Identifying subgroups of urge suppression in Obsessive-Compulsive Disorder using machine learning.

Obsessive-compulsive disorder (OCD) is phenomenologically heterogeneous. While predominant models suggest fear and harm prevention drive compulsions, many patients also experience uncomfortable sensory-based urges ("sensory phenomena") that may be associated with heightened interoceptive sensitivity. Using an urge-to-blink eyeblink suppression paradigm to model sensory-based urges, we previously found that OCD patients as a group had more eyeblink suppression failures and greater activation of sensorimotor-interoceptive regions than controls. However, conventional approaches assuming OCD homogeneity may obscure important within-group variability, impeding precision treatment development. This study investigated the heterogeneity of urge suppression failure in OCD and examined relationships with clinical characteristics and neural activation. Eighty-two patients with OCD and 38 controls underwent an fMRI task presenting 60-s blocks of eyeblink suppression alternating with free-blinking blocks. Latent profile analysis identified OCD subgroups based on number of erroneous blinks during suppression. Subgroups were compared on behavior, clinical characteristics, and brain activation during task. Three patient subgroups were identified. Despite similar overall OCD severity, the subgroup with the most erroneous eyeblinks had the highest sensory phenomena severity, interoceptive sensitivity, and subjective urge intensity. Compared to other subgroups, this subgroup exhibited more neural activity in somatosensory and interoceptive regions during the early phase (first 30 s) of blink suppression and reduced activity in the middle frontal gyrus during the late phase (second 30 s) as the suppression period elapsed. Heterogeneity of urge suppression in OCD was associated with clinical characteristics and brain function. Our results reveal potential treatment targets that could inform personalized medicine.

Sensory over-responsivity and orbitofrontal cortex connectivity in obsessive-compulsive disorder.

BACKGROUND: Sensory over-responsivity (SOR) in obsessive-compulsive disorder (OCD) is associated with illness severity and functional impairment. However, the neural substrates of SOR in OCD have not yet been directly probed. METHODS: We examined resting-state global functional connectivity markers of SOR in 119 adults with OCD utilizing the CONN-fMRI Functional Connectivity Toolbox for SPM (v21a). We quantified SOR with the sensory sensitivity and sensory avoiding subscales of the Adult and Adolescent Sensory Profile (AASP). We also measured: OCD severity, with the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) and Obsessive-Compulsive Inventory-Revised (OCI-R); sensory phenomena with the Sensory Phenomena Scale (SPS); general anxiety, with the Beck Anxiety Inventory (BAI); and depressive symptomatology, with Quick Inventory of Depressive Symptoms, Self-Report (QIDS-SR). RESULTS: There was a significant positive relationship of SOR with global connectivity in anterior and medial OFC (Brodmanns area 11, k = 154, x = 14, y = 62, z = -18, whole-brain corrected at FWE p < 0.05). LIMITATIONS: Future investigations should explore neural responses to sensory stimulation tasks in OCD and compare findings with those obtained in other conditions also characterized by high SOR, such as autism spectrum disorder. CONCLUSIONS: This study implicates OFC functional connectivity as a neurobiological mechanism of SOR in OCD and suggests that the substrates of SOR in OCD may be dissociable from both that of other symptoms in OCD, and SOR in other disorders. With replication and extension, the finding may be leveraged to develop and refine treatments for OCD and investigate the pathophysiology of SOR in other conditions.

Associations Between Suicidality and Interoception in Obsessive-Compulsive Disorder.

Background: Individuals with obsessive-compulsive disorder (OCD) are at increased risk for suicide. One potential risk factor is interoceptive sensibility (IS), which is one's subjective experience of bodily sensations. The current study examined the relationship between IS and current suicidal ideation and lifetime history of suicide attempt, controlling for relevant covariates. Methods: Participants (N = 145) were a clinical sample of individuals with OCD from the New York City area. A clinical rater administered a diagnostic interview and an OCD severity assessment, and participants completed questionnaires about demographics, IS, and suicidality. Results: Current suicidal ideation was associated with reduced trusting of the body, and lifetime history of suicide attempt was related to greater general awareness of sensation. These associations remained significant after controlling for covariates. Conclusions: These results suggest that specific facets of IS may be associated with specific domains of suicidality. Decreased body trusting may represent a feeling of disconnection from the body that facilitates desire for death. Increased noticing of bodily sensations may lead to greater mental pain, which could interact with deficits in emotion regulation to increase risk for suicide attempt. Further research on the relationships between IS and suicidality in OCD is warranted.

