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Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms., (© 2024. The Author(s).)

Background: Individuals with obsessive-compulsive disorder (OCD) show persistent avoidance behaviors, often in the absence of actual threat. Quality-of-life costs and heterogeneity support the need for novel brain-behavior intervention targets. Informed by mechanistic and anatomical studies of persistent avoidance in rodents and nonhuman primates, our goal was to test whether connections within a hypothesized persistent avoidance-related network predicted OCD-related harm avoidance (HA), a trait measure of persistent avoidance. We hypothesized that 1) HA, not an OCD diagnosis, would be associated with altered endogenous connectivity in at least one connection in the network; 2) HA-specific findings would be robust to comorbid symptoms; and 3) reliable findings would replicate in a holdout testing subsample., Methods: Using resting-state functional connectivity magnetic resonance imaging, cross-validated elastic net for feature selection, and Poisson generalized linear models, we tested which connections significantly predicted HA in our training subsample (n = 73; 71.8% female; healthy control group n = 36, OCD group n = 37); robustness to comorbidities; and replicability in a testing subsample (n = 30; 56.7% female; healthy control group n = 15, OCD group n = 15)., Results: Stronger inverse connectivity between the right dorsal anterior cingulate cortex and right basolateral amygdala and stronger positive connectivity between the right ventral anterior insula and left ventral striatum were associated with greater HA across groups. Network connections did not discriminate OCD diagnostic status or predict HA-correlated traits, suggesting sensitivity to trait HA. The dorsal anterior cingulate cortex-basolateral amygdala relationship was robust to controlling for comorbidities and medication in individuals with OCD and was also predictive of HA in our testing subsample., Conclusions: Stronger inverse dorsal anterior cingulate cortex-basolateral amygdala connectivity was robustly and reliably associated with HA across groups and in OCD. Results support the relevance of a cross-species persistent avoidance-related network to OCD, with implications for precision-based approaches and treatment., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: The zona incerta (ZI) is involved in mediating survival behaviors and is connected to a wide range of cortical and subcortical structures, including key basal ganglia nuclei. Based on these connections and their links to behavioral modulation, we propose that the ZI is a connectional hub for mediating between top-down and bottom-up control and a possible target for deep brain stimulation for obsessive-compulsive disorder., Methods: We analyzed the trajectory of cortical fibers to the ZI in nonhuman and human primates based on tracer injections in monkeys and high-resolution diffusion magnetic resonance imaging in humans. The organization of cortical and subcortical connections within the ZI were identified in the nonhuman primate studies., Results: Monkey anatomical data and human diffusion magnetic resonance imaging data showed a similar trajectory of fibers/streamlines to the ZI. Prefrontal cortex/anterior cingulate cortex terminals all converged within the rostral ZI, with dorsal and lateral areas being most prominent. Motor areas terminated caudally. Dense subcortical reciprocal connections included the thalamus, medial hypothalamus, substantia nigra/ventral tegmental area, reticular formation, and pedunculopontine nucleus and a dense nonreciprocal projection to the lateral habenula. Additional connections included the amygdala, dorsal raphe nucleus, and periaqueductal gray., Conclusions: Dense connections with dorsal and lateral prefrontal cortex/anterior cingulate cortex cognitive control areas and the lateral habenula and the substantia nigra/ventral tegmental area, coupled with inputs from the amygdala, hypothalamus, and brainstem, suggest that the rostral ZI is a subcortical hub positioned to modulate between top-down and bottom-up control. A deep brain stimulation electrode placed in the rostral ZI would not only involve connections common to other deep brain stimulation sites but also capture several critically distinctive connections., (Copyright © 2023. Published by Elsevier Inc.)

