Striatal hypoactivation during monetary loss anticipation in individuals with substance use disorders in a heterogenous urban American Indian sample.

Research suggests that disproportionate exposure to risk factors places American Indian (AI) peoples at higher risk for substance use disorders (SUD). Although SUD is linked to striatal prioritization of drug rewards over other appetitive stimuli, there are gaps in the literature related to the investigation of aversive valuation processing, and inclusion of AI samples. To address these gaps, this study compared striatal anticipatory gain and loss processing between AI-identified with SUD (SUD+; n = 52) and without SUD (SUD-; n = 35) groups from the Tulsa 1000 study who completed a monetary incentive delay (MID) task during functional magnetic resonance imaging. Results indicated that striatal activations in the nucleus accumbens (NAcc), caudate, and putamen were greatest for anticipating gains (ps < 0.001) but showed no group differences. In contrast to gains, the SUD+ exhibited lower NAcc (p = .01, d =0.53) and putamen (p = .04, d =0.40) activation to anticipating large losses than the comparison group. Within SUD+ , lower striatal responses during loss anticipations were associated with slower MID reaction times (NAcc: r = -0.43; putamen: r = -0.35) during loss trials. This is among the first imaging studies to examine underlying neural mechanisms associated with SUD within AIs. Attenuated loss processing provides initial evidence of a potential mechanism wherein blunted prediction of aversive consequences may be a defining feature of SUD that can inform future prevention and intervention targets.

Impaired XK recycling for importing manganese underlies striatal vulnerability in Huntington's disease.

Mutant huntingtin, which causes Huntington's disease (HD), is ubiquitously expressed but induces preferential loss of striatal neurons by unclear mechanisms. Rab11 dysfunction mediates homeostatic disturbance of HD neurons. Here, we report that Rab11 dysfunction also underscores the striatal vulnerability in HD. We profiled the proteome of Rab11-positive endosomes of HD-vulnerable striatal cells to look for protein(s) linking Rab11 dysfunction to striatal vulnerability in HD and found XK, which triggers the selective death of striatal neurons in McLeod syndrome. XK was trafficked together with Rab11 and was diminished on the surface of immortalized HD striatal cells and striatal neurons in HD mouse brains. We found that XK participated in transporting manganese, an essential trace metal depleted in HD brains. Introducing dominantly active Rab11 into HD striatal cells improved XK dynamics and increased manganese accumulation in an XK-dependent manner. Our study suggests that impaired Rab11-based recycling of XK onto cell surfaces for importing manganese is a driver of striatal dysfunction in Huntington's disease.

Mapping dopaminergic projections in the human brain with resting-state fMRI.

The striatum receives dense dopaminergic projections, making it a key region of the dopaminergic system. Its dysfunction has been implicated in various conditions including Parkinson's disease (PD) and substance use disorder. However, the investigation of dopamine-specific functioning in humans is problematic as current MRI approaches are unable to differentiate between dopaminergic and other projections. Here, we demonstrate that 'connectopic mapping' - a novel approach for characterizing fine-grained, overlapping modes of functional connectivity - can be used to map dopaminergic projections in striatum. We applied connectopic mapping to resting-state functional MRI data of the Human Connectome Project (population cohort; N = 839) and selected the second-order striatal connectivity mode for further analyses. We first validated its specificity to dopaminergic projections by demonstrating a high spatial correlation (r = 0.884) with dopamine transporter availability - a marker of dopaminergic projections - derived from DaT SPECT scans of 209 healthy controls. Next, we obtained the subject-specific second-order modes from 20 controls and 39 PD patients scanned under placebo and under dopamine replacement therapy (L-DOPA), and show that our proposed dopaminergic marker tracks PD diagnosis, symptom severity, and sensitivity to L-DOPA. Finally, across 30 daily alcohol users and 38 daily smokers, we establish strong associations with self-reported alcohol and nicotine use. Our findings provide evidence that the second-order mode of functional connectivity in striatum maps onto dopaminergic projections, tracks inter-individual differences in PD symptom severity and L-DOPA sensitivity, and exhibits strong associations with levels of nicotine and alcohol use, thereby offering a new biomarker for dopamine-related (dys)function in the human brain.

