Understanding the biological basis of psychiatric disease: What's next?

Psychiatric disease is one of the greatest health challenges of our time. The pipeline for conceptually novel therapeutics remains low, in part because uncovering the biological mechanisms of psychiatric disease has been difficult. We asked experts researching different aspects of psychiatric disease: what do you see as the major urgent questions that need to be addressed? Where are the next frontiers, and what are the current hurdles to understanding the biological basis of psychiatric disease?

Developmental impact of glutamate transporter overexpression on dopaminergic neuron activity and stereotypic behavior.

Obsessive-compulsive disorder (OCD) is a disabling condition that often begins in childhood. Genetic studies in OCD have pointed to SLC1A1, which encodes the neuronal glutamate transporter EAAT3, with evidence suggesting that increased expression contributes to risk. In mice, midbrain Slc1a1 expression supports repetitive behavior in response to dopaminergic agonists, aligning with neuroimaging and pharmacologic challenge studies that have implicated the dopaminergic system in OCD. These findings suggest that Slc1a1 may contribute to compulsive behavior through altered dopaminergic transmission; however, this theory has not been mechanistically tested. To examine the developmental impact of Slc1a1 overexpression on compulsive-like behaviors, we, therefore, generated a novel mouse model to perform targeted, reversible overexpression of Slc1a1 in dopaminergic neurons. Mice with life-long overexpression of Slc1a1 showed a significant increase in amphetamine (AMPH)-induced stereotypy and hyperlocomotion. Single-unit recordings demonstrated that Slc1a1 overexpression was associated with increased firing of dopaminergic neurons. Furthermore, dLight1.1 fiber photometry showed that these behavioral abnormalities were associated with increased dorsal striatum dopamine release. In contrast, no impact of overexpression was observed on anxiety-like behaviors or SKF-38393-induced grooming. Importantly, overexpression solely in adulthood failed to recapitulate these behavioral phenotypes, suggesting that overexpression during development is necessary to generate AMPH-induced phenotypes. However, doxycycline-induced reversal of Slc1a1/EAAT3 overexpression in adulthood normalized both the increased dopaminergic firing and AMPH-induced responses. These data indicate that the pathologic effects of Slc1a1/EAAT3 overexpression on dopaminergic neurotransmission and AMPH-induced stereotyped behavior are developmentally mediated, and support normalization of EAAT3 activity as a potential treatment target for basal ganglia-mediated repetitive behaviors.

Corticostriatal dynamics underlying components of binge-like consumption of palatable food in mice.

Binge eating (BE) is a maladaptive repetitive feeding behavior present across nearly all eating disorder diagnoses. Despite the substantial negative impact of BE on psychological and physiological health, its underlying neural mechanisms are largely unknown. Other repetitive behavior disorders (e.g., obsessive compulsive disorder) show dysfunction within corticostriatal circuitry. However, to date, no work has investigated the in vivo neural dynamics underlying corticostriatal activity during BE episodes. The aim of the current study was to longitudinally examine in vivo neural activity within corticostriatal regions - the infralimbic cortex (IL) and dorsolateral striatum (DLS)- in a robust pre-clinical model for BE. Female C57BL6/J mice (N = 32) were randomized to receive: 1) intermittent (daily, 2-h) binge-like access to palatable food (sweetened condensed milk) (BE), or 2) continuous, non-intermittent (24-h) access to palatable food (control). In vivo calcium imaging was performed via fiber photometry at baseline and after chronic (4 weeks) engagement in the model for BE. Specific consummatory behaviors (feeding bout onset/offset) during recordings were captured using lickometers which generated TTL outputs for precise alignment of behavior to neural data. IL showed no specific changes in neural activity related to BE. However, BE animals showed decreased DLS activity at feeding onset and offset at the chronic timepoint when compared to activity at the baseline timepoint. Additionally, BE mice had significantly lower DLS activity at feeding onset and offset at the chronic timepoint compared to control mice. These results point to a role for DLS hypofunction in chronic BE, highlighting a potential target for future treatment intervention.

Lower excitatory synaptic gene expression in orbitofrontal cortex and striatum in an initial study of subjects with obsessive compulsive disorder.

