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Recent evidence suggests that presupplementary motor area (pre‐SMA) and inferior frontal gyrus (IFG) play an important role in response inhibition. However, no study has investigated the relationship between these brain networks at resting‐state and response inhibition in obsessive–compulsive disorder (OCD). We performed resting‐state functional magnetic resonance imaging scans and then measured the response inhibition of 41 medication‐free OCD patients and 49 healthy control (HC) participants by using the stop‐signal task outside the scanner. We explored the differences between OCD and HC groups in the functional connectivity of pre‐SMA and IFG associated with the ability of motor response inhibition. OCD patients showed a longer stop‐signal reaction time (SSRT). Compared to HC, OCD patients exhibit different associations between the ability of motor response inhibition and the functional connectivity between pre‐SMA and IFG, inferior parietal lobule, dorsal anterior cingulate cortex, insula, and anterior prefrontal cortex. Additional analysis to investigate the functional connectivity difference from the seed ROIs to the whole brain voxels revealed that, compared to HC, OCD exhibited greater functional connectivity between pre‐SMA and IFG. Also, this functional connectivity was positively correlated with the SSRT score. These results provide additional insight into the characteristics of the resting‐state functional connectivity of the regions belonging to the cortico‐striato‐thalamo‐cortical circuit and the cingulo‐opercular salience network, underlying the impaired motor response inhibition of OCD. In particular, we emphasize the importance of altered functional connectivity between pre‐SMA and IFG for the pathophysiology of motor response inhibition in OCD. Obsessive–compulsive disorder patients had significantly different associations between the abilities of motor response inhibition and the resting‐state functional connectivity from pre‐SMA to IPL, IFG, dACC and anterior‐insula. Additionally, compared to healthy control, OCD exhibited greater functional connectivity between pre‐SMA and IFG, and this functional connectivity was correlated with the the abilities of motor response inhibition.

Obsessive–compulsive disorder (OCD) is a chronic, severe mental illness with up to 2–3% prevalence worldwide. In fact, OCD has been classified as one of the world's 10 leading causes of illness‐related disability according to the World Health Organization, largely because of the chronic nature of disabling symptoms.[1] Despite the severity and high prevalence of this chronic and disabling disorder, there is still relatively limited understanding of its pathophysiology. However, this is now rapidly changing due to development of powerful technologies that can be used to dissect the neural circuits underlying pathologic behaviors. In this article, we describe recent technical advances that have allowed neuroscientists to start identifying the circuits underlying complex repetitive behaviors using animal model systems. In addition, we review current surgical and stimulation‐based treatments for OCD that target circuit dysfunction. Finally, we discuss how findings from animal models may be applied in the clinical arena to help inform and refine targeted brain stimulation‐based treatment approaches.

Cortico-striato-thalamo-cortical (CSTC) loops are fundamental organizing units in mammalian brains. CSTCs process limbic, associative, and sensorimotor information in largely separated but interacting networks. CTSC loops pass through paired striatal compartments, striosome (aka patch) and matrix, segregated pools of medium spiny projection neurons with distinct embryologic origins, cortical/subcortical structural connectivity, susceptibility to injury, and roles in behaviors and diseases. Similarly, striatal dopamine modulates activity in striosome and matrix in opposite directions. Routing CSTCs through one compartment may be an anatomical basis for regulating discrete functions. We used differential structural connectivity, identified through probabilistic diffusion tractography, to distinguish the striatal compartments (striosome-like and matrix-like voxels) in living humans. We then mapped compartment-specific projections and quantified structural connectivity between each striatal compartment, the globus pallidus interna (GPi), and 20 thalamic nuclei in 221 healthy adults. We found that striosome-originating and matrix-originating streamlines were segregated within the GPi: striosome-like connectivity was significantly more rostral, ventral, and medial. Striato-pallido-thalamic streamline bundles that were seeded from striosome-like and matrix-like voxels transited spatially distinct portions of the white matter. Matrix-like streamlines were 5.7-fold more likely to reach the GPi, replicating animal tract-tracing studies. Striosome-like connectivity dominated in six thalamic nuclei (anteroventral, central lateral, laterodorsal, lateral posterior, mediodorsal-medial, and medial geniculate). Matrix-like connectivity dominated in seven thalamic nuclei (centromedian, parafascicular, pulvinar-anterior, pulvinar-lateral, ventral lateral-anterior, ventral lateral-posterior, ventral posterolateral). Though we mapped all thalamic nuclei independently, functionally-related nuclei were matched for compartment-level bias. We validated these results with prior thalamostriate tract tracing studies in non-human primates and other species; where reliable data was available, all agreed with our measures of structural connectivity. Matrix-like connectivity was lateralized (left > right hemisphere) in 18 thalamic nuclei, independent of handedness, diffusion protocol, sex, or whether the nucleus was striosome-dominated or matrix-dominated. Compartment-specific biases in striato-pallido-thalamic structural connectivity suggest that routing CSTC loops through striosome-like or matrix-like voxels is a fundamental mechanism for organizing and regulating brain networks. Our MRI-based assessments of striato-thalamic connectivity in humans match and extend the results of prior tract tracing studies in animals. Compartment-level characterization may improve localization of human neuropathologies and improve neurosurgical targeting in the GPi and thalamus.