Failures of Urge Suppression in Obsessive-Compulsive Disorder: Behavioral Modeling Using a Blink Suppression Task.

Many individuals with obsessive-compulsive disorder (OCD) report sensory-based urges (e.g. 'not-just-right experiences') in addition to, or instead of, concrete fear-based obsessions. These sensations may be comparable to normative "urges-for-action" (UFA), such as the urge to blink. While research has identified altered functioning of brain regions related to UFA in OCD, little is known about behavioral patterns of urge suppression in the disorder. Using an urge-to-blink task as a model for sensory-based urges, this study compared failures of urge suppression between OCD patients and controls by measuring eyeblinks during 60-second blocks of instructed blink suppression. Cox shared frailty models estimated the hazard of first blinks during each 60-second block and recurrent blinks following each initial erroneous blink. OCD patients demonstrated a higher hazard of first and recurrent blinks compared to controls, suggesting greater difficulty resisting repetitive sensory-based urges. Within OCD, relationships between task outcomes and symptom severity were inconsistent. Findings provide support for a deficit in delaying initial urge-induced actions and terminating subsequent actions in OCD, which is not clearly related to clinical heterogeneity. Elucidating the nature of behavioral resistance to urges is relevant for informing conceptualizations of obsessive-compulsive psychopathology and optimizing treatment outcomes.

Cognitive Neuroscience of Obsessive-Compulsive Disorder.

Cognitive neuroscientific research has the ability to yield important insights into the complex neurobiological processes underlying obsessive-compulsive disorder (OCD). This article provides an updated review of neuroimaging studies in seven neurocognitive domains. Findings from the literature are discussed in the context of obsessive-compulsive phenomenology and treatment. Expanding our knowledge of the neural mechanisms involved in OCD could help optimize treatment outcomes and guide the development of novel interventions.

Neural function underlying reward expectancy and attainment in adolescents with diverse psychiatric symptoms.

Reward dysfunction has been hypothesized to play a key role in the development of psychiatric conditions during adolescence. To help capture the complexity of reward function in youth, we used the Reward Flanker fMRI Task, which enabled us to examine neural activity during expectancy and attainment of both certain and uncertain rewards. Participants were 84 psychotropic-medication-free adolescents, including 67 with diverse psychiatric conditions and 17 healthy controls. Functional MRI used high-resolution acquisition and high-fidelity processing techniques modeled after the Human Connectome Project. Analyses examined neural activation during reward expectancy and attainment, and their associations with clinical measures of depression, anxiety, and anhedonia severity, with results controlled for family-wise errors using non-parametric permutation tests. As anticipated, reward expectancy activated regions within the fronto-striatal reward network, thalamus, occipital lobe, superior parietal lobule, temporoparietal junction, and cerebellum. Unexpectedly, however, reward attainment was marked by widespread deactivation in many of these same regions, which we further explored using cosine similarity analysis. Across all subjects, striatum and thalamus activation during reward expectancy negatively correlated with anxiety severity, while activation in numerous cortical and subcortical regions during reward attainment positively correlated with both anxiety and depression severity. These findings highlight the complexity and dynamic nature of neural reward processing in youth.

Neurocircuit models of obsessive-compulsive disorder: limitations and future directions for research.

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

Neurocircuit models of obsessive-compulsive disorder: limitations and future directions for research

Obsessive-compulsive disorder (OCD) is a common psychiatric condition classically characterized by obsessions (recurrent, intrusive and unwanted thoughts) and compulsions (excessive, repetitive and ritualistic behaviors or mental acts). OCD is heterogeneous in its clinical presentation and not all patients respond to first-line treatments. Several neurocircuit models of OCD have been proposed with the aim of providing a better understanding of the neural and cognitive mechanisms involved in the disorder. These models use advances in neuroscience and findings from neuropsychological and neuroimaging studies to suggest links between clinical profiles that reflect the symptoms and experiences of patients and dysfunctions in specific neurocircuits. Several models propose that treatments for OCD could be improved if directed to specific neurocircuit dysfunctions, thereby restoring efficient neurocognitive function and ameliorating the symptomatology of each associated clinical profile. Yet, there are several important limitations to neurocircuit models of OCD. The purpose of the current review is to highlight some of these limitations, including issues related to the complexity of brain and cognitive function, the clinical presentation and course of OCD, etiological factors, and treatment methods proposed by the models. We also provide suggestions for future research to advance neurocircuit models of OCD and facilitate translation to clinical application.