Scn1a gene reactivation after symptom onset rescues pathological phenotypes in a mouse model of Dravet syndrome.

Dravet syndrome is a severe epileptic encephalopathy caused primarily by haploinsufficiency of the SCN1A gene. Repetitive seizures can lead to endurable and untreatable neurological deficits. Whether this severe pathology is reversible after symptom onset remains unknown. To address this question, we generated a Scn1a conditional knock-in mouse model (Scn1a Stop/+) in which Scn1a expression can be re-activated on-demand during the mouse lifetime. Scn1a gene disruption leads to the development of seizures, often associated with sudden unexpected death in epilepsy (SUDEP) and behavioral alterations including hyperactivity, social interaction deficits and cognitive impairment starting from the second/third week of age. However, we showed that Scn1a gene re-activation when symptoms were already manifested (P30) led to a complete rescue of both spontaneous and thermic inducible seizures, marked amelioration of behavioral abnormalities and normalization of hippocampal fast-spiking interneuron firing. We also identified dramatic gene expression alterations, including those associated with astrogliosis in Dravet syndrome mice, that, accordingly, were rescued by Scn1a gene expression normalization at P30. Interestingly, regaining of Nav1.1 physiological level rescued seizures also in adult Dravet syndrome mice (P90) after months of repetitive attacks. Overall, these findings represent a solid proof-of-concept highlighting that disease phenotype reversibility can be achieved when Scn1a gene activity is efficiently reconstituted in brain cells.

Physical exercise influences astrocytes in the striatum of a Parkinson's disease male mouse model.

Physical exercise is considered an adjuvant treatment to Parkinson's disease (PD) patients, possibly reducing inflammatory responses in the brain. Studies have stated that physical exercise protects dopaminergic neurons in PD models produced by neurotoxins. However, few studies focused on immunohistochemically reacted astrocytes and morphometric analyses of these cells in a PD mouse model submitted to physical exercise. We investigated the effects of treadmill training on striatal astrocytes of a PD mouse model combining immunohistochemistry and western-blotting for glial fibrillary acidic protein (GFAP) with morphometric analyses. Male Swiss mice were divided into 4 groups: sedentary control (SEDCONT), exercise control (EXERCONT), sedentary Parkinson (SEDPD), and exercise Parkinson (EXERPD). Stereotaxic bilateral injections of 6-hydroxydopamine into the striatum were adopted for PD groups. Striatal astrocytes showed increased GFAP in EXERPD, and we observed a higher level of GFAP in EXERPD than SEDPD. The number of primary and secondary processes was similar in striatal astrocytes of control groups and EXERPD. The astrocyte primary processes of SEDPD were larger than those of EXERPD, EXERCONT and SEDCONT. Cell body diameters and areas showed no difference between groups. We concluded that physical exercise influences striatal astrocytes in exercised parkinsonian mice.

Dopamine depletion selectively disrupts interactions between striatal neuron subtypes and LFP oscillations.

Dopamine degeneration in Parkinson's disease (PD) dysregulates the striatal neural network and causes motor deficits. However, it is unclear how altered striatal circuits relate to dopamine-acetylcholine chemical imbalance and abnormal local field potential (LFP) oscillations observed in PD. We perform a multimodal analysis of the dorsal striatum using cell-type-specific calcium imaging and LFP recording. We reveal that dopamine depletion selectively enhances LFP beta oscillations during impaired locomotion, supporting beta oscillations as a biomarker for PD. We further demonstrate that dynamic cholinergic interneuron activity during locomotion remains unaltered, even though cholinergic tone is implicated in PD. Instead, dysfunctional striatal output arises from elevated coordination within striatal output neurons, which is accompanied by reduced locomotor encoding of parvalbumin interneurons and transient pathological LFP high-gamma oscillations. These results identify a pathological striatal circuit state following dopamine depletion where distinct striatal neuron subtypes are selectively coordinated with LFP oscillations during locomotion.

Increased functional connectivity between presupplementary motor area and inferior frontal gyrus associated with the ability of motor response inhibition in obsessive-compulsive disorder.

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.

Chronic alcohol drinking persistently suppresses thalamostriatal excitation of cholinergic neurons to impair cognitive flexibility.