Tourette syndrome (TS) is a neuropsychiatric disorder with the core phenomenon of tics, whose origin and temporal pattern are unclear. We investigated the When and Where of tic generation and resting state networks (RSNs) via functional magnetic resonance imaging (fMRI). Tic-related activity and the underlying RSNs in adult TS were studied within one fMRI session. Participants were instructed to lie in the scanner and to let tics occur freely. Tic onset times, as determined by video-observance were used as regressors and added to preceding time-bins of 1 s duration each to detect prior activation. RSN were identified by independent component analysis (ICA) and correlated to disease severity by the means of dual regression. Two seconds before a tic, the supplementary motor area (SMA), ventral primary motor cortex, primary sensorimotor cortex and parietal operculum exhibited activation; 1 s before a tic, the anterior cingulate, putamen, insula, amygdala, cerebellum and the extrastriatal-visual cortex exhibited activation; with tic-onset, the thalamus, central operculum, primary motor and somatosensory cortices exhibited activation. Analysis of resting state data resulted in 21 components including the so-called default-mode network. Network strength in those regions in SMA of two premotor ICA maps that were also active prior to tic occurrence, correlated significantly with disease severity according to the Yale Global Tic Severity Scale (YGTTS) scores. We demonstrate that the temporal pattern of tic generation follows the cortico-striato-thalamo-cortical circuit, and that cortical structures precede subcortical activation. The analysis of spontaneous fluctuations highlights the role of cortical premotor structures. Our study corroborates the notion of TS as a network disorder in which abnormal RSN activity might contribute to the generation of tics in SMA.

Tic disorder (TD) is a developmental neuropsychiatric disorder that primarily occurs during childhood and impacts the quality of life and psychosocial function of patients. The pathogenesis of TD involves the dysregulation of the cortico-striato-thalamo-cortical (CSTC) circuit and metabolic abnormalities may serve an important role. The aim of the present study was to detect and analyze the metabolic abnormalities in the CSTC circuit in TD, providing a reference value for the study of its pathogenesis. A total of 10 male Wistar rats were randomly divided into the control (CK) group (n=5) and the TD group (n=5). Each rat received a daily intraperitoneal injection of 0.9% saline or 3,3′-iminodipropionitrile for 7 consecutive days. Tissues were collected from the striatum and cortex, and ultra-performance liquid chromatography-tandem mass spectrometry was used to measure metabolite concentrations in the brain tissue samples. Significant differences in the metabolites and metabolic pathways of the CK and TD groups were observed. In the striatum, 13 differentially present metabolites were observed between the CK group and TD group, while 21 differentially present metabolites were identified in the cortex. In the CSTC circuit, the common significantly differentially present metabolites were progesterone, corticosterone, deoxycorticosterone, 11-dehydrocorticosterone, chenodeoxycholic acid and hyodeoxycholic acid. The common differentially present metabolic pathways were 'steroid hormone biosynthesis' and 'aldosterone synthesis and secretion'. Notably, the abnormality of the 'tryptophan metabolism' pathway was only present in the cortex. These results indicated that there were metabolic abnormalities in the CSTC circuit in TD. The most significantly differentially present metabolite was progesterone. 'Steroid hormone biosynthesis' and 'aldosterone synthesis and secretion' were the significantly altered metabolic pathways in TD.