Obsessive compulsive disorder (OCD) is a severe illness that affects 2-3% of people worldwide. OCD neuroimaging studies have consistently shown abnormal activity in brain regions involved in decision-making (orbitofrontal cortex [OFC]) and action selection (striatum). However, little is known regarding molecular changes that may contribute to abnormal function. We therefore examined expression of synaptic genes in post-mortem human brain samples of these regions from eight pairs of unaffected comparison and OCD subjects. Total grey matter tissue samples were obtained from medial OFC (BA11), lateral OFC (BA47), head of caudate, and nucleus accumbens (NAc). Quantitative polymerase chain reaction (qPCR) was then performed on a panel of transcripts encoding proteins related to excitatory synaptic structure, excitatory synaptic receptors/transporters, and GABA synapses. Relative to unaffected comparison subjects, OCD subjects had significantly lower levels of several transcripts related to excitatory signaling in both cortical and striatal regions. However, a majority of transcripts encoding excitatory synaptic proteins were lower in OFC but not significantly different in striatum of OCD subjects. Composite transcript level measures supported these findings by revealing that reductions in transcripts encoding excitatory synaptic structure proteins and excitatory synaptic receptors/transporters occurred primarily in OFC of OCD subjects. In contrast, transcripts associated with inhibitory synaptic neurotransmission showed minor differences between groups. The observed lower levels of multiple glutamatergic transcripts across both medial and lateral OFC may suggest an upstream causal event. Together, these data provide the first evidence of molecular abnormalities in brain regions consistently implicated in OCD human imaging studies.

Hippocampal-prefrontal input supports spatial encoding in working memory.

Spatial working memory, the caching of behaviourally relevant spatial cues on a timescale of seconds, is a fundamental constituent of cognition. Although the prefrontal cortex and hippocampus are known to contribute jointly to successful spatial working memory, the anatomical pathway and temporal window for the interaction of these structures critical to spatial working memory has not yet been established. Here we find that direct hippocampal-prefrontal afferents are critical for encoding, but not for maintenance or retrieval, of spatial cues in mice. These cues are represented by the activity of individual prefrontal units in a manner that is dependent on hippocampal input only during the cue-encoding phase of a spatial working memory task. Successful encoding of these cues appears to be mediated by gamma-frequency synchrony between the two structures. These findings indicate a critical role for the direct hippocampal-prefrontal afferent pathway in the continuous updating of task-related spatial information during spatial working memory.

Strengthened Inputs from Secondary Motor Cortex to Striatum in a Mouse Model of Compulsive Behavior.

Hyperactivity in striatum is associated with compulsive behaviors in obsessive-compulsive disorder (OCD) and related illnesses, but it is unclear whether this hyperactivity is due to intrinsic striatal dysfunction or abnormalities in corticostriatal inputs. Understanding the cellular and circuit properties underlying striatal hyperactivity could help inform the optimization of targeted stimulation treatments for compulsive behavior disorders. To investigate the cellular and synaptic abnormalities that may underlie corticostriatal dysfunction relevant to OCD, we used the Sapap3 knock-out (Sapap3-KO) mouse model of compulsive behaviors, which also exhibits hyperactivity in central striatum. Ex vivo electrophysiology in double-transgenic mice was used to assess intrinsic excitability and functional synaptic input in spiny projection neurons (SPNs) and fast-spiking interneurons (FSIs) in central striatum of Sapap3-KOs and wild-type (WT) littermates. While we found no differences in intrinsic excitability of SPNs or FSIs between Sapap3-KOs and WTs, excitatory drive to FSIs was significantly increased in KOs. Contrary to predictions, lateral orbitofrontal cortex-striatal synapses were not responsible for this increased drive; optogenetic stimulation revealed that lateral orbitofrontal cortex input to SPNs was reduced in KOs (∼3-fold) and unchanged in FSIs. However, secondary motor area (M2) postsynaptic responses in central striatum were significantly increased (∼6-fold) in strength and reliability in KOs relative to WTs. These results suggest that increased M2-striatal drive may contribute to both in vivo striatal hyperactivity and compulsive behaviors, and support a potential role for presupplementary/supplementary motor cortical regions in the pathology and treatment of compulsive behavior disorders.SIGNIFICANCE STATEMENT These findings highlight an unexpected contribution of M2 projections to striatal dysfunction in the Sapap3-KO obsessive-compulsive disorder (OCD)-relevant mouse model, with M2 inputs strengthened by at least sixfold onto both spiny projection neurons and fast-spiking interneurons in central striatum. Because M2 is thought to be homologous to presupplementary/supplementary motor areas (pre-SMA/SMA) in humans, regions important for movement preparation and behavioral sequencing, these data are consistent with a model in which increased drive from M2 leads to excessive selection of sequenced motor patterns. Together with observations of hyperactivity in pre-SMA/SMA in both OCD and Tourette syndrome, and evidence that pre-SMA is a potential target for repetitive transcranial magnetic stimulation treatment in OCD, these results support further dissection of the role of M2 in compulsivity.

