Correlation between compulsive behaviors and plastic changes in the dendritic spines of the prefrontal cortex and dorsolateral striatum of male rats.

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD.

Thermocoagulation as a Surgical Approach for the Treatment of Obsessive-Compulsive Disorder in Refractory Patients: Systematic Review

Obsessive-compulsive disorder (OCD), a disabling chronic neuropsychiatric disease, entails high economic costs to society and has high morbidity and mortality rates. The first-line treatments for OCD are selective serotonin reuptake inhibitors and cognitivebehavioral therapy. However, this disorder has the highest refractory index to noninvasive treatment. Alternatively, ablative thermocoagulation neurosurgical techniques have shown efficacy and few adverse effects. The present systematic review aimed to identify validated protocols to observe the effectiveness of ablative procedures in the treatment of severe and refractory OCD, as well as their possible adverse effects and benefits. This review supports the effectiveness of ablative methods by presenting them as a safe non-experimental therapeutic option for cases of highlyrefractory OCD. Additional relevant findings were the improvement in cognitive function, functional capacity, affective orientation, and quality of life, which contribute to the destigmatization of this surgical technique. Further controlled studies may lead to the individualization of recommendations of targets for ablative thermocoagulation.

Toward identifying reproducible brain signatures of obsessive-compulsive profiles: rationale and methods for a new global initiative.

BACKGROUND: Obsessive-compulsive disorder (OCD) has a lifetime prevalence of 2-3% and is a leading cause of global disability. Brain circuit abnormalities in individuals with OCD have been identified, but important knowledge gaps remain. The goal of the new global initiative described in this paper is to identify robust and reproducible brain signatures of measurable behaviors and clinical symptoms that are common in individuals with OCD. A global approach was chosen to accelerate discovery, to increase rigor and transparency, and to ensure generalizability of results. METHODS: We will study 250 medication-free adults with OCD, 100 unaffected adult siblings of individuals with OCD, and 250 healthy control subjects at five expert research sites across five countries (Brazil, India, Netherlands, South Africa, and the U.S.). All participants will receive clinical evaluation, neurocognitive assessment, and magnetic resonance imaging (MRI). The imaging will examine multiple brain circuits hypothesized to underlie OCD behaviors, focusing on morphometry (T1-weighted MRI), structural connectivity (Diffusion Tensor Imaging), and functional connectivity (resting-state fMRI). In addition to analyzing each imaging modality separately, we will also use multi-modal fusion with machine learning statistical methods in an attempt to derive imaging signatures that distinguish individuals with OCD from unaffected siblings and healthy controls (Aim #1). Then we will examine how these imaging signatures link to behavioral performance on neurocognitive tasks that probe these same circuits as well as to clinical profiles (Aim #2). Finally, we will explore how specific environmental features (childhood trauma, socioeconomic status, and religiosity) moderate these brain-behavior associations. DISCUSSION: Using harmonized methods for data collection and analysis, we will conduct the largest neurocognitive and multimodal-imaging study in medication-free subjects with OCD to date. By recruiting a large, ethno-culturally diverse sample, we will test whether there are robust biosignatures of core OCD features that transcend countries and cultures. If so, future studies can use these brain signatures to reveal trans-diagnostic disease dimensions, chart when these signatures arise during development, and identify treatments that target these circuit abnormalities directly. The long-term goal of this research is to change not only how we conceptualize OCD but also how we diagnose and treat it.

Self-reported and neurocognitive impulsivity in obsessive-compulsive disorder.

