Cortico-striatal-thalamo-cortical Research Articles

Aberrant Functional Connectivity of the Salience Network in Adult Patients with Tic Disorders: A Resting-State fMRI Study.

Tic disorders (TD) are characterized by the presence of motor and/or vocal tics. Common neurophysiological frameworks suggest dysregulations of the cortico-striatal-thalamo-cortical (CSTC) brain circuit that controls movement execution. Besides common tics, there are other "non-tic" symptoms that are primarily related to sensory perception, sensorimotor integration, attention, and social cognition. The existence of these symptoms, the sensory tic triggers, and the modifying effect of attention and cognitive control mechanisms on tics may indicate the salience network's (SN) involvement in the neurophysiology of TD. Resting-state functional MRI measurements were performed in 26 participants with TD and 25 healthy controls (HC). The group differences in resting-state functional connectivity patterns were measured based on seed-to-voxel connectivity analyses. Compared to HC, patients with TD exhibited altered connectivity between the core regions of the SN (insula, anterior cingulate cortex, and temporoparietal junction) and sensory, associative, and motor-related cortices. Furthermore, connectivity changes were observed in relation to the severity of tics in the TD group. The SN, particularly the insula, is likely to be an important site of dysregulation in TD. Our results provide evidence for large-scale neural deviations in TD beyond the CSTC pathologies. These findings may be relevant for developing treatment targets.

Psychological factors and brain magnetic resonance imaging metrics associated with fatigue in persons with multiple sclerosis

BackgroundBesides demographics and clinical factors, psychological variables and brain-tissue changes have been associated with fatigue in persons with multiple sclerosis (pwMS). Identifying predictors of fatigue could help to improve therapeutic approaches for pwMS.Therefore, we investigated predictors of fatigue using a multifactorial approach. Methods136 pwMS and 49 normal controls (NC) underwent clinical, neuropsychological, and magnetic resonance imaging examinations. We assessed fatigue using the “Fatigue Scale for Motor and Cognitive Functions”, yielding a total, motor, and cognitive fatigue score. We further analyzed global and subcortical brain volumes, white matter lesions and microstructural changes (examining fractional anisotropy; FA) along the cortico striatal thalamo cortical (CSTC) loop. Potential demographic, clinical, psychological, and magnetic resonance imaging predictors of total, motor, and cognitive fatigue were explored using multifactorial linear regression models. Results53% of pwMS and 20% of NC demonstrated fatigue. Besides demographics and clinical data, total fatigue in pwMS was predicted by higher levels of depression and reduced microstructural tissue integrity in the CSTC loop (adjusted R2 = 0.52, p < 0.001). More specifically, motor fatigue was predicted by lower education, female sex, higher physical disability, higher levels of depression, and self-efficacy (adjusted R2 = 0.54, p < 0.001). Cognitive fatigue was also predicted by higher levels of depression and lower self-efficacy, but in addition by FA reductions in the CSTC loop (adjusted R2 = 0.45, p < 0.001). ConclusionsOur results indicate that depression and self-efficacy strongly predict fatigue in MS. Incremental variance in total and cognitive fatigue was explained by microstructural changes along the CSTC loop, beyond demographics, clinical, and psychological variables.

Acetyl-11-keto-beta boswellic acid(AKBA) modulates CSTC-pathway by activating SIRT-1/Nrf2-HO-1 signalling in experimental rat model of obsessive-compulsive disorder: Evidenced by CSF, blood plasma and histopathological alterations

Obsessive-Compulsive disorder (OCD) is a long-term and persistent mental illness characterised by obsessive thoughts and compulsive behaviours. Numerous factors can contribute to the development or progression of OCD. These factors may result from the dysregulation of multiple intrinsic cellular pathways, including SIRT-1, Nrf2, and HO-1. Inhibitors of selective serotonin reuptake (SSRIs) are effective first-line treatments for OCD. In our ongoing research, we have investigated the role of SIRT-1, Nrf2, and HO-1, as well as the neuroprotective potential of Acetyl-11-keto-beta boswellic acid (AKBA) against behavioural and neurochemical changes in rodents treated with 8-OH-DPAT. In addition, the effects of AKBA were compared to those of fluvoxamine (FLX), a standard OCD medication. Injections of 8-OH-DPAT into the intra-dorso raphe nuclei (IDRN) of rats for seven days induced repetitive and compulsive behaviour accompanied by elevated oxidative stress, inflammatory processes, apoptosis, and neurotransmitter imbalances in CSF, blood plasma, and brain samples. Chronic administration of AKBA at 50 mg/kg and 100 mg/kg p.o. restored histopathological alterations in the cortico-striatal-thalamo-cortical (CSTC) pathway, including the cerebral cortex, striatum, and hippocampal regions. Our investigation revealed that when AKBA and fluvoxamine were administered together, the alterations were restored to a greater degree than when administered separately. These findings demonstrate that the neuroprotective effect of AKBA can serve as an effective basis for developing a novel OCD treatment.