The two-step task, avoidance, and OCD.

In this invited review, we argue for the need to determine whether appetitive and aversive behaviors, be they goal-directed or habitual, share overlapping neural circuitry. To motivate our argument, we first summarize what is currently known about the neural circuits governing aversive and appetitive behaviors by focusing first on the three hypothesized phases of avoidance learning, and then on goal-directed and habitual reward seeking. We then provide several reasons to believe that the neural circuits of appetitive and aversive instrumental behaviors are not completely overlapping. We next discuss an experimental strategy to determine the extent of overlap based on a new computational framework that improves the identification of goal-directed and habitual actions regardless of valence. Finally, we discuss recent work in obsessive-compulsive disorder that uses this computational framework to determine whether patients perform appetitive and aversive versions of the same task using the same behavioral strategies and neural circuits.

OCD candidate gene SLC1A1/EAAT3 impacts basal ganglia-mediated activity and stereotypic behavior.

Obsessive-compulsive disorder (OCD) is a chronic, disabling condition with inadequate treatment options that leave most patients with substantial residual symptoms. Structural, neurochemical, and behavioral findings point to a significant role for basal ganglia circuits and for the glutamate system in OCD. Genetic linkage and association studies in OCD point to SLC1A1, which encodes the neuronal glutamate/aspartate/cysteine transporter excitatory amino acid transporter 3 (EAAT3)/excitatory amino acid transporter 1 (EAAC1). However, no previous studies have investigated EAAT3 in basal ganglia circuits or in relation to OCD-related behavior. Here, we report a model of Slc1a1 loss based on an excisable STOP cassette that yields successful ablation of EAAT3 expression and function. Using amphetamine as a probe, we found that EAAT3 loss prevents expected increases in (i) locomotor activity, (ii) stereotypy, and (iii) immediate early gene induction in the dorsal striatum following amphetamine administration. Further, Slc1a1-STOP mice showed diminished grooming in an SKF-38393 challenge experiment, a pharmacologic model of OCD-like grooming behavior. This reduced grooming is accompanied by reduced dopamine D1 receptor binding in the dorsal striatum of Slc1a1-STOP mice. Slc1a1-STOP mice also exhibit reduced extracellular dopamine concentrations in the dorsal striatum both at baseline and following amphetamine challenge. Viral-mediated restoration of Slc1a1/EAAT3 expression in the midbrain but not in the striatum results in partial rescue of amphetamine-induced locomotion and stereotypy in Slc1a1-STOP mice, consistent with an impact of EAAT3 loss on presynaptic dopaminergic function. Collectively, these findings indicate that the most consistently associated OCD candidate gene impacts basal ganglia-dependent repetitive behaviors.

The Role of Response Inhibition in Medicated and Unmedicated Obsessive-Compulsive Disorder Patients: Evidence from the Stop-Signal Task.

BACKGROUND: Numerous studies have investigated response inhibition (RI) in obsessive-compulsive disorder (OCD), with many reporting that OCD patients demonstrate deficits in RI as compared to controls. However, reported effect sizes tend to be modest and results have been inconsistent, with some studies finding intact RI in OCD. To date, no study has examined the effect of medications on RI in OCD patients. METHODS: We analyzed results from a stop-signal task to probe RI in 65 OCD patients (32 of whom were medicated) and 58 healthy controls (HCs). RESULTS: There was no statistically significant difference in stop-signal reaction time between the OCD group and the HC group, or between the medicated and unmedicated OCD patients. However, variability was significantly greater in the medicated OCD group compared to the unmedicated group. CONCLUSIONS: These results indicate that some samples of OCD patients do not have deficits in RI, making it unlikely that deficient RI underlies repetitive behaviors in all OCD patients. Future research is needed to fully elucidate the impact of medication use on stop-signal performance. Implications for future research on the cognitive processes underlying repetitive thoughts and behaviors are discussed.