BACKGROUND: Although a behavioural addiction model of obsessive-compulsive disorder (OCD) has been proposed, it is still unclear if and how self-report and neurocognitive measures of impulsivity (such as risk-taking-, reflection- and motor-impulsivities) are impaired and/or inter-related in this particular clinical population. METHODS: Seventeen OCD patients and 17 age-, gender-, education- and IQ-matched controls completed the Barratt Impulsivity Scale, the Obsessive-Compulsive Inventory-Revised, and the Beck Depression Inventory and were evaluated with the Yale-Brown Obsessive-Compulsive Scale and three computerized paradigms including reward (the Cambridge Gambling Task), reflection (the Information Sampling Task) and motor impulsivity (Stop Signal Task). RESULTS: Despite not differing from healthy controls in any neurocognitive impulsivity domain, OCD patients demonstrated increased impulsivity in a self-report measure (particularly attentional impulsivity). Further, attentional impulsivity was predicted by severity of obsessive-compulsive symptoms. CONCLUSIONS: Our findings suggest that OCD is characterized by a subjective (rather than objective) impulsivity; in addition, self-reported impulsivity was largely determined by severity of OCD symptoms.

Theoretical models of Obsessive-Compulsive Disorder (OCD): a perspective on future approaches

Obsessive-Compulsive disorder (OCD) is a common psychiatric condition that leads to significant impairment in everyday life. Advancements in neurobiological investigations contributed to a better understanding of pathophysiological mechanisms behind OCD, leading to the understanding that current models employed to conceptualize OCD are not adequate and might be a significant factor in precluding further advancements in how OCD is treated. In this paper, we will use OCD as a model to discuss the limitations of the current diagnostic systems in Psychiatry and to present the novel perspectives based on neurobiological findings that might lead to considerable advancements in treatments for OCD.

No evidence of attentional bias toward angry faces in patients with obsessive-compulsive disorder

Objective: Although attentional bias (AB) toward angry faces is well established in patients with anxiety disorders, it is still poorly studied in obsessive-compulsive disorder (OCD). We investigated whether OCD patients present AB toward angry faces, whether AB is related to symptom severity and whether AB scores are associated with specific OCD symptom dimensions. Method: Forty-eight OCD patients were assessed in clinical evaluations, intelligence testing and a dot-probe AB paradigm that used neutral and angry faces as stimuli. Analyses were performed with a one-sample t-test, Pearson correlations and linear regression. Results: No evidence of AB was observed in OCD patients, nor was there any association between AB and symptom severity or dimension. Psychiatric comorbidity did not affect our results. Conclusion: In accordance with previous studies, we were unable to detect AB in OCD patients. To investigate whether OCD patients have different brain activation patterns from anxiety disorder patients, future studies using a transdiagnostic approach should evaluate AB in OCD and anxiety disorder patients as they perform AB tasks under functional neuroimaging protocols.

Initial findings of striatum tripartite model in OCD brain samples based on transcriptome analysis.

Obsessive-compulsive disorder (OCD) is a psychiatric disorder characterized by obsessions and/or compulsions. Different striatal subregions belonging to the cortico-striato-thalamic circuitry (CSTC) play an important role in the pathophysiology of OCD. The transcriptomes of 3 separate striatal areas (putamen (PT), caudate nucleus (CN) and accumbens nucleus (NAC)) from postmortem brain tissue were compared between 6 OCD and 8 control cases. In addition to network connectivity deregulation, different biological processes are specific to each striatum region according to the tripartite model of the striatum and contribute in various ways to OCD pathophysiology. Specifically, regulation of neurotransmitter levels and presynaptic processes involved in chemical synaptic transmission were shared between NAC and PT. The Gene Ontology terms cellular response to chemical stimulus, response to external stimulus, response to organic substance, regulation of synaptic plasticity, and modulation of synaptic transmission were shared between CN and PT. Most genes harboring common and/or rare variants previously associated with OCD that were differentially expressed or part of a least preserved coexpression module in our study also suggest striatum subregion specificity. At the transcriptional level, our study supports differences in the 3 circuit CSTC model associated with OCD.

Evolution of gamma knife capsulotomy for intractable obsessive-compulsive disorder.

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.

Layer-specific reduced neuronal density in the orbitofrontal cortex of older adults with obsessive-compulsive disorder.

