of Tics; An Evolving Story

Background:Tics, defined as quick, rapid, sudden, recurrent, non-rhythmic motor movements or vocalizations are required components of Tourette Syndrome (TS) - a complex disorder characterized by the presence of fluctuating, chronic motor and vocal tics, and the presence of co-existing neuropsychological problems. Despite many advances, the underlying pathophysiology of tics/TS remains unknown.Objective:To address a variety of controversies surrounding the pathophysiology of TS. More specifically: 1) the configuration of circuits likely involved; 2) the role of inhibitory influences on motor control; 3) the classification of tics as either goal-directed or habitual behaviors; 4) the potential anatomical site of origin, e.g. cortex, striatum, thalamus, cerebellum, or other(s); and 5) the role of specific neurotransmitters (dopamine, glutamate, GABA, and others) as possible mechanisms (Abstract figure).Methods:Existing evidence from current clinical, basic science, and animal model studies are reviewed to provide: 1) an expanded understanding of individual components and the complex integration of the Cortico-Basal Ganglia-Thalamo-Cortical (CBGTC) circuit - the pathway involved with motor control; and 2) scientific data directly addressing each of the aforementioned controversies regarding pathways, inhibition, classification, anatomy, and neurotransmitters.Conclusion:Until a definitive pathophysiological mechanism is identified, one functional approach is to consider that a disruption anywhere within CBGTC circuitry, or a brain region inputting to the motor circuit, can lead to an aberrant message arriving at the primary motor cortex and enabling a tic. Pharmacologic modulation may be therapeutically beneficial, even though it might not be directed toward the primary abnormality.

Controversies Surrounding the Pathophysiology of Tics.

Tics are sudden, rapid, recurrent, nonrhythmic motor movements or vocalizations (phonic productions) that are commonly present in children and are required symptoms for the diagnosis of Tourette syndrome. Despite their frequency, the underlying pathophysiology of tics/Tourette syndrome remains unknown. In this review, we discuss a variety of controversies surrounding the pathophysiology of tics, including the following: Are tics voluntary or involuntary? What is the role of the premonitory urge? Are tics due to excess excitatory or deficient inhibition? Is it time to adopt the contemporary version of the cortico-basal ganglia-thalamocortical (CBGTC) circuit? and Do we know the primary abnormal neurotransmitter in Tourette syndrome? Data from convergent clinical and animal model studies support complex interactions among the various CBGTC sites and neurotransmitters. Advances are being made; however, numerous pathophysiologic questions persist.

Linking Pathological Oscillations With Altered Temporal Processing in Parkinsons Disease: Neurophysiological Mechanisms and Implications for Neuromodulation.

Emerging evidence suggests that Parkinson's disease (PD) results from disrupted oscillatory activity in cortico-basal ganglia-thalamo-cortical (CBGTC) and cerebellar networks which can be partially corrected by applying deep brain stimulation (DBS). The inherent dynamic nature of such oscillatory activity might implicate that is represents temporal aspects of motor control. While the timing of muscle activities in CBGTC networks constitute the temporal dimensions of distinct motor acts, these very networks are also involved in somatosensory processing. In this respect, a temporal aspect of somatosensory processing in motor control concerns matching predicted (feedforward) and actual (feedback) sensory consequences of movement which implies a distinct contribution to demarcating the temporal order of events. Emerging evidence shows that such somatosensory processing is altered in movement disorders. This raises the question how disrupted oscillatory activity is related to impaired temporal processing and how/whether DBS can functionally restore this. In this perspective article, the neural underpinnings of temporal processing will be reviewed and translated to the specific alternated oscillatory neural activity specifically found in Parkinson's disease. These findings will be integrated in a neurophysiological framework linking somatosensory and motor processing. Finally, future implications for neuromodulation will be discussed with potential implications for strategy across a range of movement disorders.

Toward adaptive deep brain stimulation for dystonia.

The presence of abnormal neural oscillations within the cortico-basal ganglia-thalamo-cortical (CBGTC) network has emerged as one of the current principal theories to explain the pathophysiology of movement disorders. In theory, these oscillations can be used as biomarkers and thereby serve as a feedback signal to control the delivery of deep brain stimulation (DBS). This new form of DBS, dependent on different characteristics of pathological oscillations, is called adaptive DBS (aDBS), and it has already been applied in patients with Parkinson's disease. In this review, the authors summarize the scientific research to date on pathological oscillations in dystonia and address potential biomarkers that might be used as a feedback signal for controlling aDBS in patients with dystonia.