Evaluation of iron deposition in the motor CSTC loop of a Chinese family with paroxysmal kinesigenic dyskinesia using quantitative susceptibility mapping.

Previous studies have revealed structural, functional, and metabolic changes in brain regions inside the cortico-striatal-thalamo-cortical (CSTC) loop in patients with paroxysmal kinesigenic dyskinesia (PKD), whereas no quantitative susceptibility mapping (QSM)-related studies have explored brain iron deposition in these areas. A total of eight familial PKD patients and 10 of their healthy family members (normal controls) were recruited and underwent QSM on a 3T magnetic resonance imaging system. Magnetic susceptibility maps were reconstructed using a multi-scale dipole inversion algorithm. Thereafter, we specifically analyzed changes in local mean susceptibility values in cortical regions and subcortical nuclei inside the motor CSTC loop. Compared with normal controls, PKD patients had altered brain iron levels. In the cortical gray matter area involved with the motor CSTC loop, susceptibility values were generally elevated, especially in the bilateral M1 and PMv regions. In the subcortical nuclei regions involved with the motor CSTC loop, susceptibility values were generally lower, especially in the bilateral substantia nigra regions. Our results provide new evidence for the neuropathogenesis of PKD and suggest that an imbalance in brain iron levels may play a role in PKD.

18.1 Beware of COVID-19 Roadblocks on the Frontostriatal Highway: Implications of the COVID-19 Pandemic for Youth With Tic Disorders

The neuropsychological profile of youth with chronic tic disorders (CTD) is characterized by an interaction between cognitive, motor, and emotional regulation skills. This triad can be linked to dysregulation within 3 parallel pathways comprising the cortico-striatal-thalamo-cortical (CSTC) network, and it likely accounts for high rates of comorbidity with CTD and OCD and ADHD. Youth with CTD may also be more vulnerable to learning, social, and other mood difficulties, and they may be at more risk of these challenges because of the COVID-19 pandemic.

Cingulum bundle connectivity in treatment-refractory compared to treatment-responsive patients with bipolar disorder and healthy controls: a tractography and surgical targeting analysis.

The clinical response of patients with bipolar disorder to medical treatment is variable. A better understanding of the underlying neural circuitry involved in bipolar treatment responsivity subtypes may provide insight into treatment resistance and aid in identifying an effective surgical target for deep brain stimulation (DBS) specific to the disorder. Despite considerable imaging research related to the disease, a paucity of comparative imaging analyses of treatment responsiveness exists. There are also no DBS targets designed expressly for patients with bipolar disorder. Therefore, the authors analyzed cingulum bundle axonal connectivity in relation to cortico-striatal-thalamo-cortical (CSTC) loops implicated in bipolar disorder across subjects who are responsive to treatment (RSP) and those who are refractory to therapy (REF), compared to healthy controls (HCs). Twenty-five subjects with bipolar disorder (13 RSP and 12 REF), diagnosed using the Mini International Neuropsychiatric Interview and classified with standardized rating scales, and 14 HCs underwent MRI with diffusion sequences for probabilistic diffusion-weighted tractography analysis. Image processing and tractography were performed using MRTrix. Region of interest (ROI) masks were created manually for 10 anterior cingulum bundle subregions, including surgical targets previously evaluated for the treatment of bipolar disorder (cingulotomy and subgenual cingulate DBS targets). Cortical and subcortical ROIs of brain areas thought to be associated with bipolar disorder and described in animal tract-tracing models were created via FreeSurfer. The number of axonal projections from the cingulum bundle subregion ROIs to cortical/subcortical ROIs for each group was compared. Significant differences were found across groups involving cingulum bundle and CSTC loops. Subjects in the RSP group had increased connections from rostral cingulum bundle to medial orbitofrontal cortex, which is part of the limbic CSTC loop, whereas subjects in the REF group had increased connectivity from rostral cingulum bundle to thalamus. Additionally, compared to HCs, both RSP and REF subjects had decreased cingulum bundle dorsal connectivity (dorsal anterior/posterior cingulate, dorsomedial/lateral frontal cortex) and increased cingulum bundle ventral connectivity (subgenual cingulate, frontal pole, lateral orbitofrontal cortex) involving limbic and associative CSTC loops. Findings demonstrate that bipolar treatment responsivity may be associated with significant differences in cingulum bundle connectivity in relation to CSTC loops, which may help identify a surgical target for bipolar disorder treatment via DBS in the future.