Relationships between interoceptive sensibility and resting-state functional connectivity of the insula in obsessive-compulsive disorder.

Patients with obsessive-compulsive disorder (OCD) exhibit abnormality in their subjective perception of internal sensation, a process known as interoceptive sensibility (IS), as well as altered functioning of the insula, a key neural structure for interoception. We investigated the multivariate structure of IS in 77 OCD patients and 53 controls and examined associations of IS with resting-state functional connectivity (FC) of the insula within the OCD group. For each group, principal component analysis was performed on 8 subscales of the Multidimensional Assessment of Interoceptive Awareness assessing putatively "adaptive" and "maladaptive" aspects of IS. Associations between IS components and insula FC in the OCD group were evaluated using seed regions placed in each of 3 subdivisions of the insula (posterior, anterior dorsal, and anterior ventral). Behaviorally, controls showed a 2-component solution broadly categorized into "adaptive" and "maladaptive" IS, while OCD patients exhibited a 3-component solution. The general tendency to notice or be aware of sensation loaded onto an "adaptive" IS component in controls but loaded onto both "adaptive" and "maladaptive" IS components in OCD. Within OCD, insula FC was differentially associated with distinct aspects of IS, identifying network connections that could serve as future targets for the modulation of IS in OCD.

Cortical and Subcortical Dysmetabolism Are Dynamic Markers of Clinical Disability and Course in Anti-LGI1 Encephalitis.

BACKGROUND AND OBJECTIVES: This [18F]fluorodeoxyglucose (FDG) PET study evaluates the accuracy of semiquantitative measurement of putaminal hypermetabolism in identifying anti-leucine-rich, glioma-inactivated-1 (LGI1) protein autoimmune encephalitis (AE). In addition, the extent of brain dysmetabolism, their association with clinical outcomes, and longitudinal metabolic changes after immunotherapy in LGI1-AE are examined. METHODS: FDG-PET scans from 49 age-matched and sex-matched subjects (13 in LGI1-AE group, 15 in non-LGI1-AE group, 11 with Alzheimer disease [AD], and 10 negative controls [NCs]) and follow-up scans from 8 patients with LGI1 AE on a median 6 months after immunotherapy were analyzed. Putaminal standardized uptake value ratios (SUVRs) normalized to global brain (P-SUVRg), thalamus (P/Th), and midbrain (P/Mi) were evaluated for diagnostic accuracy. SUVRg was applied for all other analyses. RESULTS: P-SUVRg, P/Th, and P/Mi were higher in LGI1-AE group than in non-LGI1-AE group, AD group, and NCs (all p < 0.05). P/Mi and P-SUVRg differentiated LGI1-AE group robustly from other groups (areas under the curve 0.84-0.99). Mediotemporal lobe (MTL) SUVRg was increased in both LGI1-AE and non-LGI1-AE groups when compared with NCs (both p < 0.05). SUVRg was decreased in several frontoparietal regions and increased in pallidum, caudate, pons, olfactory, and inferior occipital gyrus in LGI1-AE group when compared with that in NCs (all p < 0.05). In LGI1-AE group, both MTL and putaminal hypermetabolism were reduced after immunotherapy. Normalization of regional cortical dysmetabolism associated with clinical improvement at the 6- and 20-month follow-up. DISCUSSION: Semiquantitative measurement of putaminal hypermetabolism with FDG-PET may be used to distinguish LGI1-AE from other pathologies. Metabolic abnormalities in LGI1-AE extend beyond putamen and MTL into other subcortical and cortical regions. FDG-PET may be used in evaluating disease evolution in LGI1-AE. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that semiquantitative measures of putaminal metabolism on PET can differentiate patients with LGI1-AE from patients without LGI1-AE, patients with AD, or NCs.