Neuroplasticity in the cerebello-thalamo-basal ganglia pathway: A longitudinal in vivo MRI study in male songbirds

Similar to human speech, bird song is controlled by several pathways including a cortico-basal ganglia-thalamo-cortical (C-BG-T-C) loop. Neurotoxic disengagement of the basal ganglia component, i.e. Area X, induces long-term changes in song performance, while most of the lesioned area regenerates within the first months. Importantly however, the timing and spatial extent of structural neuroplastic events potentially affecting other constituents of the C-BG-T-C loop is not clear. We designed a longitudinal MRI study where changes in brain structure were evaluated relative to the time after neurotoxic lesioning or to vocal performance. By acquiring both Diffusion Tensor Imaging and 3-dimensional anatomical scans, we were able to track alterations in respectively intrinsic tissue properties and local volume. Voxel-based statistical analyses revealed structural remodeling remote to the lesion, i.e. in the thalamus and, surprisingly, the cerebellum, both peaking within the first two months after lesioning Area X. Voxel-wise correlations between song performance and MRI parameters uncovered intriguing brain-behavior relationships in several brain areas pertaining to the C-BG-T-C loop supervising vocal motor control. Our results clearly point to structural neuroplasticity in the cerebellum induced by basal ganglia (striatal) damage and might point to the existence of a human-like cerebello-thalamic-basal ganglia pathway capable of modifying vocal motor output.

Functional Connectivity of the Corticobasal Ganglia-Thalamocortical Network in Parkinson Disease: A Systematic Review and Meta-Analysis with Cross-Validation.

Purpose To quantitatively summarize the functional connectivity (FC) feature of the corticobasal ganglia-thalamocortical (CBTC) network in patients with Parkinson disease (PD) by means of a meta-analysis with cross-validation. Materials and Methods For this prospective study, a systematic literature search in the PubMed and EMBASE databases was performed for resting-state functional magnetic resonance (MR) imaging studies of PD published between January 2000 and May 2017. Then, a coordinate-based meta-analysis was conducted by Effect Size-Signed Differential Mapping. A cross-validation analysis was performed by using an independent resting-state functional MR imaging data set that contained 25 patients with PD and 19 age-, sex-, and education-matched healthy control participants. Two-sample t test was performed on FC maps between PD and control groups. Results Thirty studies with 854 patients with PD and 831 control participants were included in this meta-analysis. The main meta-analysis found increased FC in the left pre- and postcentral gyrus in patients with PD compared with healthy control participants (z = 2.6; P < .001). The abnormality of the postcentral gyrus was further confirmed by subgroup meta-analyses on medication-naive (n = 25; z = 2.2; P < .001) and medication-off (n = 11; z = 1.5; P < .001) experiments, which suggested that the finding was unaffected by medication. The abnormality of the postcentral gyrus was cross-validated by the independent data set (t = 5.0; P < .05), which suggested a high reproducibility and generalizability. Conclusion This meta-analysis emphasizes the left postcentral gyrus as a critical region in PD, which may become a potential target for clinical intervention. © RSNA, 2018 Online supplemental material is available for this article.

Intrinsic functional connectivity of cortico-basal ganglia-thalamo-cortical circuitry underlying psychomotor retardation in major depressive disorder

IntroductionPsychomotor retardation (PMR) in depression is analogous to the hypokinesia in Parkinson's disease, which is associated with the unbalanced direct and indirect pathways of cortico-basal ganglia-thalamo-cortical (CBTC) circuitry. This study hypothesized PMR in major depressive disorder (MDD) should be associated with the hyperactivity of CBTC indirect pathways.ObjectivesTo substantiate the hypothesis that the PMR symptom of MDD might attribute to the hyperactivity of the ortico-basal ganglia-thalamo-cortical indirect pathway which could inhibit psychomotor performance.MethodsWe investigated the intrinsic stiato-subthalamic nucleus (STN)-thalamic functional connectivity (FC), three pivotal hubs of the indirect pathway, in 30 MDD patients with PMR (PMR group) and well matched 30 patients without PMR (NPMR group) at baseline, and 11 patients of each group at follow-up who remitted after antidepressant treatment.ResultsThe results showed increased STN-striatum FC of PMR group at baseline and no more discrepancy at follow-up, and significant correlation between PMR severity and thalamo-STN FC.ConclusionsOur findings suggested the increased STN- striatum FC should be considered as a state biomarker to distinguish MDD patients with PMR from patients without PMR at acute period, and thalamo-STN FC could be identified as the predictor of the PMR severity for MDD patients.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The dopaminergic polymorphisms in psychomotor retardation of depression: A pathway-based imaging genetics association study