PREPULSE INHIBITION DEFICITS ONLY IN FEMALES WITH OBSESSIVE-COMPULSIVE DISORDER.

BACKGROUND: Deficits in sensorimotor gating have been hypothesized to underlie the inability to inhibit repetitive thoughts and behaviors. To test this hypothesis, this study assessed prepulse inhibition (PPI), a measure of sensorimotor gating, across three psychiatric disorders (obsessive-compulsive disorder [OCD], social anxiety disorder [SAD], and anorexia nervosa [AN]) whose clinical presentations include repetitive thoughts and behaviors METHODS: We tested acoustic PPI in unmedicated individuals with OCD (n = 45), SAD (n = 37), and AN (n = 26), and compared their results to matched healthy volunteers (n = 62). All participants completed a structured clinical interview and a clinical assessment of psychiatric symptom severity. RESULTS: Percent PPI was significantly diminished in females with OCD compared to healthy female volunteers (P = .039). No other differences between healthy volunteers and participants with disorders (male or female) were observed. Percent PPI was not correlated with severity of obsessions and compulsions, as measured by the Yale-Brown Obsessive Compulsive Scale. CONCLUSIONS: This is the first study to assess PPI in participants with SAD or AN, and the largest study to assess PPI in participants with OCD. We found PPI deficits only in females with OCD, which suggests that the cortico-striato-pallido-thalamic and pontine circuitry (believed to underlie PPI) differs between males and females with OCD. Given that PPI deficits were only present in females with OCD and not related to repetitive thoughts and behaviors, our results do not support the hypothesis that sensorimotor gating deficits, as measured by PPI, underlie the inability to inhibit repetitive thoughts and behaviors in individuals with OCD, SAD, and AN.

DISSECTING OCD CIRCUITS: FROM ANIMAL MODELS TO TARGETED TREATMENTS.

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.

Assessing neurocognitive function in psychiatric disorders: a roadmap for enhancing consensus.

It has been challenging to identify core neurocognitive deficits that are consistent across multiple studies in patients with Obsessive Compulsive Disorder (OCD). In turn, this leads to difficulty in translating findings from human studies into animal models to dissect pathophysiology. In this article, we use primary data from a working memory task in OCD patients to illustrate this issue. Working memory deficiencies have been proposed as an explanatory model for the evolution of checking compulsions in a subset of OCD patients. However, findings have been mixed due to variability in task design, examination of spatial vs. verbal working memory, and heterogeneity in patient populations. Two major questions therefore remain: first, do OCD patients have disturbances in working memory? Second, if there are working memory deficits in OCD, do they cause checking compulsions? In order to investigate these questions, we tested 19 unmedicated OCD patients and 23 matched healthy controls using a verbal working memory task that has increased difficulty/task-load compared to classic digit-span tasks. OCD patients did not significantly differ in their performance on this task compared to healthy controls, regardless of the outcome measure used (i.e. reaction time or accuracy). Exploratory analyses suggest that a subset of patients with predominant doubt/checking symptoms may have decreased memory confidence despite normal performance on trials with the highest working memory load. These results suggest that other etiologic factors for checking compulsions should be considered. In addition, they serve as a touchstone for discussion, and therefore help us to generate a roadmap for increasing consensus in the assessment of neurocognitive function in psychiatric disorders.

Forebrain EAAT3 Overexpression Increases Susceptibility to Amphetamine-Induced Repetitive Behaviors.

Obsessive-compulsive disorder (OCD) is a debilitating psychiatric disorder characterized by intrusive obsessive thoughts and compulsive behaviors. Multiple studies have shown the association of polymorphisms in the SLC1A1 gene with OCD. The most common of these OCD-associated polymorphisms increases the expression of the encoded protein, excitatory amino acid transporter 3 (EAAT3), a neuronal glutamate transporter. Previous work has shown that increased EAAT3 expression results in OCD-relevant behavioral phenotypes in rodent models. In this study, we created a novel mouse model with targeted, reversible overexpression of Slc1a1 in forebrain neurons. The mice do not have a baseline difference in repetitive behavior but show increased hyperlocomotion following a low dose of amphetamine (3 mg/kg) and increased stereotypy following a high dose of amphetamine (8 mg/kg). We next characterized the effect of amphetamine on striatal cFos response and found that amphetamine increased cFos throughout the striatum in both control and Slc1a1-overexpressing (OE) mice, but Slc1a1-OE mice had increased cFos expression in the ventral striatum relative to controls. We used an unbiased machine classifier to robustly characterize the behavioral response to different doses of amphetamine and found a unique response to amphetamine in Slc1a1-OE mice, relative to controls. Lastly, we found that the differences in striatal cFos expression in Slc1a1-OE mice were driven by cFos expression specifically in D1 neurons, as Slc1a1-OE mice had increased cFos in D1 ventral medial striatal neurons, implicating this region in the exaggerated behavioral response to amphetamine in Slc1a1-OE mice.