The 43rd Annual Meeting of the Canadian College of Neuropsychopharmacology, November 4, 2021Role of histone 3.3 lysine 27 methylation in conferring enduring stress susceptibilityDecreased medial prefrontal cortex glutamate levels in perimenopausal womenNovel treatments for autism-spectrum disorder based on genomics and systems biologyDissecting the role of DCC-positive prefrontal cortex projections in susceptibility to social defeat stress in adulthoodChronic desipramine induces norepinephrine

| 10:30 am | Opening of Meeting | || | 10:45 am | Opening Remarks – Dr. Jeff Daskalakis, CCNP

Fentanyl-induced changes in brain activity in awake nonhuman primates at 9.4 Tesla.

Functional magnetic resonance imaging (fMRI) has been used to study the influence of opioids on neural circuitry implicated in opioid use disorder, such as the cortico-striatal-thalamo-cortical (CSTC) circuit. Given the increase in fentanyl-related deaths, this study was conducted to characterize the effects of fentanyl on patterns of brain activation in awake nonhuman primates. Four squirrel monkeys were acclimated to awake scanning procedures conducted at 9.4 Tesla. Subsequently, test sessions were conducted in which a dose of fentanyl that reliably maintains intravenous (IV) self-administration behavior in monkeys, 1μg/kg, was administered and the effects on patterns of brain activity were assessed using: (1) a pharmacological regressor to elucidate fentanyl-induced patterns of neural activity, and (2) seed-based approaches targeting bilateral anterior cingulate, thalamus, or nucleus accumbens (NAc) to determine alterations in CSTC functional connectivity. Results showed a functional inhibition of BOLD signal in brain regions that mediate behavioral effects of opioid agonists, such as cingulate cortex, striatum and midbrain. Functional connectivity between each of the seed regions and areas involved in motoric, sensory and cognition-related behavior generally decreased. In contrast, NAc functional connectivity with other striatal regions increased. These results indicate that fentanyl produces changes within CSTC circuitry that may reflect key features of opioid use disorder (e.g. persistent drug-taking/seeking) and thereby contribute to long-term disruptions in behavior and addiction. They also indicate that fMRI in alert nonhuman primates can detect drug-induced changes in neural circuits and, in turn, may be useful for investigating the effectiveness of medications to reverse drug-induced dysregulation.

41.1 UNDERSTANDING PSYCHOSOCIAL FUNCTIONING IN TIC DISORDERS THROUGH NEUROPSYCHOLOGICAL EVALUATION

Tic spectrum disorders have been linked to atypical development or dysregulation within parallel pathways comprising the cortico-striatal-thalamo-cortical (CSTC) network. These pathways regulate cognitive, motor, and affective processing, likely accounting for the high rates of comorbidity between Tourette’s disorder (TD), OCD, and ADHD. The emotional, social, and behavioral challenges shared by children and adolescents with these diagnoses can impair functioning at home, at school, and with peers, potentially increasing the risk for secondary mental health disorders (eg, depression). Neuropsychological testing is an important tool in characterizing an individual child’s functioning to determine the risk for psychosocial difficulties and points of intervention across a child’s functional domains. Drawing from published literature and clinical experience, an overview of neuropsychological testing and areas to target when evaluating children and adolescents who have tic spectrum disorders will be provided. Although most children and adolescents have typical intellectual functioning, children and adolescents who have tic spectrum disorders may present with select weaknesses in cognitive functioning, including attentional regulation and cognitive efficiency. There may also be higher rates of difficulties with motor skills, learning, and social communication. Identification of a child or adolescent’s specific vulnerabilities through neuropsychological evaluation can lead to tailored interventions at home, at school, and in social domains. Focusing on bolstering executive functioning and improving social skills is particularly important in improving quality of life and outcomes in youth with these challenging neurodevelopmental conditions.

