Over the past two decades, circuit-based neurosurgical procedures have gained increasing acceptance as a safe and efficacious approach to the treatment of the intractable obsessive-compulsive ...disorder (OCD). Lesions and deep brain stimulation (DBS) of the longitudinal corticofugal white matter tracts connecting the prefrontal cortex with the striatum, thalamus, subthalamic nucleus (STN), and brainstem implicate orbitofrontal, medial prefrontal, frontopolar, and ventrolateral cortical networks in the symptoms underlying OCD. The highly parallel distributed nature of these networks may explain the relative lack of adverse effects observed following surgery. Additional pre-post studies of cognitive tasks in more surgical patients are needed to confirm the role of these networks in OCD and to define therapeutic responses to surgical intervention.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Orographic precipitation results from complex interactions between terrain, large-scale flow, turbulent motions, and microphysical processes. This study appeals to polarimetric radar data in ...conjunction with surface-based disdrometer observations, airborne particle probes, and reanalysis data to study these processes and their interactions as observed during the Olympic Mountain Experiment (OLYMPEX). Radar and disdrometer observations from OLYMPEX, which was conducted over the Olympic Peninsula in the winter of 2015, revealed 3 times as much rain fell over elevated sites compared to those along the ocean and coast. Several events were marked by significant water vapor transport and strong onshore flow. Detailed analysis of four cases demonstrated that the warm sector, which previous authors noted to be a period of strong orographic enhancement over the terrain, is associated not only with deeper warm cloud regions, but also deeper cold cloud regions, with the latter supporting the growth of dendritic ice crystals between 4 and 6 km. This dendritic growth promotes enhanced aggregation just above the melting layer, which then seeds the warm cloud layer below, allowing additional drop growth via coalescence. Periods of subsynoptic variability associated with mesoscale boundaries and low-level jets are shown to locally modify both the ice microphysics as well as surface drop-size distributions. This study explores the spatial and temporal variability of precipitation, cloud microphysics, and their relationship over the complex terrain of the Olympic Peninsula.
Significance Statement
This study appeals to polarimetric radar, aircraft particle probes, disdrometer data, and reanalysis to investigate the complex interactions between large frontal systems, terrain, and microphysical processes contributing to precipitation characteristics at the surface over the Olympic Peninsula. The study finds that the precipitation is a complex function of the synoptic regime, distance inland, and terrain height. Ice microphysical processes aloft act to modulate the surface rain drop size distributions, and are more important in contributing to higher rain accumulations inland during the later phases of the warm sector, particularly over the middle terrain heights (100–500 m).
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Background We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Methods Fifteen patients with chronic, severe, ...highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale—24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Results Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Conclusions Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system
. We have previously shown that ...the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells
, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10
GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly
. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Obsessive-compulsive disorder (OCD) is a heterogeneous and disabling condition; however, no studies have examined symptom categories or subtypes as predictors of long-term clinical course in adults ...with primary OCD.
A total of 213 adults with DSM-IV OCD were recruited from several mental health treatment sites between July 2001 and February 2006 as part of the Brown Longitudinal Obsessive Compulsive Study, a prospective, naturalistic study of treatment-seeking adults with primary OCD. OCD symptoms were assessed annually over the 5-year follow-up period using the Longitudinal Interval Follow-Up Evaluation.
Thirty-nine percent of participants experienced either a partial (22.1%) or a full (16.9%) remission. Two OCD symptom dimensions impacted remission. Participants with primary obsessions regarding overresponsibility for harm were nearly twice as likely to experience a remission (P < .05), whereas only 2 of 21 participants (9.5%) with primary hoarding achieved remission. Other predictors of increased remission were lower OCD severity (P < .0001) and shorter duration of illness (P < .0001). Fifty-nine percent of participants who remitted subsequently relapsed. Participants with obsessive-compulsive personality disorder were more than twice as likely to relapse (P < .005). Participants were also particularly vulnerable to relapse if they experienced partial remission versus full remission (70% vs 45%; P < .05).
The contributions of OCD symptom categories and comorbid obsessive-compulsive personality disorder are critically important to advancing our understanding of the prognosis and ultimately the successful treatment of OCD. Longer duration of illness was also found to be a significant predictor of course, highlighting the critical importance of early detection and treatment of OCD. Furthermore, having full remission as a treatment target is an important consideration for the prevention of relapse in this disorder.