IntroductionSeveral lines of evidence implicate dopamine is involved in the psychomotor retardation (PMR) in major depressive disorder (MDD). Besides, abnormal cerebral blood flow (CBF) of PMR was also found in the cortico-basal ganglia-thalamo-cortical (CBTC) circuitry. We hypothesize that the polymorphisms of the dopaminergic pathway should be associated the abnormal CBF in the CBTC circuitry.ObjectiveTo investigate the association of the polymorphisms throughout the dopaminergic pathway with the cerebral blood flow (CBF) of PMR in MDD.MethodsThe blood sample of 63 patients (23 PMR, 40 NPMR) were collected for genotyping the dopaminergic polymorphisms (92 SNPs from10 genes). After quality controlling, 15 SNPs in 8 candidate genes were entered into the mass univariate modeling analysis. For the statistical analysis, patients with unqualified fMRI image and unmatched demographic data were ruled out. Consequently 56 patients (23 PMR, 33 NPMR) were taken into the statistical analysis.ResultsGenotype-by PMR associations with the CBF differences predominately distributed in bilateral prefrontal cortex (PFC), temporal cortex, and striatum, the left thalamus, the right primary motor cortex, insular cortex, fusiform gyri, and lingual gyri. There were significant negative correlation between the CBF of the PFC and the PMR severity. However, the CBF of the striatum and the thalamus were positively correlated with the PMR severity.ConclusionsThe polymorphisms of dopaminergic pathway are associated with not only CSTC circuitry, but also some other brain regions involving in cognition and emotion controlling. While the increased CBF of PFC might suppress PMR, the increased CBF of striatum and thalamus adversely aggravate PMR.

A reinforcement-learning account of Tourette syndrome

BackgroundTourette syndrome (TS) has long been thought to involve dopaminergic disturbances, given the effectiveness of antipsychotics in diminishing tics. Molecular-imaging studies have, by and large, confirmed that there are specific alterations in the dopaminergic system in TS. In parallel, multiple lines of evidence have implicated the motor cortico-basal ganglia-thalamo-cortical (CBGTC) loop in TS. Finally, several studies demonstrate that patients with TS exhibit exaggerated habit learning. This talk will present a computational theory of TS that ties together these multiple findings.MethodsThe computational theory builds on computational reinforcement-learning models, and more specifically on a recent model of the role of the direct and indirect basal-ganglia pathways in learning from positive and negative outcomes, respectively.ResultsA model defined by a small set of equations that characterize the role of dopamine in modulating learning and excitability in the direct and indirect pathways explains, in an integrated way: (1) the role of dopamine in the development of tics; (2) the relation between dopaminergic disturbances, involvement of the motor CBGTC loop, and excessive habit learning in TS; (3) the mechanism of action of antipsychotics in TS; and (4) the psychological and neural mechanisms of action of habit-reversal training, the main behavioral therapy for TS.ConclusionsA simple computational model, thoroughly grounded on computational theory and basic-science findings concerning dopamine and the basal ganglia, provides an integrated, rigorous mathematical explanation for a broad range of empirical findings in TS.Disclosure of interestThe author has not supplied his declaration of competing interest.

From reinforcement learning models to psychiatric and neurological disorders

Over the last decade and a half, reinforcement learning models have fostered an increasingly sophisticated understanding of the functions of dopamine and cortico-basal ganglia-thalamo-cortical (CBGTC) circuits. More recently, these models, and the insights that they afford, have started to be used to understand important aspects of several psychiatric and neurological disorders that involve disturbances of the dopaminergic system and CBGTC circuits. We review this approach and its existing and potential applications to Parkinson's disease, Tourette's syndrome, attention-deficit/hyperactivity disorder, addiction, schizophrenia and preclinical animal models used to screen new antipsychotic drugs. The approach's proven explanatory and predictive power bodes well for the continued growth of computational psychiatry and computational neurology.

Can lesions of GPe correct HD deficits?

Huntington's disease (HD) is a heritable, fatal neurodegenerative disorder caused by a mutation in the Huntingtin gene. It is characterized by chorea, as well as cognitive and psychiatric symptoms. Histopathologically, there is a massive loss of striatal projection neurons and less but significant loss in other areas throughout the cortico-basal ganglia-thalamocortical (CBGTC) loop. The mutant huntingtin protein has been implicated in numerous functions, including an important role in synaptic transmission. Most studies on anatomical and physiological alterations in HD have focused on striatum and cerebral cortex. However, based on recent CBGTC projectome evidence, the need to study other pathways has become increasingly clear. In this review, we examine the current status of our knowledge of morphological and electrophysiological alterations of those pathways in animal models of HD. Based on recent studies, there is accumulating evidence that synaptic disconnection, particularly along excitatory pathways, is pervasive and almost universal in HD, thus supporting a critical role of the huntingtin protein in synaptic transmission.