Neurobiological models have provided consistent evidence of the involvement of cortical-subcortical circuitry in obsessive-compulsive disorder (OCD). The orbitofrontal cortex (OFC), involved in motivation and emotional responses, is an important regulatory node within this circuitry. However, OFC abnormalities at the cellular level have so far not been studied. To address this question, we have recruited a total of seven senior individuals from the Sao Paulo Autopsy Services who were diagnosed with OCD after an extensive post-mortem clinical evaluation with their next of kin. Patients with cognitive impairment were excluded. The OCD cases were age- and sex-matched with 7 control cases and a total of 14 formalin-fixed, serially cut, and gallocyanin-stained hemispheres (7 subjects with OCD and 7 controls) were analyzed stereologically. We estimated laminar neuronal density, volume of the anteromedial (AM), medial orbitofrontal (MO), and anterolateral (AL) areas of the OFC. We found statistically significant layer- and region-specific lower neuron densities in our OCD cases that added to a deficit of 25% in AM and AL and to a deficit of 21% in MO, respectively. The volumes of the OFC areas were similar between the OCD and control groups. These results provide evidence of complex layer and region-specific neuronal deficits/loss in old OCD cases which could have a considerable impact on information processing within orbitofrontal regions and with afferent and efferent targets.

No evidence of attentional bias toward angry faces in patients with obsessive-compulsive disorder.

OBJECTIVE: Although attentional bias (AB) toward angry faces is well established in patients with anxiety disorders, it is still poorly studied in obsessive-compulsive disorder (OCD). We investigated whether OCD patients present AB toward angry faces, whether AB is related to symptom severity and whether AB scores are associated with specific OCD symptom dimensions. METHOD: Forty-eight OCD patients were assessed in clinical evaluations, intelligence testing and a dot-probe AB paradigm that used neutral and angry faces as stimuli. Analyses were performed with a one-sample t-test, Pearson correlations and linear regression. RESULTS: No evidence of AB was observed in OCD patients, nor was there any association between AB and symptom severity or dimension. Psychiatric comorbidity did not affect our results. CONCLUSION: In accordance with previous studies, we were unable to detect AB in OCD patients. To investigate whether OCD patients have different brain activation patterns from anxiety disorder patients, future studies using a transdiagnostic approach should evaluate AB in OCD and anxiety disorder patients as they perform AB tasks under functional neuroimaging protocols.

When patients with OCD decide to seek, and not to avoid harm: The problem of suicidality in OCD.

Obsessive-compulsive disorder (OCD) is a chronic, distressing, and disabling condition associated with a high risk of suicidal behavior and death by suicide. In this study, the authors describe two cases of OCD patients who developed recurrent suicidal behaviors in response to stressful life events that appeared to "confirm" their obsessive beliefs (termed "confirmatory events"). In both cases, the authors used accepted strategies for treating suicidality in other contexts (such as antidepressants, lithium, and electroconvulsive therapy), which proved unsuccessful. Future studies should investigate personalized strategies to treat suicidality and prevent suicide in OCD patients.

Activation of cortical and striatal regions during the expression of a naturalistic compulsive-like behavior in the rabbit.

Nest building behavior in the pregnant rabbit (Oryctolagus cuniculus) can serve as a model for compulsions in obsessive compulsive disorder (OCD). Previous work showed that the "straw carrying" phase of nest building (during which the rabbit repeatedly collects straw in its mouth, carries it into the nest box and deposits it there, and then returns to collect more) is associated with increased c-FOS expression (a marker of neuronal activity) in the orbitofrontal, anterior cingulate, and piriform cortices. In the present study, we quantified c-FOS expression in the caudate and putamen, as well as in the primary motor, somatosensory, and prefrontal cortices of: (1) pregnant rabbits given straw (PREG + STRAW); pregnant rabbits not given straw (PREG); (3) estrous rabbits given straw (ESTROUS + STRAW); and (4) estrous rabbits not given straw (ESTROUS). We found that straw carrying was associated with increased c-FOS expression in the dorsal putamen, ventral caudate, primary motor cortex, and somatosensory cortex. Additionally, a correlational analysis of PREG + STRAW animals revealed that these regions, along with the premotor and prelimbic cortices, were significantly intercorrelated with respect to c-FOS expression, suggesting their "coactivation" during repetitive straw carrying. By contrast, behavioral interactions of non-pregnant (ESTROUS) rabbits with straw (e.g., sniffing, nibbling it) were associated with a distinct pattern of c-FOS expression that included the medial and ventral putamen. c-FOS expression in PREG + STRAW rabbits is similar to patterns of regional brain activity in OCD patients exposed to obsession-provoking stimuli, as well as to those observed in healthy human mothers responding to infant-associated stimuli.