Deep brain stimulation is a promising therapeutic approach for patients with treatment-resistant obsessive-compulsive disorder, a condition linked to abnormalities in corticobasal ganglia networks. Effective targets are placed in one of four subcortical areas with the goal of capturing prefrontal, anterior cingulate, and basal ganglia connections linked to the limbic system. These include the anterior limb of the internal capsule, the ventral striatum, the subthalamic nucleus, and a midbrain target. The goal of this review is to examine these 4 targets with respect to the similarities and differences of their connections. Following a review of the connections for each target based on anatomic studies in nonhuman primates, we examine the accuracy of diffusion magnetic resonance imaging tractography to replicate those connections in nonhuman primates, before evaluating the connections in the human brain based on diffusion magnetic resonance imaging tractography. Results demonstrate that the four targets generally involve similar connections, all of which are part of the internal capsule. Nonetheless, some connections are unique to each site. Delineating the similarities and differences across targets is a critical step for evaluating and comparing the effectiveness of each and how circuits contribute to the therapeutic outcome. It also underscores the importance that the terminology used for each target accurately reflects its position and its anatomic connections, so as to enable comparisons across clinical studies and for basic scientists to probe mechanisms underlying deep brain stimulation., (Copyright © 2020 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Obsessive-compulsive disorder is among the most disabling psychiatric disorders. Although deep brain stimulation is considered an effective treatment, its use in clinical practice is not fully established. This is, at least in part, due to ambiguity about the best suited target and insufficient knowledge about underlying mechanisms. Recent advances suggest that changes in broader brain networks are responsible for improvement of obsessions and compulsions, rather than local impact at the stimulation site. These findings were fueled by innovative methodological approaches using brain connectivity analyses in combination with neuromodulatory interventions. Such a connectomic approach for neuromodulation constitutes an integrative account that aims to characterize optimal target networks. In this critical review, we integrate findings from connectomic studies and deep brain stimulation interventions to characterize a neural network presumably effective in reducing obsessions and compulsions. To this end, we scrutinize methodologies and seemingly conflicting findings with the aim to merge observations to identify common and diverse pathways for treating obsessive-compulsive disorder. Ultimately, we propose a unified network that-when modulated by means of cortical or subcortical interventions-alleviates obsessive-compulsive symptoms., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Obsessive-Compulsive Disorder (OCD) is characterized by repetitive avoidance behavior which is distressing and associated with marked impairment of everyday life. Recently, paradigms have been designed to explore the hypothesis that avoidance behavior in OCD is consistent with a formal conception of habit. Such studies have involved a devaluation paradigm, in which the value of a previously rewarded cue is altered so that avoidance is no longer necessary. We employed a rule-based avoidance task which included a devaluation, examining behavioral performance on the task and their neural correlates using functional MRI in groups of participants with OCD (n = 44) and healthy control participants (n = 46). Neuroimaging data were analyzed using a general linear model (GLM), modelling valued, devalued and control cues, as well as feedback events. First, while no overall effect of OCD was seen on devaluation performance, patients with longer illness duration showed poorer devaluation performance (χ 2  = 13.84, p < 0.001). Reduced devaluation was related to impaired learning on the overtraining phase of the task, and to enhanced feedback activation in the caudate and parietal lobe during within-scanner retraining (T = 5.52, p&#95;FWE = 0.003), across all participants. Second, a significant interaction effect was observed in the premotor cortex (F = 29.03, p&#95;FWE = 0.007) coupled to the devalued cue. Activations were divergent in participants with OCD (lower activation) and healthy controls (higher activation) who did not change responding to the devalued cue following devaluation, and intermediate in participants who did change responding (T = 5.39, p&#95;FWE = 0.003). Finally, consistent with previous work, medial orbitofrontal cortex activation coupled to valued cues was reduced in OCD compared to controls (T = 3.49, p&#95;FWE = 0.009). The findings are discussed in terms of a prediction error-based model of goal-directed and habitual control: specifically, how goal-directed control might be diminished in OCD in favor of habits. They suggest that illness duration might be significant determinant of variation in impaired goal-directed learning in OCD, and be a factor relevant for understanding discrepancies across studies. Overall, the study shows the potential of conceptual replication attempts to provide complementary insights into compulsive behavior and its associated neural circuitry in OCD., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