Despite the development of effective pharmacologic and cognitive behavioral treatments for obsessive-compulsive disorder (OCD), some patients continue to be treatment-refractory and severely ...impaired. Fiber tracts connecting orbitofrontal and dorsal anterior cingulate cortex with subcortical nuclei have been the target of neurosurgical lesions as well as deep brain stimulation in these patients. We report on the safety and efficacy of ventral gamma capsulotomy for patients with intractable OCD.
Fifty-five patients with severely disabling, treatment-refractory OCD received bilateral lesions in the ventral portion of the anterior limb of the internal capsule over a 20-year period using the Leksell Gamma Knife. The patients were prospectively followed over 3 years with psychiatric, neurologic, and neuropsychological assessments of safety and efficacy, as well as structural neuroimaging.
Thirty-one of 55 patients (56%) had an improvement in the primary efficacy measure, the Yale-Brown Obsessive Compulsive Scale, of ≥35% over the 3-year follow-up period. Patients had significant improvements in depression, anxiety, quality of life, and global functioning. Patients tolerated the procedure well without significant acute adverse events. Five patients (9%) developed transient edema that required short courses of dexamethasone. Three patients (5%) developed cysts at long-term follow-up, 1 of whom developed radionecrosis resulting in an ongoing minimally conscious state.
Gamma Knife ventral capsulotomy is an effective radiosurgical procedure for many treatment-refractory OCD patients. A minority of patients developed cysts at long-term follow-up, 1 of whom had permanent neurological sequelae.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Deep brain stimulation (DBS) of the anterior limb of the internal capsule has been shown to be beneficial in the short term for obsessive-compulsive disorder (OCD) patients who exhaust conventional ...therapies. Nuttin et al, who published the first DBS for OCD series, found promising results using a capsule target immediately rostral to the anterior commissure extending into adjacent ventral capsule/ventral striatum (VC/VS). Published long-term outcome data are limited to four patients. In this collaborative study, 10 adult OCD patients meeting stringent criteria for severity and treatment resistance had quadripolar stimulating leads implanted bilaterally in the VC/VS. DBS was activated openly 3 weeks later. Eight patients have been followed for at least 36 months. Group Yale-Brown Obsessive Compulsive Scale (YBOCS) scores decreased from 34.6+/-0.6 (mean+/-SEM) at baseline (severe) to 22.3+/-2.1 (moderate) at 36 months (p < 0.001). Four of eight patients had a > or =35% decrease in YBOCS severity at 36 months; in two patients, scores declined between 25 and 35%. Global Assessment of Functioning scores improved from 36.6+/-1.5 at baseline to 53.8+/-2.5 at 36 months (p < 0.001). Depression and anxiety also improved, as did self-care, independent living, and work, school, and social functioning. Surgical adverse effects included an asymptomatic hemorrhage, a single seizure, and a superficial infection. Psychiatric adverse effects included transient hypomanic symptoms, and worsened depression and OCD when DBS was interrupted by stimulator battery depletion. This open study found promising long-term effects of DBS in highly treatment-resistant OCD.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS;
Goodman, Price, Rasmussen, Mazure, Delgado, et al., 1989
) is acknowledged as the gold standard measure of obsessive-compulsive disorder (OCD) ...symptom severity. A number of areas where the Y-BOCS may benefit from revision have emerged in past psychometric studies of the Severity Scale and Symptom Checklist. Therefore, we created the Yale-Brown Obsessive-Compulsive Scale-Second Edition (Y-BOCS-II) by revising the Severity Scale item content and scoring framework, integrating avoidance into the scoring of Severity Scale items, and modifying the Symptom Checklist content and format. One hundred thirty treatment-seeking adults with OCD completed a battery of measures assessing OCD symptom severity and typology and depressive and anxious symptomology. Interrater and test-retest reliability were assessed on a subsample of participants. The Y-BOCS-II showed strong internal consistency for the Symptom Checklist (Kuder-Richardson-20 = .91) and Severity Scale (α = .89). Test-retest and interrater reliabilities were both high (intraclass correlations > .85). Confirmatory factor analyses did not show adequate fit with previous models of the Y-BOCS. Exploratory factor analysis revealed a two-factor solution generally consistent with the Obsession and Compulsion Severity subscales. Construct validity was supported by strong correlations with clinician-rated measures of OCD symptom severity and moderate correlations with measures of worry and depressive symptoms. Taken together, the Y-BOCS-II has excellent psychometric properties in assessing the presence and severity of obsessive-compulsive symptoms. Although the Y-BOCS remains a reliable and valid measure, the Y-BOCS-II may provide an alternative method of assessing symptom presence and severity.