The inner world of overactive monitoring: neural markers of interoception in obsessive-compulsive disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) patients typically overmonitor their own behavior, as shown by symptoms of excessive doubt and checking. Although this is well established for the patients' relationship with external stimuli in the environment, no study has explored their monitoring of internal body signals, a process known to be affected in anxiety-related syndromes. Here, we explored this issue through a cardiac interoception task that measures sensing of heartbeats. Our aim was to explore key behavioral and electrophysiological aspects of internal-cue monitoring in OCD, while examining their potential distinctiveness in this condition. METHOD: We administered a heartbeat detection (HBD) task (with related interoceptive confidence and awareness measures) to three matched groups (OCD patients, panic disorder patients, healthy controls) and recorded ongoing modulations of two task-relevant electrophysiological markers: the heart evoked potential (HEP) and the motor potential (MP). RESULTS: Behaviorally, OCD patients outperformed controls and panic patients in the HBD task. Moreover, they exhibited greater amplitude modulation of both the HEP and the MP during cardiac interoception. However, they evinced poorer confidence and awareness of their interoceptive skills. CONCLUSIONS: Convergent behavioral and electrophysiological data showed that overactive monitoring in OCD extends to the sensing of internal bodily signals. Moreover, this pattern discriminated OCD from panic patients, suggesting a condition-distinctive alteration. Our results highlight the potential of exploring interoceptive processes in the OCD spectrum to better characterize the population's cognitive profile. Finally, these findings may lay new bridges between somatic theories of emotion and cognitive models of OCD.

The Child Behavior Checklist-Obsessive-Compulsive Subscale Detects Severe Psychopathology and Behavioral Problems Among School-Aged Children.

OBJECTIVE: The aims of this study were (1) to assess obsessive-compulsive symptoms (OCS) dimensionally in a school-aged community sample and to correlate them with clinical and demographical variables; (2) to determine a subgroup with significant OCS ("at-risk for OCD") using the Child Behavior Checklist (CBCL-OCS) and (3) to compare it with the rest of the sample; (4) To review the CBCL-OCS subscale properties as a screening tool for pediatric OCD. METHODS: Data from the Brazilian High Risk Cohort were analyzed. The presence and severity of OCS were assessed through the CBCL-OCS subscale. DSM-IV psychiatric diagnoses were obtained by the Developmental and Well-Being Assessment. Behavioral problems were assessed using the Strengths and Difficulties Questionnaire, the Youth Strengths Inventory, and the CBCL internalizing and externalizing behavior subscales. RESULTS: A total of 2512 (mean age: 8.86 ± 1.84 years; 55.0% male) children were included. Moderate correlations were found between OCS severity and functional impairment (r = 0.36, p < 0.001). Children with higher levels of OCS had higher rates of psychiatric comorbidity and behavioral problems (p < 0.001). A score of 5 or higher in the CBCL-OCS scale determined an "at-risk for OCD" subgroup, comprising 9.7% of the sample (n = 244), with behavioral patterns and psychiatric comorbidities (e.g., tics [odds ratios, OR = 6.41, p < 0.001]), anxiety disorders grouped [OR = 3.68, p < 0.001] and depressive disorders [OR = 3.0, p < 0.001] very similar to those described in OCD. Sensitivity, specificity, positive predictive value, and negative predictive value of the CBCL-OCS for OCD diagnosis were, respectively, 48%, 91.5%; 15.1%, and 98.2%. CONCLUSIONS: The dimensional approach suggests that the presence of OCS in children is associated with higher rates of comorbidity, behavioral problems, and impairment. The "at-risk for OCD" group defined by the CBCL revealed a group of patients phenotypically similar to full blown OCD.