For more than half a century, stereotactic neurosurgical procedures have been available to treat patients with severe, debilitating symptoms of obsessive-compulsive disorder (OCD) that have proven refractory to extensive, appropriate pharmacological, and psychological treatment. Although reliable predictors of outcome remain elusive, the establishment of narrower selection criteria for neurosurgical candidacy, together with a better understanding of the functional neuroanatomy implicated in OCD, has resulted in improved clinical efficacy for an array of ablative and non-ablative intervention techniques targeting the cingulum, internal capsule, and other limbic regions. It was against this backdrop that gamma knife capsulotomy (GKC) for OCD was developed. In this paper, we review the history of this stereotactic radiosurgical procedure, from its inception to recent advances. We perform a systematic review of the existing literature and also provide a narrative account of the evolution of the procedure, detailing how the procedure has changed over time, and has been shaped by forces of evidence and innovation. As the procedure has evolved and adverse events have decreased considerably, favorable response rates have remained attainable for approximately one-half to two-thirds of individuals treated at experienced centers. A reduction in obsessive-compulsive symptom severity may result not only from direct modulation of OCD neural pathways but also from enhanced efficacy of pharmacological and psychological therapies working in a synergistic fashion with GKC. Possible complications include frontal lobe edema and even the rare formation of delayed radionecrotic cysts. These adverse events have become much less common with new radiation dose and targeting strategies. Detailed neuropsychological assessments from recent studies suggest that cognitive function is not impaired, and in some domains may even improve following treatment. We conclude this review with discussions covering topics essential for further progress of this therapy, including suggestions for future trial design given the unique features of GKC therapy, considerations for optimizing stereotactic targeting and dose planning using biophysical models, and the use of advanced imaging techniques to understand circuitry and predict response. GKC, and in particular its modern variant, gamma ventral capsulotomy, continues to be a reliable treatment option for selected cases of otherwise highly refractory OCD.

Background: Existing functional connectivity studies of obsessive-compulsive disorder (OCD) support a model of circuit dysfunction. However, these group-level observations have failed to yield neuroimaging biomarkers sufficient to serve as a test for the OCD diagnosis, predict current or future symptoms, or predict treatment response, perhaps because these studies failed to account for the substantial intersubject variability in structural and functional brain organization., Methods: We used functional regions, localized in each of 41 individual OCD patients, to identify cortical connectivity biomarkers of both global and dimension-specific symptom severity and to detect functional connections that track changes in symptom severity following intensive residential treatment., Results: Global OCD symptom severity was directly linked to dysconnectivity between large-scale intrinsic brain networks-particularly among the dorsal attention, default, and frontoparietal networks. Changes within a subset of connections among these networks were associated with symptom resolution. Additionally, distinct and nonoverlapping cortical connectivity biomarkers were identified that were significantly associated with the severity of contamination/washing and responsibility for harm/checking symptoms, highlighting the contribution of dissociable neural networks to specific OCD symptom dimensions. By contrast, when we defined functional regions conventionally, using a population-level brain atlas, we could no longer identify connectivity biomarkers of severity or improvement for any of the symptom dimensions., Conclusions: Our findings would seem to encourage the use of individual-level approaches to connectivity analyses to better delineate the cortical and subcortical networks underlying symptom severity and improvement at the dimensional level in OCD patients., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

OBJECTIVE Deep brain stimulation (DBS) is a reversible, nonlesion-based treatment for patients with intractable obsessive-compulsive disorder (OCD). The first studies on DBS for OCD stimulating the ventral capsule/ventral striatum (VC/VS) yielded encouraging results for this neuroanatomical site's therapeutic efficacy. This investigation was conducted to better understand which regions of the cortico-striatal-thalamic-cortical network were acutely affected by VC/VS DBS for OCD. Furthermore, the objective was to identify which brain regions demonstrated changes in perfusion, as stimulation was applied across a dorsoventral lead axis that corresponded to different anatomical locations in the VC/VS. METHODS Six patients receiving VC/VS DBS for OCD underwent oxygen-15 positron emission tomography ( 15 O-PET) scanning. Monopolar DBS was delivered at each of the 4 different electrodes on the stimulating lead in the VC/VS. The data were analyzed using SPM5. Paired t-tests were run in SPSS to identify significant changes in regional cerebral blood flow (rCBF) between stimulation conditions. Pearson's r correlations were run between these significant changes in rCBF and changes in OCD and depressive symptom severity. RESULTS Perfusion in the dorsal anterior cingulate cortex (dACC) significantly increased when monopolar DBS was turned on at the most ventral DBS contact, and this increase in dACC activity was correlated with reductions in depressive symptom severity (r(5) = -0.994, p = 0.001). Perfusion in the thalamus, striatum, and globus pallidus significantly increased when DBS was turned on at the most dorsal contact. CONCLUSIONS DBS of the VC/VS appears to modulate activity in the regions implicated in the pathophysiology of OCD. Different regions in the cortico-striatal-thalamic-cortical circuit showed increased perfusion based on whether the stimulation was more ventral or dorsal along the lead axis in the VC/VS. Evidence was found that DBS at the most ventral site was associated with clinical changes in depressive symptom severity, but not OCD symptom severity.