Antiglutamatergic agents for obsessive-compulsive disorder: Where are we now and what are possible future prospects?

Recent data suggest that obsessive-compulsive disorder (OCD) is driven by an imbalance among the habit learning system and the goal-directed system. The frontostriatal loop termed cortico-striatal-thalamo-cortical (CSTC) circuitry loop is involved in habits and their dysfunction plays an important role in OCD. Glutamatergic neurotransmission is the principal neurotransmitter implicated in the CSTC model of OCD. Hyperactivity in the CSTC loop implies a high level of glutamate in the cortical-striatal pathways as well as a dysregulation of GABAergic transmission, and could represent the pathophysiology of OCD. Moreover, the dysregulation of glutamate levels can lead to neurotoxicity, acting as a neuronal excitotoxin. The hypothesis of a role of neurotoxicity in the pathophysiology of OCD clinically correlates to the importance of an early intervention for patients. Indeed, some studies have shown that a reduction of duration of untreated illness is related to an earlier onset of remission. Although robust data supporting a progression of such brain changes are not available so far, an early intervention could help interrupt damage from neurotoxicity. Moreover, agents targeting glutamate neurotransmission may represent promising therapeutical option in OCD patients.

Treatment Approaches Based on Neuroscientific Data in Patients With Obsessive-Compulsive Disorder

Background: Obsessive-compulsive disorder (OCD) is a severe psychological disorder that can be very disabling. Recent increasing neuroscientific data about OCD has provided important evidence that has started to change our knowledge about treatment. This paper offers an applied perspective of neuroscience on diagnosis and treatment preparation for people with OCD disease. The main aim is to enhance clinician-researcher communication to promote the conversion of developments in neuroscience research into better treatment for patients with OCD. Methods: A PubMed search was performed using the keywords "obsessive-compulsive disorder", "neuroimaging methods", "neuroscience", and "neurological treatment". The search provided sufficient articles published in peer-reviewed journals from 1995 to 2021. The data were obtained from these various sources and were included in this review. Results: The advancement of neurotherapeutic techniques targeting the cortico-striatal-thalamo-cortical (CSTC) circuit is the subject of a circuit dysregulation system. Also, according to neuroimaging studies, reductions in D2 receptors (about -18%), GABAA receptors (-15%), and cingulate 5-HT1A receptors (-18%) in patients with OCD were reported compared with healthy controls. Conclusion: The result suggests that DA, 5-HT, and GABA have considerable roles in anxiety- and compulsion-related disorders such as OCD. For patients with OCD, these core neuroscience themes collectively guide formulation and clinical preparation.

The neurobiology of environmentally induced stereotypic behaviours in captive animals: assessing the basal ganglia pathways and cortico-striatal-thalamo-cortical circuitry hypotheses

Abstract The neurobiology of environmentally induced stereotypic behaviours (SBs) (e.g., pacing in zoo carnivores, crib-biting in horses, tail chasing in dogs) is hypothesized to involve altered functioning within the basal ganglia (‘Basal Ganglia (BG) Pathways Hypotheses’) and/or between the basal ganglia and cortex (‘Cortico-Striatal-Thalamo-Cortical (CSTC) Circuits Hypotheses’). We review four decades of relevant studies, critically assessing support for both hypotheses. Currently no BG Pathways or CSTC Circuits hypothesis is fully supported. While some results are partially consistent with some hypotheses (decreased subthalamic nucleus activity in deer mice and C58 mice); others (nucleus accumbens activity in mink and C57 mice) seem to reflect individual differences in SB, but not environmental effects. Yet others can be tentatively rejected: neither elevated striatal dopamine nor the cortico-striatal connection of the sensorimotor circuit seem to be involved for most species studied to date. Further research is now important for understanding the impact of captivity on animals’ functioning.