An Avoidance-Based Rodent Model of Exposure With Response Prevention Therapy for Obsessive-Compulsive Disorder.

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.

Reduced prefrontal activation in pediatric patients with obsessive-compulsive disorder during verbal episodic memory encoding.

OBJECTIVE: Patients with obsessive-compulsive disorder (OCD) often present with deficits in episodic memory, and there is evidence that these difficulties may be secondary to executive dysfunction, that is, impaired selection and/or application of memory-encoding strategies (mediation hypothesis). Semantic clustering is an effective strategy to enhance encoding of verbal episodic memory (VEM) when word lists are semantically related. Self-initiated mobilization of this strategy has been associated with increased activity in the prefrontal cortex, particularly the orbitofrontal cortex, a key region in the pathophysiology of OCD. We therefore studied children and adolescents with OCD during uncued semantic clustering strategy application in a VEM functional magnetic resonance imaging (fMRI)-encoding paradigm. METHOD: A total of 25 pediatric patients with OCD (aged 8.1-17.5 years) and 25 healthy controls (HC, aged 8.1-16.9) matched for age, gender, handedness, and IQ were evaluated using a block design VEM paradigm that manipulated semantically related and unrelated words. RESULTS: The semantic clustering strategy score (SCS) predicted VEM performance in HC (p < .001, R(2) = 0.635), but not in patients (p = .099). Children with OCD also presented hypoactivation in the dorsomedial prefrontal cortex (cluster-corrected p < .001). Within-group analysis revealed a negative correlation between Yale-Brown Obsessive Compulsive Scale scores and activation of orbitofrontal cortex in the group with OCD. Finally, a positive correlation between age and SCS was found in HC (p = .001, r = 0.635), but not in patients with OCD (p = .936, r = 0.017). CONCLUSION: Children with OCD presented altered brain activation during the VEM paradigm and absence of expected correlation between SCS and age, and between SCS and total words recalled. These results suggest that different neural mechanisms underlie self-initiated semantic clustering in OCD.

Transcranial direct current stimulation in obsessive-compulsive disorder: emerging clinical evidence and considerations for optimal montage of electrodes.

BACKGROUND: Neuromodulation techniques for obsessive-compulsive disorder (OCD) treatment have expanded with greater understanding of the brain circuits involved. Transcranial direct current stimulation (tDCS) might be a potential new treatment for OCD, although the optimal montage is unclear. OBJECTIVE: To perform a systematic review on meta-analyses of repetitive transcranianal magnetic stimulation (rTMS) and deep brain stimulation (DBS) trials for OCD, aiming to identify brain stimulation targets for future tDCS trials and to support the empirical evidence with computer head modeling analysis. METHODS: Systematic reviews of rTMS and DBS trials on OCD in Pubmed/MEDLINE were searched. For the tDCS computational analysis, we employed head models with the goal of optimally targeting current delivery to structures of interest. RESULTS: Only three references matched our eligibility criteria. We simulated four different electrodes montages and analyzed current direction and intensity. CONCLUSION: Although DBS, rTMS and tDCS are not directly comparable and our theoretical model, based on DBS and rTMS targets, needs empirical validation, we found that the tDCS montage with the cathode over the pre-supplementary motor area and extra-cephalic anode seems to activate most of the areas related to OCD.

Brain structural correlates of sensory phenomena in patients with obsessive-compulsive disorder.