Hyperactivity of indirect pathway-projecting spiny projection neurons promotes compulsive behavior.

Compulsive behaviors are a hallmark symptom of obsessive compulsive disorder (OCD). Striatal hyperactivity has been linked to compulsive behavior generation in correlative studies in humans and causal studies in rodents. However, the contribution of the two distinct striatal output populations to the generation and treatment of compulsive behavior is unknown. These populations of direct and indirect pathway-projecting spiny projection neurons (SPNs) have classically been thought to promote or suppress actions, respectively, leading to a long-held hypothesis that increased output of direct relative to indirect pathway promotes compulsive behavior. Contrary to this hypothesis, here we find that indirect pathway hyperactivity is associated with compulsive grooming in the Sapap3-knockout mouse model of OCD-relevant behavior. Furthermore, we show that suppression of indirect pathway activity using optogenetics or treatment with the first-line OCD pharmacotherapy fluoxetine is associated with reduced grooming in Sapap3-knockouts. Together, these findings highlight the striatal indirect pathway as a potential treatment target for compulsive behavior.

Examination of onset trajectories and persistence of binge-like eating behavior in mice after intermittent palatable food exposure.

Binge eating is a persistent behavior associated with a chronic course of illness and poor treatment outcomes. While clinical research is unable to capture the full course of binge eating, preclinical approaches offer the opportunity to examine binge-like eating from onset through chronic durations, allowing identification of factors contributing to binge eating persistence. The present study quantified the trajectories of binge-like eating onset and modeled cycles of abstinence/relapse to develop a translational model for binge eating persistence. Adult male and female C57Bl6/J mice were randomized to a binge-like palatable food access schedule (daily 2-hr, 3×/week) or continuous, nonbinge like palatable food access for 12 days (Experiment 1). Persistence of palatable food consumption in both binge-like palatable food access groups was then examined across three cycles of forced abstinence and reexposure to palatable food (incubation) to model the persistence of binge eating in clinical populations. Mice with daily 2-hr palatable food access escalated their intake more than mice in the 3×/week or continuous groups (Experiment 1). This pattern was more pronounced in females. In addition, this pattern of palatable food intake reemerged across multiple cycles of behavioral incubation (Experiment 2). These findings provide a model of binge-like eating in mice that can be used in future studies examining both environmental factors and neural mechanisms contributing to binge eating persistence. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Distinct Patterns of Abnormal Lateral Orbitofrontal Cortex Activity During Compulsive Grooming and Reversal Learning Normalize After Fluoxetine.

BACKGROUND: Patients with obsessive-compulsive disorder (OCD) display disrupted performance and abnormal lateral orbitofrontal cortex (LOFC) activity during reversal learning tasks. However, it is unknown whether compulsions and reversal learning deficits share a common neural substrate. To answer this question, we measured neural activity with in vivo calcium imaging in LOFC during compulsive grooming and reversal learning before and after fluoxetine treatment. METHODS: Sapap3 knockout (KO) mice were used as a model for OCD-relevant behaviors. Sapap3 KOs and control littermates were injected with a virus encoding GCaMP6f and implanted with gradient-index lenses to visualize LOFC activity using miniature microscopes. Grooming, reversal learning, and neural activity were measured pre- and post-fluoxetine treatment (18 mg/kg, 4 weeks). RESULTS: Baseline compulsive grooming and reversal learning impairments in KOs improved after fluoxetine treatment. In addition, KOs displayed distinct patterns of abnormal LOFC activity during grooming and reversal learning, both of which normalized after fluoxetine. Finally, reversal learning-associated neurons were distributed randomly among grooming-associated neurons (i.e., overlap is what would be expected by chance). CONCLUSIONS: In OCD, LOFC is disrupted during both compulsive behaviors and reversal learning, but whether these behaviors share common neural underpinnings is unknown. We found that LOFC plays distinct roles in compulsive grooming and impaired reversal learning and their improvement with fluoxetine. These findings suggest that LOFC plays separate roles in pathophysiology and treatment of different perseverative behaviors in OCD.