Functional connectivity changes and symptoms improvement after personalized, double-daily dosing, repetitive transcranial magnetic stimulation in obsessive-compulsive disorder: A pilot study

Backgroundintrusive thoughts and compulsive behaviors that characterize obsessive compulsive disorder (OCD) are associated to aberrant resting state functional connectivity (rsFC) patterns within the cortico-striatal-thalamo-cortical (CSTC) circuits. A high percentage of OCD patients do not respond to conventional pharmacological treatments or psychotherapy. In these patients, inhibitory repetitive transcranial magnetic stimulation (rTMS) of the Supplementary Motor Area (SMA) resulted in a significant clinical benefit. MethodsIn the current study, we applied a novel protocol of 1-week MRI-guided individualized double-daily sessions of rTMS treatment (1-Hz; 110% of resting Motor Threshold/7200 pulses/day), to bilateral SMA in 9 OCD patients. We tested its (i) feasibility-safety, (ii) clinical efficacy and (iii) rsFC related changes. ResultsPatients reported no side effects during and after rTMS. Personalized rTMS treatment led to a significant improvement of OCD symptoms (average 25%; p = .005) and persistence of benefit up to 3-month follow-up. rsFC analysis revealed a significant reduction of connectivity patterns between bilateral SMA and subcortical regions, specifically in the basal ganglia and thalamus. Additional analysis showed that OCD symptoms severity correlates with a higher connectivity pattern between bilateral SMA and subcortical regions. ConclusionsrTMS double-daily sessions are safe, feasible and effective in OCD. The clinical outcomes, that are consistent with those found in our previous RCT, are linked to a decreased connectivity between SMA and subcortical brain areas implicated in control over obsessions and maladaptive compulsive behavior.

Case Report of Dual-Site Neurostimulation and Chronic Recording of Cortico-Striatal Circuitry in a Patient With Treatment Refractory Obsessive Compulsive Disorder.

Psychiatric disorders are increasingly understood as dysfunctions of hyper- or hypoconnectivity in distributed brain circuits. A prototypical example is obsessive compulsive disorder (OCD), which has been repeatedly linked to hyper-connectivity of cortico-striatal-thalamo-cortical (CSTC) loops. Deep brain stimulation (DBS) and lesions of CSTC structures have shown promise for treating both OCD and related disorders involving over-expression of automatic/habitual behaviors. Physiologically, we propose that this CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP). Here we report the results from the pilot patient in an Early Feasibility study (https://clinicaltrials.gov/ct2/show/NCT03184454) in which we use the Medtronic Activa PC+ S device to simultaneously record and stimulate in the supplementary motor area (SMA) and ventral capsule/ventral striatum (VC/VS). We hypothesized that frequency-mismatched stimulation should disrupt coherence and reduce compulsive symptoms. The patient reported subjective improvement in OCD symptoms and showed evidence of improved cognitive control with the addition of cortical stimulation, but these changes were not reflected in primary rating scales specific to OCD and depression, or during blinded cortical stimulation. This subjective improvement was correlated with increased SMA and VC/VS coherence in the alpha, beta, and gamma bands, signals which persisted after correcting for stimulation artifacts. We discuss the implications of this research, and propose future directions for research in network modulation in OCD and more broadly across psychiatric disorders.

Brain functional connectivity in chronic tic disorders and Gilles de la Tourette syndrome.

The pathophysiology of chronic tic disorder (cTD) and Gilles de la Tourette syndrome (GTS) is characterized by the dysfunction of both motor and non - motor cortico - striatal - thalamo - cortical (CSTC) circuitries, which leads to tic release and comorbids. A role of fronto - parietal network (FPN) connectivity breakdown has been postulated for tic pathogenesis, given that the FPN entertain connections with limbic, paralimbic, and CSTC networks. Our study was aimed at characterizing the FPN functional connectivity in cTD and GTS in order to assess the role of its deterioration in tic severity and the degree of comorbids. We recorded scalp EEG during resting state in patients with cTD and GTS. The eLORETA current source densities were analyzed, and the lagged phase synchronization (LPS) was calculated to estimate nonlinear functional connectivity between cortical areas. We found that the FPN functional connectivity in delta band was more detrimental in more severe GTS patients. Also, the sensorimotor functional connectivity in beta2 band was stronger in more severe cTD and GTS patients. FPN functional connectivity deterioration correlated with comorbids presence and severity in patients with GTS. Our data suggest that a FPN disconnection may contribute to the motoric symptomatology and comorbid severity in GTS, whereas sensorimotor disconnection may contribute to tic severity in cTD and GTS. Although preliminary, our study points out a differently disturbed brain connectivity between patients with cTD and GTS. This may serve as diagnostic marker and potentially interesting base to develop pharmacological and noninvasive neuromodulation trials aimed at reducing tic symptomatology.