BACKGROUND: Sensory phenomena (SP) are uncomfortable feelings, including bodily sensations, sense of inner tension, "just-right" perceptions, feelings of incompleteness, or "urge-only" phenomena, which have been described to precede, trigger or accompany repetitive behaviours in individuals with obsessive-compulsive disorder (OCD). Sensory phenomena are also observed in individuals with tic disorders, and previous research suggests that sensorimotor cortex abnormalities underpin the presence of SP in such patients. However, to our knowledge, no studies have assessed the neural correlates of SP in patients with OCD. METHODS: We assessed the presence of SP using the University of São Paulo Sensory Phenomena Scale in patients with OCD and healthy controls from specialized units in São Paulo, Brazil, and Barcelona, Spain. All participants underwent a structural magnetic resonance examination, and brain images were examined using DARTEL voxel-based morphometry. We evaluated grey matter volume differences between patients with and without SP and healthy controls within the sensorimotor and premotor cortices. RESULTS: We included 106 patients with OCD and 87 controls in our study. Patients with SP (67% of the sample) showed grey matter volume increases in the left sensorimotor cortex in comparison to patients without SP and bilateral sensorimotor cortex grey matter volume increases in comparison to controls. No differences were observed between patients without SP and controls. LIMITATIONS: Most patients were medicated. Participant recruitment and image acquisition were performed in 2 different centres. CONCLUSION: We have identified a structural correlate of SP in patients with OCD involving grey matter volume increases within the sensorimotor cortex; this finding is in agreement with those of tic disorder studies showing that abnormal activity and volume increases within this region are associated with the urges preceding tic onset.

Tic symptom dimensions and their heritabilities in Tourette's syndrome.

INTRODUCTION: Gilles de la Tourette's syndrome (TS) is both genotypically and phenotypically heterogeneous. Gene-finding strategies have had limited success, possibly because of symptom heterogeneity. OBJECTIVE: This study aimed at specifically investigating heritabilities of tic symptom factors in a relatively large sample of TS patients and family members. PARTICIPANTS AND METHODS: Lifetime tic symptom data were collected in 494 diagnosed individuals in two cohorts of TS patients from the USA (n=273) and the Netherlands (n=221), and in 351 Dutch family members. Item-level factor analysis, using a tetrachoric correlation matrix in SAS (v9.2), was carried out on 23 tic symptoms from the Yale Global Tic Severity Scale. RESULTS: Three factors were identified explaining 49% of the total variance: factor 1, complex vocal tics and obscene behaviour; factor 2, body tics; and factor 3, head/neck tics. Using Sequential Oligogenic Linkage Analysis Routine, moderate heritabilities were found for factor 1 (h2r=0.21) and factor 3 (h2r=0.25). Lower heritability was found for overall tic severity (h2r=0.19). Bivariate analyses indicated no genetic associations between tic factors. CONCLUSION: These findings suggest that (i) three tic factors can be discerned with a distinct underlying genetic architecture and that (ii) considering the low tic heritabilities found, only focusing on the narrow-sense TS phenotype and leaving out comorbidities that are part of the broader sense tic phenotype may lead to missing heritability. Although these findings need replication in larger independent samples, they might have consequences for future genetic studies in TS.

Clomipramine demethylation rate is important on the outcome of obsessive-compulsive disorder treatment.

The aim of this study was to investigate the influence of demethylation rate on the outcome of obsessive-compulsive disorder patients treated with clomipramine. Eighteen patients meeting the DSM-IV criteria for obsessive-compulsive disorder received 150-300 mg of clomipramine daily in a single-blind design for 12 weeks. The patients were evaluated with the Clinical Global Impression scale and the Yale-Brown Obsessive-Compulsive Scale (YBOCS). Clinical assessment and serum measurements of clomipramine and desmethylclomipramine were carried out at baseline and after 3, 6, 8, 10, and 12 weeks. A greater improvement in Clinical Global Impression scale rating was associated with a lower desmethylclomipramine/daily dose and the total clomipramine and desmethylclomipramine/daily dose. Moreover, an improved response on the YBOCS-obsession score was associated with higher serum levels of clomipramine and the total clomipramine and desmethylclomipramine/daily dose. Patients with a greater reduction in baseline YBOCS rating had a lower desmethylclomipramine/clomipramine ratio. These data suggest that a lower demethylation rate correlates with better clinical outcome.