Psychiatric neurosurgery, specifically stereotactic ablation, has continued since the 1940s, mainly at a few centers in Europe and the US. Since the late 1990s, the resurgence of interest in this field has been remarkable; reports of both lesion procedures and the newer technique of deep brain stimulation (DBS) have increased rapidly. In early 2009, the US FDA granted limited humanitarian approval for DBS for otherwise intractable obsessive-compulsive disorder (OCD), the first such approval for a psychiatric illness. Several factors explain the emergence of DBS and continued small-scale use of refined lesion procedures. DBS and stereotactic ablation have been successful and widely used for movement disorders. There remains an unmet clinical need: current drug and behavioral treatments offer limited benefit to some seriously ill people. Understandings of the neurocircuitry underlying psychopathology and the response to treatment, while still works in progress, are much enhanced. Here, we review modern lesion procedures and DBS for OCD in the context of neurocircuitry. A key issue is that clinical benefit can be obtained after surgeries targeting different brain structures. This fits well with anatomical models, in which circuits connecting orbitofrontal cortex (OFC), medial prefrontal cortex (mPFC), basal ganglia, and thalamus are central to OCD pathophysiology and treatment response. As in movement disorders, dedicated interdisciplinary teams, here led by psychiatrists, are required to implement these procedures and maintain care for patients so treated. Available data, although limited, support the promise of stereotactic ablation or DBS in carefully selected patients. Benefit in such cases appears not to be confined to obsessions and compulsions, but includes changes in affective state. Caution is imperative, and key issues in long-term management of psychiatric neurosurgery patients deserve focused attention. DBS and contemporary ablation also present different patterns of potential benefits and burdens. Translational research to elucidate how targeting specific nodes in putative OCD circuitry might lead to therapeutic gains is accelerating in tandem with clinical use.

Object: Deep brain stimulation (DBS) of the ventral [anterior internal] capsule/ventral striatum (VC/VS) is under investigation as an alternative to anterior capsulotomy for severe obsessive-compulsive disorder (OCD). In neuroimaging studies of patients with OCD, dysfunction in the orbitofrontal and anterior cingulate cortex, striatum, and thalamus has been identified; and modulation of activity in this circuit has been observed following successful nonsurgical treatment. The purpose of the current study was to test hypotheses regarding changes in regional cerebral blood flow (rCBF) during acute DBS at the VC/VS target in patients with OCD who were participating in a clinical DBS trial., Methods: Six patients enrolled in a DBS trial for OCD underwent positron emission tomography to measure rCBF; the rCBF measured during acute DBS at high frequency was then compared with those measured during DBS at low frequency and off (control) conditions. On the basis of neuroanatomical knowledge about the VC/VS and neuroimaging data on OCD, the authors predicted that acute DBS at this target would result in modulation of activity within the implicated frontal-basal ganglia-thalamic circuit. Data were analyzed using statistical parametric mapping. In a comparison of acute high-frequency DBS with control conditions, the authors found significant activation of the orbitofrontal cortex, anterior cingulate cortex, striatum, globus pallidus, and thalamus., Conclusions: Acute DBS at the VC/VS target is associated with activation of the circuitry implicated in OCD. Further studies will be necessary to replicate these findings and to determine the neural effects associated with chronic VC/VS DBS. Moreover, additional data are needed to investigate whether pretreatment imaging profiles can be used to predict a patient's subsequent clinical response to chronic DBS.

Background: Mood, cognitive, and behavioural changes have been reported with deep brain stimulation (DBS) in the thalamus, globus pallidus interna, and anterior limb of the internal capsule/nucleus accumbens region., Objective: To investigate panic and fear resulting from DBS., Methods: Intraoperative DBS in the region of the right and then left anterior limb of the internal capsule and nucleus accumbens region was undertaken to treat a 52 year old man with treatment refractory obsessive-compulsive disorder (OCD). Mood, anxiety, OCD, alertness, heart rate, and subjective feelings were recorded during intraoperative test stimulation and at follow up programming sessions., Results: DBS at the distal (0) contact (cathode 0-, anode 2+, pulse width 210 ms, rate 135 Hz, at 6 volts) elicited a panic attack (only seen at the (0) contact). The patient felt flushed, hot, fearful, and described himself as having a "panic attack." His heart rate increased from 53 to 111. The effect (present with either device) was witnessed immediately after turning the device on, and abruptly ceased in the off condition, Conclusions: DBS of the anterior limb of the internal capsule and nucleus accumbens region caused severe "panic." This response may result from activation of limbic and autonomic networks.