Treating Psychiatric Illness Through Targeted Network Disruption and Electrical Biomarker Identification

Obsessive-Compulsive Disorder (OCD), has been linked to hyper-connectivity of Cortico-Striatal-Thalamo-Cortical (CSTC) loops. Deep brain stimulation (DBS) of CSTC structures has shown promise for treating OCD. Physiologically, we propose that CSTC hyper-connectivity may be reflected in high synchrony of neural firing between loop structures, which could be measured as coherent oscillations in the local field potential (LFP).

TICCY, STICKY, AND PICKY: HOW TO UNDERSTAND, DISENTANGLE, AND MANAGE CHILDHOOD ONSET REPETITIVE BEHAVIORS

Obsessive-compulsive spectrum disorders (OCSD), including OCD, body dysmorphic disorder (BDD), body-focused repetitive behaviors (BFRBs, such as trichotillomania and skin-picking disorder), and chronic tic disorders/Tourette’s disorder (TD) share overlapping clinical phenomenology and associated dysregulated subcortical neurocircuitry. The cortico-striatal-thalamo-cortical (CSTC) neural pathway is involved in the regulation of behaviors (cognitive and emotional), and as such, disruption can result in a variety of undesired, repetitive manifestations (ie, tics, obsessions/compulsions, picking/pulling). Given the frequent co-occurrence of OCSD and tic disorders—especially in the pediatric population—delineating between compulsions, symptoms of BDD, complex tics, and BFRBs poses clinical challenges and has significant treatment implications. The aim of this presentation is to teach attendees the epidemiology, phenomenology, underlying neurocircuitry, and treatment approaches for pediatric OCSD and tic disorders.

51.2 THOUGHTS, FEELINGS, ACTION! UNDERSTANDING PSYCHOSOCIAL FUNCTIONING IN OCD AND TIC DISORDERS THROUGH NEUROPSYCHOLOGICAL EVALUATIONS

OCD and tic disorders have both been linked to atypical development or dysregulation within parallel pathways comprising the cortico-striatal-thalamo-cortical (CSTC) network. These pathways regulate cognitive, motor, and affective processing, probably accounting for the high rates of comorbidity between OCD, Tourette’s disorder, and ADHD. The emotional and behavioral challenges shared by children with these diagnoses can impair functioning at home, at school, and with peers, potentially increasing risk for secondary mental health disorders (eg, depression). Neuropsychological testing is an important tool in characterizing an individual child’s functioning to determine risk for psychosocial difficulties and points of intervention across a child’s functional domains.

215. Recording and Disrupting Cortical-Striatal Hyperconnectivity in Obsessive-Compulsive Disorder

It has been proposed that Deep Brain Stimulation (DBS) works through altering brain networks that are implicated in psychiatric illness. In the case of obsessive-compulsive disorder (OCD), it is argued that a Cortico-Striatal-Thalamo-Cortical (CSTC) network is hyperconnected, leading to perseverative thought and behavior. We aim to disrupt this hyperconnectivity in CSTC by simultaneously stimulating striatal and cortical parts of this network via DBS.

Global and local excitation and inhibition shape the dynamics of the cortico-striatal-thalamo-cortical pathway

The cortico-striatal-thalamo-cortical (CSTC) pathway is a brain circuit that controls movement execution, habit formation and reward. Hyperactivity in the CSTC pathway is involved in obsessive compulsive disorder (OCD), a neuropsychiatric disorder characterized by the execution of repetitive involuntary movements. The striatum shapes the activity of the CSTC pathway through the coordinated activation of two classes of medium spiny neurons (MSNs) expressing D1 or D2 dopamine receptors. The exact mechanisms by which balanced excitation/inhibition (E/I) of these cells controls the network dynamics of the CSTC pathway remain unclear. Here we use non-linear modeling of neuronal activity and bifurcation theory to investigate how global and local changes in E/I of MSNs regulate the activity of the CSTC pathway. Our findings indicate that a global and proportionate increase in E/I pushes the system to states of generalized hyper-activity throughout the entire CSTC pathway. Certain disproportionate changes in global E/I trigger network oscillations. Local changes in the E/I of MSNs generate specific oscillatory behaviors in MSNs and in the CSTC pathway. These findings indicate that subtle changes in the relative strength of E/I of MSNs can powerfully control the network dynamics of the CSTC pathway in ways that are not easily predicted by its synaptic connections.