Exposure to addictive substances impairs flexible decision making. Cognitive flexibility is mediated by striatal cholinergic interneurons (CINs). However, how chronic alcohol drinking alters cognitive flexibility through CINs remains unclear. Here, we report that chronic alcohol consumption and withdrawal impaired reversal of instrumental learning. Chronic alcohol consumption and withdrawal also caused a long-lasting (21 days) reduction of excitatory thalamic inputs onto CINs and reduced pause responses of CINs in the dorsomedial striatum (DMS). CINs are known to inhibit glutamatergic transmission in dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) but facilitate this transmission in D2-MSNs, which may contribute to flexible behavior. We discovered that chronic alcohol drinking impaired CIN-mediated inhibition in D1-MSNs and facilitation in D2-MSNs. Importantly, in vivo optogenetic induction of long-term potentiation of thalamostriatal transmission in DMS CINs rescued alcohol-induced reversal learning deficits. These results demonstrate that chronic alcohol drinking reduces thalamic excitation of DMS CINs, compromising their regulation of glutamatergic transmission in MSNs, which may contribute to alcohol-induced impairment of cognitive flexibility. These findings provide a neural mechanism underlying inflexible drinking in alcohol use disorder.

Altered resting-state functional connectivity of the frontal-striatal circuit in elderly with apathy.

Apathy is defined as reduction of goal-directed behaviors and a common nuisance syndrome of neurodegenerative and psychiatric disease. The underlying mechanism of apathy implicates changes of the front-striatal circuit, but its precise alteration is unclear for apathy in healthy aged people. The aim of our study is to investigate how the frontal-striatal circuit is changed in elderly with apathy using resting-state functional MRI. Eighteen subjects with apathy (7 female, 63.7 ± 3.0 years) and eighteen subjects without apathy (10 female, 64.8 ± 3.0 years) who underwent neuropsychological assessment and MRI measurement were recruited. We compared functional connectivity with/within the striatum between the apathy and non-apathy groups. The seed-to-voxel group analysis for functional connectivity between the striatum and other brain regions showed that the connectivity was decreased between the ventral rostral putamen and the right dorsal anterior cingulate cortex/supplementary motor area in the apathy group compared to the non-apathy group while the connectivity was increased between the dorsal caudate and the left sensorimotor area. Moreover, the ROI-to-ROI analysis within the striatum indicated reduction of functional connectivity between the ventral regions and dorsal regions of the striatum in the apathy group. Our findings suggest that the changes in functional connectivity balance among different frontal-striatum circuits contribute to apathy in elderly.

Prior Methamphetamine Use Disorder History Does Not Impair Interoceptive Processing of Soft Touch in HIV Infection.

INTRODUCTION: Interoception, defined as the sense of the internal state of one's body, helps motivate goal-directed behavior. Prior work has shown that methamphetamine (METH) use disorder is associated with altered interoception, and that this may contribute to risky behavior. As people with HIV (PWH) may also experience disrupted bodily sensations (e.g., neuropathy), an important question is whether PWH with a history of METH use disorder might exhibit greater impairment of interoceptive processing. METHODS: Eighty-three participants stratified by HIV infection and a past history of methamphetamine use disorder experienced a soft touch paradigm that included slow brush strokes on the left forearm and palm during blood-oxygen level-dependent functional MRI acquisition. To assess differences in interoception and reward, voxelwise analyses were constrained to the insula, a hub for the evaluation of interoceptive cues, and the striatum, which is engaged in reward processing. RESULTS: Overall, individuals with a history of METH use disorder had an attenuated neural response to pleasant touch in both the insula and striatum. Longer abstinence was associated with greater neural response to touch in the insula, suggesting some improvement in responsivity. However, only PWH with no METH use disorder history had lower brain activation in the insula relative to non-using seronegative controls. CONCLUSIONS: Our findings suggest that while METH use disorder history and HIV infection independently disrupt the neural processes associated with interoception, PWH with METH use disorder histories do not show significant differences relative to non-using seronegative controls. These findings suggest that the effects of HIV infection and past methamphetamine use might not be additive with respect to interoceptive processing impairment.