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CEKLJ, FFLJ, NUK, ODKLJ, PEFLJ, UPUK
In everyday life, humans perform sequences of tasks. These tasks may be disrupted in people with obsessive-compulsive disorder (OCD). Symptoms, such as compulsions, can be considered sequential and ...often cause repetitions of tasks that disrupt daily living (e.g., checking the stove while cooking). Motor sequences have been used to study behavioral deficits in OCD. However, not all sequences are motor sequences. Some are more "abstract" in that they are composed of a series of tasks (e.g., chopping and stirring) rather than being dependent on individual actions or stimuli. These abstract task sequences require cognitive control mechanisms for their execution. Although theory has proposed deficits in these sequences in OCD as well, they have not been directly investigated. We tested the hypotheses that OCD participants exhibit deficits in the control mechanisms specific to abstract task sequences and more general flexible behavior (measured with task switching within the sequences), relative to health controls (HCs) and clinical controls (participants with anxiety disorders ANX). A total of 112 participants completed abstract task sequences consisting of simple categorization tasks. Surprisingly, participants with OCD did not perform worse than HCs or ANX. However, ANX participants showed impairments specific to sequential control that did not extend to more general flexible control. Thus, we showed a novel behavioral dissociation between OCD and ANX specific to abstract task sequential control. These results also implicate deficits in specific frontal sequential control neural circuitry in ANX and not in OCD, where implicit sequential deficits may more closely align with striatal circuits.In everyday life, humans perform sequences of tasks. These tasks may be disrupted in people with obsessive-compulsive disorder (OCD). Symptoms, such as compulsions, can be considered sequential and often cause repetitions of tasks that disrupt daily living (e.g., checking the stove while cooking). Motor sequences have been used to study behavioral deficits in OCD. However, not all sequences are motor sequences. Some are more "abstract" in that they are composed of a series of tasks (e.g., chopping and stirring) rather than being dependent on individual actions or stimuli. These abstract task sequences require cognitive control mechanisms for their execution. Although theory has proposed deficits in these sequences in OCD as well, they have not been directly investigated. We tested the hypotheses that OCD participants exhibit deficits in the control mechanisms specific to abstract task sequences and more general flexible behavior (measured with task switching within the sequences), relative to health controls (HCs) and clinical controls (participants with anxiety disorders ANX). A total of 112 participants completed abstract task sequences consisting of simple categorization tasks. Surprisingly, participants with OCD did not perform worse than HCs or ANX. However, ANX participants showed impairments specific to sequential control that did not extend to more general flexible control. Thus, we showed a novel behavioral dissociation between OCD and ANX specific to abstract task sequential control. These results also implicate deficits in specific frontal sequential control neural circuitry in ANX and not in OCD, where implicit sequential deficits may more closely align with striatal circuits.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract Background Obsessive-compulsive disorder is treated with exposure with response prevention (ERP) therapy, in which patients are repeatedly exposed to compulsive triggers but prevented from ...expressing their compulsions. Many compulsions are an attempt to avoid perceived dangers, and the intent of ERP is to extinguish compulsions. Patients failing ERP therapy are candidates for deep brain stimulation (DBS) of the ventral capsule/ventral striatum, which facilitates patients’ response to ERP therapy. An animal model of ERP would be useful for understanding the neural mechanisms of extinction in obsessive-compulsive disorder. Methods Using a platform-mediated signaled avoidance task, we developed a rodent model of ERP called extinction with response prevention (Ext-RP), in which avoidance-conditioned rats are given extinction trials while blocking access to the avoidance platform. Following 3 days of Ext-RP, rats were tested with the platform unblocked to evaluate persistent avoidance. We then assessed if pharmacologic inactivation of lateral orbitofrontal cortex (lOFC) or DBS of the ventral striatum reduced persistent avoidance. Results Following Ext-RP training, most rats showed reduced avoidance at test (Ext-RP success), but a subset persisted in their avoidance (Ext-RP failure). Pharmacologic inactivation of lOFC eliminated persistent avoidance, as did DBS applied to the ventral striatum during Ext-RP. Conclusions DBS of ventral striatum has been previously shown to inhibit lOFC activity. Thus, activity in lOFC, which is known to be hyperactive in obsessive-compulsive disorder, may be responsible for impairing patients’ response to ERP therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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