Major depressive disorder (MDD), characterized by low mood or anhedonia, is commonly associated with a greater suicidal susceptibility. There are numerous suicide-related findings pertaining to the dorsolateral prefrontal cortex (DLPFC), caudate nucleus and thalamus, which form a cortico-striato-thalamo-cortical (CSTC) circuit responsible for executive function and working memory. An aberrant CSTC circuitry is hypothesized to be implicated in depressed patients with a high suicidal risk. 27 MDD patients were assessed with the Nurses Global Assessment of Suicide Risk (NGASR), following which 14 patients were classified into a high suicide risk group (NGASR ≥ 12) and 13 patients were assigned to a low suicide risk group (NGASR < 6). All 27 patients were enrolled with 25 healthy controls for resting-state magnetoencephalography (MEG). Cross-frequency coupling (CFC) measured the phase of alpha-band (8–13 Hz) as it modulated to cortical gamma-band (30–48 Hz). There was a significantly lower alpha-to-gamma phase-amplitude coupling (PAC) between the right caudate and left thalamus in high-risk suicide group compared to both the low-risk suicide group and healthy controls. The presence of a weaker coupling between the right caudate and left thalamus is indicative of a caudothalamic abnormality in suicidally depressed patients. This implies that a disruption of CSTC loop could result in executive dysfunction and working memory impairment, leading to an increased suicidal risk in MDD patients. In the future, this preliminary study has the possibility of being replicated on a larger scale, and hence validates caudothalamic dysfunction as a reliable neuroimaging biomarker for suicide in depression.

Attention, suggestion, context and expectation can all exert top-down influence on bottom-up processes (e.g., stimulus-driven mechanisms). Identifying the functional neuroanatomy that subserves top-down influences on sensory information processing can unlock the neural substrates of how suggestion can modulate behavior. Using functional magnetic resonance imaging (fMRI), we scanned 10 healthy participants (five men) viewing five bistable figures. Participants received a directional cue to perceive a particular spatial orientation a few seconds before the bistable figure appeared. After presentation, participants pressed a button to indicate their locking into the one desired orientation of the two possible interpretations. Participants additionally performed tests of impulse control and sustained attention. Our findings reveal the role of specific frontostriatal structures in selecting a particular orientation for bistable figures, including dorsolateral prefrontal regions and the putamen. Additional contrasts further bolstered the role of the frontostriatal system in the top-down processing of competing visual perceptions. Separate correlations of behavioral variables with fMRI activations support the idea that the frontostriatal system may mediate attentional control when selecting among competing visual perceptions. These results may generalize to other psychological functions. With special relevance to clinical neuroscience and applications involving attention, expectation and suggestion (e.g., hypnosis), our results address the importance of frontostriatal circuitry in behavioral modulation.

Cognitive theories of obsessive-compulsive disorder (OCD) stress the importance of dysfunctional beliefs in the development and maintenance of the disorder. However, a neurobiological understanding of these cognitive models, including thought-action fusion (TAF), is surprisingly lacking. Thus, this functional magnetic resonance imaging study aimed to investigate whether altered functional connectivity (FC) is associated with the TAF paradigm in OCD patients. Forty-one OCD patients and 47 healthy controls (HCs) participated in a functional magnetic resonance imaging study using a TAF task, in which they were asked to read the name of a close or a neutral person in association with positive and negative statements. The conventional TAF condition (negative statements/close person) induced significant FC between the regions of interest (ROIs) identified using multivoxel pattern analysis and the visual association areas, default mode network subregions, affective processing, and several subcortical regions in both groups. Notably, sparser FC was observed in OCD patients. Further analysis confined to the cortico-striato-thalamo-cortical (CSTC) and affective networks demonstrated that OCD patients exhibited reduced ROI FC with affective regions and greater ROI FC with CSTC components in the TAF condition compared to HCs. Within the OCD patients, middle cingulate cortex-insula FC was correlated with TAF and responsibility scores. Our TAF paradigm revealed altered context-dependent engagement of the CSTC and affective networks in OCD patients. These findings suggest that the neurobiology of cognitive models corresponds to current neuroanatomical models of OCD. Further, they elucidate the underlying neurobiological mechanisms of OCD at the circuit-based level.

Obsessive–compulsive disorder (OCD) is characterized by obsessions (persistent, intrusive, unwanted thoughts, images or impulses) and compulsions (mental or physical acts performed to reduce the anxiety associated with obsessions). Neuroimaging and animal studies have implicated hyperactivation of frontal cortico-striato-thalamo-cortical circuits (CSTC). Genetic studies have demonstrated a significant hereditary component to OCD although the exact genetic risk factors for OCD have not been identified. Selective serotonin reuptake inhibitors and cognitive–­behavioral therapy are first-line, evidence-based treatments for OCD. Although a substantial majority of both ­children and adults with OCD improve with evidence-based treatments, approximately one-quarter of individuals with OCD do not respond to them. Antipsychotic augmentation is an additional pharmacological treatment strategy with proven efficacy in treatment-refractory OCD. Other emerging treatments for OCD include deep brain ­stimulation, glutamate modulating agents, and repetitive transcranial magnetic stimulation.