Imbalance between default mode and sensorimotor connectivity is associated with perseverative thinking in obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is highly heterogeneous. Although perseverative negative thinking (PT) is a feature of OCD, little is known about its neural mechanisms or relationship to clinical heterogeneity in the disorder. In a sample of 85 OCD patients, we investigated the relationships between self-reported PT, clinical symptom subtypes, and resting-state functional connectivity measures of local and global connectivity. Results indicated that PT scores were highly variable within the OCD sample, with greater PT relating to higher severity of the "unacceptable thoughts" symptom dimension. PT was positively related to local connectivity in subgenual anterior cingulate cortex (ACC), pregenual ACC, and the temporal poles-areas that are part of, or closely linked to, the default mode network (DMN)-and negatively related to local connectivity in sensorimotor cortex. While the majority of patients showed higher local connectivity strengths in sensorimotor compared to DMN regions, OCD patients with higher PT scores had less of an imbalance between sensorimotor and DMN connectivity than those with lower PT scores, with healthy controls exhibiting an intermediate pattern. Clinically, this imbalance was related to both the "unacceptable thoughts" and "symmetry/not-just-right-experiences" symptom dimensions, but in opposite directions. These effects remained significant after accounting for variance related to psychiatric comorbidity and medication use in the OCD sample, and no significant relationships were found between PT and global connectivity. These data indicate that PT is related to symptom and neural variability in OCD. Future work may wish to target this circuity when developing personalized interventions for patients with these symptoms.

Affective and somatic symptom clusters in depression and their relationship to treatment outcomes in the STAR*D sample.

BACKGROUND: The heterogenous nature of depression continues to stymie efforts to identify biomarkers or predict treatment response. Efforts leveraging large datasets to define more uniform subtypes of depression or subgroups of depressed patients have considered only small subsets of symptoms. We aimed to understand how inclusion of more diverse complaints would impact data-emergent symptom and patient clusters. METHODS: We applied principal components analysis to baselineInventory of Depressive Symptomatology data from 1491 patients with major depressive disorder to derive naturally co-occurring symptom subsets before utilizing k-means clustering to divide patients into groups based on standardized residuals of each symptom subset score. We evaluated the clinical utility of our approach by comparing how cluster membership impacted response to citalopram. RESULTS: Prinicpal components analysis identified nine naturally co-occurring symptom subsets: core affective symptoms, appetite/weight loss, anxiety, somatic symptoms, insomnia, negative intrusive thoughts, leaden paralysis/mood quality, diurnal mood variation, and irritability. Cluster analysis identified two patient groups, differing significantly in 7 of 9 c symptom subsets. Patients distinguished by the prominence of somatic versus core affective symptoms exhibited less reduction in depression severity with citalopram treatment. LIMITATIONS: Results depend not only on raw data, but also parameter selection, and interpretation. Replication is indicated. CONCLUSIONS: Findings are consistent with previous reports linking somatic symptoms to treatment resistance and demonstrating that SSRIs are most effective in treating affective symptoms. A novel distinction between physical somatic symptoms and psychic anxiety highlights the utility of assessing a broad spectrum of symptoms when exploring heterogeneity in depression and the need for treatments targeting physical somatic symptoms specifically.

Localized task-invariant emotional valence encoding revealed by intracranial recordings.

The ability to distinguish between negative, positive and neutral valence is a key part of emotion perception. Emotional valence has conceptual meaning that supersedes any particular type of stimulus, although it is typically captured experimentally in association with particular tasks. We sought to identify neural encoding for task-invariant emotional valence. We evaluated whether high-gamma responses (HGRs) to visually displayed words conveying emotions could be used to decode emotional valence from HGRs to facial expressions. Intracranial electroencephalography was recorded from 14 individuals while they participated in two tasks, one involving reading words with positive, negative, and neutral valence, and the other involving viewing faces with positive, negative, and neutral facial expressions. Quadratic discriminant analysis was used to identify information in the HGR that differentiates the three emotion conditions. A classifier was trained on the emotional valence labels from one task and was cross-validated on data from the same task (within-task classifier) as well as the other task (between-task classifier). Emotional valence could be decoded in the left medial orbitofrontal cortex and middle temporal gyrus, both using within-task classifiers and between-task classifiers. These observations suggest the presence of task-independent emotional valence information in the signals from these regions.

Peripheral immune cell reactivity and neural response to reward in patients with depression and anhedonia.