Unilateral Intrastriatal 6-Hydroxydopamine Lesion in Mice: A Closer Look into Non-Motor Phenotype and Glial Response.

Parkinson's disease (PD) is a prevalent movement disorder characterized by the progressive loss of dopaminergic neurons in substantia nigra pars compacta (SNpc). The 6-hydroxydopamine (6-OHDA) lesion is still one of the most widely used techniques for modeling Parkinson's disease (PD) in rodents. Despite commonly used in rats, it can be challenging to reproduce a similar lesion in mice. Moreover, there is a lack of characterization of the extent of behavioral deficits and of the neuronal loss/neurotransmitter system in unilateral lesion mouse models. In this study, we present an extensive behavioral and histological characterization of a unilateral intrastriatal 6-OHDA mouse model. Our results indicate significant alterations in balance and fine motor coordination, voluntary locomotion, and in the asymmetry's degree of forelimb use in 6-OHDA lesioned animals, accompanied by a decrease in self-care and motivational behavior, common features of depressive-like symptomatology. These results were accompanied by a decrease in tyrosine hydroxylase (TH)-labelling and dopamine levels within the nigrostriatal pathway. Additionally, we also identify a marked astrocytic reaction, as well as proliferative and reactive microglia in lesioned areas. These results confirm the use of unilateral intrastriatal 6-OHDA mice for the generation of a mild model of nigrostriatal degeneration and further evidences the recapitulation of key aspects of PD, thereby being suitable for future studies beholding new therapeutical interventions for this disease.

Predicting Neuropsychiatric Symptoms of Parkinson's Disease with Measures of Striatal Dopaminergic Deficiency.

BACKGROUND: The role of nigrostriatal dopaminergic neurons degeneration is well established in the pathophysiology of Parkinson's disease. However, it is unclear if and how the degeneration of the dopamine pathways affects the manifestation of the neuropsychiatric symptoms (NPS) of Parkinson's Disease (PD). Dopamine transporter (DAT) imaging, a technique to measure the reduction in dopamine transporters is increasingly used as a tool in the diagnosis of PD. METHODS: In this study, we examine if the baseline dopamine transporter density in the striatum measured by the Striatal Binding Ratio (SBR) is associated with the longitudinal onset and/or progression of NPS in PD as measured by part 1 of Movement Disorder Society - Unified Parkinson's Disease Rating Scale, over four years. Data of patients with PD and an abnormal screening present on 123I-ioflupane single-proton emission computed tomography were obtained from Parkinson's Progression Markers Initiative (PPMI) database. Latent Growth Modeling (LGM), a statistical technique that can model the change over time while considering the variability in the rate of change at the individual level, was used to examine the progression of NPS over time. RESULTS: The results indicate the SBR did not correlate with the baseline NPS but did correlate with the rate of change of NPS (p<0.001) over the next four years, even after eliminating age-related variance, which can be a significant confounding factor. CONCLUSION: In conclusion, this study showed gradual worsening in NPS in patients with Parkinson's disease, which inversely correlates with the density of the dopamine transporters as measured by SBR at baseline.

DNA methylation of Vesicular Glutamate Transporters in the mesocorticolimbic brain following early-life stress and adult ethanol exposure-an explorative study.

DNA methylation and gene expression can be altered by early life stress (ELS) and/or ethanol consumption. The present study aimed to investigate whether DNA methylation of the Vesicular Glutamate Transporters (Vglut)1-3 is related to previously observed Vglut1-3 transcriptional differences in the ventral tegmental area (VTA), nucleus accumbens (Acb), dorsal striatum (dStr) and medial prefrontal cortex (mPFC) of adult rats exposed to ELS, modelled by maternal separation, and voluntary ethanol consumption. Targeted next-generation bisulfite sequencing was performed to identify the methylation levels on 61 5'-cytosine-phosphate-guanosine-3' sites (CpGs) in potential regulatory regions of Vglut1, 53 for Vglut2, and 51 for Vglut3. In the VTA, ELS in ethanol-drinking rats was associated with Vglut1-2 CpG-specific hypomethylation, whereas bidirectional Vglut2 methylation differences at single CpGs were associated with ELS alone. Exposure to both ELS and ethanol, in the Acb, was associated with lower promoter and higher intronic Vglut3 methylation; and in the dStr, with higher and lower methylation in 26% and 43% of the analyzed Vglut1 CpGs, respectively. In the mPFC, lower Vglut2 methylation was observed upon exposure to ELS or ethanol. The present findings suggest Vglut1-3 CpG-specific methylation signatures of ELS and ethanol drinking, underlying previously reported Vglut1-3 transcriptional differences in the mesocorticolimbic brain.