Resting-State Functional Connectivity Differences Following Experimental Manipulation of the Orbitofrontal Cortex in Two Directions via Theta-Burst Stimulation.

Compulsive behaviors (CBs) have been linked to orbitofrontal cortex (OFC) function in animal and human studies. However, brain regions function not in isolation but as components of widely distributed brain networks-such as those indexed via resting-state functional connectivity (RSFC). Sixty-nine individuals with CB disorders were randomized to receive a single session of neuromodulation targeting the left OFC-intermittent theta-burst stimulation (iTBS) or continuous TBS (cTBS)-followed immediately by computer-based behavioral "habit override" training. OFC seeds were used to quantify RSFC following iTBS and following cTBS. Relative to cTBS, iTBS showed increased RSFC between right OFC (Brodmann's area 47) and other areas, including dorsomedial prefrontal cortex (dmPFC), occipital cortex, and a priori dorsal and ventral striatal regions. RSFC connectivity effects were correlated with OFC/frontopolar target engagement and with subjective difficulty during habit-override training. Findings help reveal neural network-level impacts of neuromodulation paired with a specific behavioral context, informing mechanistic intervention development.

The prefrontal cortex and OCD.

Obsessive Compulsive Disorder (OCD) is a highly prevalent and severe neuropsychiatric disorder, with an incidence of 1.5-3% worldwide. However, despite the clear public health burden of OCD and relatively well-defined symptom criteria, effective treatments are still limited, spotlighting the need for investigation of the neural substrates of the disorder. Human neuroimaging studies have consistently highlighted abnormal activity patterns in prefrontal cortex (PFC) regions and connected circuits in OCD during both symptom provocation and performance of neurocognitive tasks. Because of recent technical advances, these findings can now be leveraged to develop novel targeted interventions. Here we will highlight current theories regarding the role of the prefrontal cortex in the generation of OCD symptoms, discuss ways in which this knowledge can be used to improve treatments for this often disabling illness, and lay out challenges in the field for future study.

Intact amphetamine-induced behavioral sensitization in mice with increased or decreased neuronal glutamate transporter SLC1A1/EAAT3.

Repeated amphetamine treatment results in locomotor sensitization, a phenomenon that may relate to the development of psychosis and addiction. Evidence suggests that interactions between dopaminergic and glutamatergic systems are involved in amphetamine sensitization. We previously demonstrated that the neuronal excitatory amino acid transporter (Slc1a1/EAAT3) produces bidirectional, expression-dependent effects on the response to acute amphetamine. Here, using mice with decreased or increased expression of EAAT3, we found that chronic alterations in EAAT3 expression do not significantly impact amphetamine-induced locomotor sensitization. Compensation by other glutamate transporters cannot be ruled out in this important neuroadaptive phenomenon.

A double-blind study assessing the impact of orbitofrontal theta burst stimulation on goal-directed behavior.

Patients with disorders of compulsivity show impairments in goal-directed behavior, which have been linked to orbitofrontal cortex (OFC) dysfunction. We recently showed that continuous theta burst stimulation (cTBS), which reduces OFC activity, had a beneficial effect on compulsive behaviors both immediately and at 1 week follow-up compared with inhibitory TBS (iTBS). In this same sample, we investigated whether two behavioral measures of goal-directed control (devaluation success on a habit override task; model-based planning on the two-step task) were also affected by acute modulation of OFC activity. Overall, model-based planning and devaluation success were significantly related to each other and (for devaluation success) to symptoms in our transdiagnostic clinical sample. These measures were moderately to highly stable across time. In individuals with low levels of model-based planning, active cTBS improved devaluation success. Analogous to previously reported clinical effects, this effect was specific to cTBS and not iTBS. Overall, results suggested that measures of goal directed behavior are reliable but less affected by cTBS than clinical self-report. Future research should continue to examine longitudinal changes in behavioral measures to determine their temporal relationship with symptom improvement after treatment. (PsycInfo Database Record (c) 2022 APA, all rights reserved).