Increased levels of peripheral cytokines have been previously associated with depression in preclinical and clinical research. Although the precise nature of peripheral immune dysfunction in depression remains unclear, evidence from animal studies points towards a dysregulated response of peripheral leukocytes as a risk factor for stress susceptibility. This study examined dynamic release of inflammatory blood factors from peripheral blood mononuclear cells (PBMC) in depressed patients and associations with neural and behavioral measures of reward processing. Thirty unmedicated patients meeting criteria for unipolar depressive disorder and 21 healthy control volunteers were enrolled. PBMCs were isolated from whole blood and stimulated ex vivo with lipopolysaccharide (LPS). Olink multiplex assay was used to analyze a large panel of inflammatory proteins. Participants completed functional magnetic resonance imaging with an incentive flanker task to probe neural responses to reward anticipation, as well as clinical measures of anhedonia and pleasure including the Temporal Experience of Pleasure Scale (TEPS) and the Snaith-Hamilton Pleasure Scale (SHAPS). LPS stimulation revealed larger increases in immune factors in depressed compared to healthy subjects using an aggregate immune score (t49 = 2.83, p = 0.007). Higher peripheral immune score was associated with reduced neural responses to reward anticipation within the ventral striatum (VS) (r = -0.39, p = 0.01), and with reduced anticipation of pleasure as measured with the TEPS anticipatory sub-score (r = -0.318, p = 0.023). Our study provides new evidence suggesting that dynamic hyper-reactivity of peripheral leukocytes in depressed patients is associated with blunted activation of the brain reward system and lower subjective anticipation of pleasure.

Interoception and Obsessive-Compulsive Disorder: A Review of Current Evidence and Future Directions.

Disrupted interoceptive processes are present in a range of psychiatric conditions, and there is a small but growing body of research on the role of interoception in obsessive-compulsive disorder (OCD). In this review, we outline dimensions of interoception and review current literature on the processing of internal bodily sensations within OCD. Investigations in OCD utilizing objective measures of interoception are limited and results mixed, however, the subjective experience of internal bodily sensations appears to be atypical and relate to specific patterns of symptom dimensions. Further, neuroimaging investigations suggest that interoception is related to core features of OCD, particularly sensory phenomena and disgust. Interoception is discussed in the context of treatment by presenting an overview of existing interventions and suggesting how modifications aimed at better targeting interoceptive processes could serve to optimize outcomes. Interoception represents a promising direction for multi-method research in OCD, which we expect, will prove useful for improving current interventions and identifying new treatment targets.

Phase 1 study of sorafenib and irinotecan in pediatric patients with relapsed or refractory solid tumors.

BACKGROUND: Sorafenib,an orally bioavailable, multitarget tyrosine kinase inhibitor, and irinotecan, a topoisomerase I inhibitor, have demonstrated activity in pediatric and adult malignancies. We evaluated the toxicity, pharmacokinetic (PK), and pharmacogenomic (PGX) profile of sorafenib with irinotecan in children with relapsed or refractory solid tumors and assessed the feasibility of incorporating patient-reported outcome (PRO) measures as an adjunct to traditional endpoints. METHODS: Sorafenib, continuous oral twice daily dosing, was administered with irinotecan, orally, once daily days 1-5, repeated every 21 days (NCT01518413). Based on tolerability, escalation of sorafenib followed by escalation of irinotecan was planned. Three patients were initially enrolled at each dose level. Sorafenib and irinotecan PK analyses were performed during cycle 1. PRO measurements were collected during cycles 1 and 2. RESULTS: Fifteen patients were evaluable. Two of three patients at dose level 2 experienced dose-limiting toxicity (DLT), grade 3 diarrhea, and grade 3 hyponatremia. Therefore, dose level 1 was expanded to 12 patients and two patients had DLT, grade 4 thrombocytopenia, grade 3 elevated lipase. Nine of 15 (60%) patients had a best response of stable disease with four patients receiving ≥6 cycles. CONCLUSIONS: The recommended dose for pediatric patients was sorafenib 150 mg/m2 /dose twice daily with irinotecan 70 mg/m2 /dose daily × 5 days every 21 days. This oral outpatient regimen was well tolerated and resulted in prolonged disease stabilization. There were no significant alterations in the PK profile of either agent when administered in combination. Patients were willing and able to report their subjective experiences with this regimen.

Impact of the KCNQ2/3 Channel Opener Ezogabine on Reward Circuit Activity and Clinical Symptoms in Depression: Results From a Randomized Controlled Trial.