Dorsal and ventral striatal functional connectivity shifts play a potential role in internet gaming disorder.

Animal models suggest transitions from non-addictive to addictive behavioral engagement are associated with ventral-to-dorsal striatal shifts. However, few studies have examined such features in humans, especially in internet gaming disorder (IGD), a proposed behavioral addiction. We recruited 418 subjects (174 with IGD; 244 with recreational game use (RGU)). Resting-state fMRI data were collected and functional connectivity analyses were performed based on ventral and dorsal striatal seeds. Correlations and follow-up spectrum dynamic causal model (spDCM) analyses were performed to examine relationships between the ventral/dorsal striatum and middle frontal gyrus (MFG). Longitudinal data were also analysed to investigate changes over time. IGD relative to RGU subjects showed lower ventral-striatum-to-MFG (mostly involving supplementary motor area (SMA)) and higher dorsal-striatum-to-MFG functional connectivity. spDCM revealed that left dorsal-striatum-to-MFG connectivity was correlated with IGD severity. Longitudinal data within IGD and RGU groups found greater dorsal striatal connectivity with the MFG in IGD versus RGU subjects. These findings suggest similar ventral-to-dorsal striatal shifts may operate in IGD and traditional addictions.

Social impairments in mice lacking the voltage-gated potassium channel Kv3.1.

Parvalbumin (PV)-expressing neurons have been implicated in the pathology of autism spectrum disorders (ASD). Loss of PV expression and/or reduced number of PV-expressing neurons have been reported not only in genetic and environmental rodent models of ASD, but also in post-mortem analyses of brain tissues from ASD vs. healthy control human subjects. PV-expressing neurons play a pivotal role in the maintenance of the balance between excitation and inhibition within neural circuits in part because of their fast-spiking properties. Their high firing rate is mostly regulated by the voltage-gated potassium channel Kv3.1. It is yet unknown whether disturbances in the electrophysiological properties of PV-expressing neurons per se can lead to behavioral disturbances. We assessed locomotor activity, social interaction, recognition and memory, and stereotypic behaviors in Kv3.1 wild-type (WT) and knockout (KO) mice. We then used Western Blot analyses to measure the impact of Kv3.1 deficiency on markers of GABA transmission (PV and GAD67) and neural circuit activity (Egr1). Deficiency in Kv3.1 channel is sufficient to induce social deficits, hyperactivity and stereotypic behaviors. These behavioral changes were independent of changes in GAD67 levels and associated with increased levels of PV protein in the prefrontal cortex and striatum. These findings reveal that a loss of PV expression is not a necessary factor to induce an ASD-like phenotype in mice and support the need for further investigation to fully understand the contribution of PV-expressing neurons to ASD pathology.

Altered corticostriatal synchronization associated with compulsive-like behavior in APP/PS1 mice.

Mild behavioral impairment (MBI), which can include compulsive behavior, is an early sign of Alzheimer's disease (AD), but its underlying neural mechanisms remain unclear. Here, we show that 3-5-month-old APP/PS1 mice display obsessive-compulsive disorder (OCD)-like behavior. The number of parvalbumin-positive (PV) interneurons and level of high gamma (γhigh) oscillation are significantly decreased in the striatum of AD mice. This is accompanied by enhanced ß-γhigh coupling and firing rates of putative striatal projection neurons (SPNs), indicating decorrelation between PV interneurons and SPNs. Local field potentials (LFPs) simultaneously recorded in prefrontal cortex (PFC) and striatum (Str) demonstrate a decrease in γhigh-band coherent activity and spike-field coherence in corticostriatal circuits of APP/PS1 mice. Furthermore, levels of GABAB receptor (GABABR), but not GABAA receptor (GABAAR), and glutamatergic receptors, were markedly reduced, in line with presymptomatic AD-related behavioral changes. These findings suggest that MBI occurs as early as 3-5 months in APP/PS1 mice and that altered corticostriatal synchronization may play a role in mediating the behavioral phenotypes observed.

Coordinated increase of reliable cortical and striatal ensemble activations during recovery after stroke.

Skilled movements rely on a coordinated cortical and subcortical network, but how this network supports motor recovery after stroke is unknown. Previous studies focused on the perilesional cortex (PLC), but precisely how connected subcortical areas reorganize and coordinate with PLC is unclear. The dorsolateral striatum (DLS) is of interest because it receives monosynaptic inputs from motor cortex and is important for learning and generation of fast reliable actions. Using a rat focal stroke model, we perform chronic electrophysiological recordings in motor PLC and DLS during long-term recovery of a dexterous skill. We find that recovery is associated with the simultaneous emergence of reliable movement-related single-trial ensemble spiking in both structures along with increased cross-area alignment of spiking. Our study highlights the importance of consistent neural activity patterns across brain structures during recovery and suggests that modulation of cross-area coordination can be a therapeutic target for enhancing motor function post-stroke.

Locomotor activity and resting local field potential oscillatory rhythms of 6-OHDA mouse model of Parkinson's disease in response to acute and repeated treatments with L-dopa.

Phase-amplitude coupling (PAC) of local field potential (LFP) has been recognized as higher-order representation of brain states. Neuronal loss in the striatum leads to Parkinson's disease (PD) symptoms and modifies LFP oscillation. However, PAC in the striatum of PD mouse model induced by 6-hydroxydopamne (6-OHDA) remained to be investigated. Male Swiss albino ICR mice were implanted with intracranial electrode and injected with 6-OHDA to the left striatum. Levodopa (L-dopa) (10 mg/kg, oral) was used for treatment once a day from day 15-19. Locomotor activity and resting LFP signals were selectively analyzed on day 15 and 19. One-way ANOVA revealed significant decreases in travelled distance induced by 6-OHDA on both days (p ≤ 0.05). However, the decreased travelled distances were significantly reversed by L-dopa. On day 15, LFP powers of theta, alpha, beta and low gamma waves were significantly increased by 6-OHDA injection and the powers of beta and low gamma were significantly reversed to control level by treatment with L-dopa. On day 19, LFP powers of delta, theta, alpha, beta and low gamma waves were significantly increased by 6-OHDA injection and the powers of low gamma were significantly reversed to control level by treatment with L-dopa. Theta-gamma PAC analyses also confirmed significant increase in modulation index (MI) induced by 6-OHDA on day 19. However, L-dopa failed to significantly reverse the MI to control level. These findings indicated theta-gamma coupling in the striatum of PD mouse model. Taken together, change in striatal theta-gamma PAC might be one of biomarkers in addition to hypokinesia and increased LFP powers that reflect disrupted neural mechanisms in PD mouse model.

Fronto-striatal structures related with model-based control as an endophenotype for obsessive-compulsive disorder.

Recent theories suggest a shift from model-based goal-directed to model-free habitual decision-making in obsessive-compulsive disorder (OCD). However, it is yet unclear, whether this shift in the decision process is heritable. We investigated 32 patients with OCD, 27 unaffected siblings (SIBs) and 31 healthy controls (HCs) using the two-step task. We computed behavioral and reaction time analyses and fitted a computational model to assess the balance between model-based and model-free control. 80 subjects also underwent structural imaging. We observed a significant ordered effect for the shift towards model-free control in the direction OCD > SIB > HC in our computational parameter of interest. However less directed analyses revealed no shift towards model-free control in OCDs. Nonetheless, we found evidence for reduced model-based control in OCDs compared to HCs and SIBs via 2nd stage reaction time analyses. In this measure SIBs also showed higher levels of model-based control than HCs. Across all subjects these effects were associated with the surface area of the left medial/right dorsolateral prefrontal cortex. Moreover, correlations between bilateral putamen/right caudate volumes and these effects varied as a function of group: they were negative in SIBs and OCDs, but positive in HCs. Associations between fronto-striatal regions and model-based reaction time effects point to a potential endophenotype for OCD.