OBJECTIVE: Preclinical studies point to the KCNQ2/3 potassium channel as a novel target for the treatment of depression and anhedonia, a reduced ability to experience pleasure. The authors conducted the first randomized placebo-controlled trial testing the effect of the KCNQ2/3 positive modulator ezogabine on reward circuit activity and clinical outcomes in patients with depression. METHODS: Depressed individuals (N=45) with elevated levels of anhedonia were assigned to a 5-week treatment period with ezogabine (900 mg/day; N=21) or placebo (N=24). Participants underwent functional MRI during a reward flanker task at baseline and following treatment. Clinical measures of depression and anhedonia were collected at weekly visits. The primary endpoint was the change from baseline to week 5 in ventral striatum activation during reward anticipation. Secondary endpoints included depression and anhedonia severity as measured using the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Snaith-Hamilton Pleasure Scale (SHAPS), respectively. RESULTS: The study did not meet its primary neuroimaging endpoint. Participants in the ezogabine group showed a numerical increase in ventral striatum response to reward anticipation following treatment compared with participants in the placebo group from baseline to week 5. Compared with placebo, ezogabine was associated with a significantly larger improvement in MADRS and SHAPS scores and other clinical endpoints. Ezogabine was well tolerated, and no serious adverse events occurred. CONCLUSIONS: The study did not meet its primary neuroimaging endpoint, although the effect of treatment was significant on several secondary clinical endpoints. In aggregate, the findings may suggest that future studies of the KCNQ2/3 channel as a novel treatment target for depression and anhedonia are warranted.

White matter microstructure and its relation to clinical features of obsessive-compulsive disorder: findings from the ENIGMA OCD Working Group.

Microstructural alterations in cortico-subcortical connections are thought to be present in obsessive-compulsive disorder (OCD). However, prior studies have yielded inconsistent findings, perhaps because small sample sizes provided insufficient power to detect subtle abnormalities. Here we investigated microstructural white matter alterations and their relation to clinical features in the largest dataset of adult and pediatric OCD to date. We analyzed diffusion tensor imaging metrics from 700 adult patients and 645 adult controls, as well as 174 pediatric patients and 144 pediatric controls across 19 sites participating in the ENIGMA OCD Working Group, in a cross-sectional case-control magnetic resonance study. We extracted measures of fractional anisotropy (FA) as main outcome, and mean diffusivity, radial diffusivity, and axial diffusivity as secondary outcomes for 25 white matter regions. We meta-analyzed patient-control group differences (Cohen's d) across sites, after adjusting for age and sex, and investigated associations with clinical characteristics. Adult OCD patients showed significant FA reduction in the sagittal stratum (d = -0.21, z = -3.21, p = 0.001) and posterior thalamic radiation (d = -0.26, z = -4.57, p < 0.0001). In the sagittal stratum, lower FA was associated with a younger age of onset (z = 2.71, p = 0.006), longer duration of illness (z = -2.086, p = 0.036), and a higher percentage of medicated patients in the cohorts studied (z = -1.98, p = 0.047). No significant association with symptom severity was found. Pediatric OCD patients did not show any detectable microstructural abnormalities compared to controls. Our findings of microstructural alterations in projection and association fibers to posterior brain regions in OCD are consistent with models emphasizing deficits in connectivity as an important feature of this disorder.

Abnormal semantic processing of threat words associated with excitement and hostility symptoms in schizophrenia.

BACKGROUND: Schizophrenia (SZ) is associated with devastating emotional, cognitive and language impairments. Understanding the deficits in each domain and their interactions is important for developing novel, targeted psychotherapies. This study tested whether negative-threat word processing is altered in individuals with SZ compared to healthy controls (HC), in relation to SZ symptom severity across domains. METHODS: Thirty-one SZ and seventeen HC subjects were scanned with functional magnetic resonance imaging while silently reading negative-threat and neutral words. Post-scan, subjects rated the valence of each word. The effects of group (SZ, HC), word type (negative, neutral), task period (early, late), and severity of clinical symptoms (positive, negative, excitement/hostility, cognitive, depression/anxiety), on word valence ratings and brain activation, were analyzed. RESULTS: SZ and HC subjects rated negative versus neutral words as more negative. The SZ subgroup with severe versus mild excitement/hostility symptoms rated the negative words as more negative. SZ versus HC subjects hyperactivated left language areas (angular gyrus, middle/inferior temporal gyrus (early period)) and the amygdala (early period) to negative words, and the amygdala (late period) to neutral words. In SZ, activation to negative versus neutral words in left dorsal temporal pole and dorsal anterior cingulate was positively correlated with excitement/hostility scores. CONCLUSIONS: A negatively-biased behavioral response to negative-threat words was seen in SZ with severe versus mild excitement/hostility symptoms. The biased behavioral response was mediated by hyperactivation of brain networks associated with semantic processing of emotion concepts. Thus, word-level semantic processing may be a relevant psychotherapeutic target in SZ.