Joseph A. Himle

Action-Monitoring Dysfunction in Obsessive-Compulsive Disorder

Evidence suggests that a hyperactive frontal-striatal-thalamic-frontal circuit is associated with the symptoms of obsessive-compulsive disorder (OCD), but there is little agreement about the function of the exaggerated activity. We report electrophysiological evidence suggesting that part of this system monitors events and generates error signals when the events conflict with an individuals internal standards or goals. Nine individuals with OCD and 9 age-, sex-, and education-matched control participants performed a speeded reaction time task. The error-related negativity, an event-related brain potential component that reflects action-monitoring processes, was enhanced in the individuals with OCD. The magnitude of this enhancement correlated with symptom severity. Dipole modeling suggested that the locus of the enhancement corresponded to medial frontal regions, possibly the anterior cingulate cortex.

Error-related hyperactivity of the anterior cingulate cortex in obsessive-compulsive disorder

BACKGROUND Hyperactivity of the anterior cingulate cortex (ACC) in patients with obsessive-compulsive disorder (OCD) has been shown to increase with symptom provocation and to normalize with treatment-induced symptom reduction. Although the functional significance of anterior cingulate involvement in OCD remains unknown, electrophysiological evidence has linked this region to error-processing abnormalities in patients with OCD. In this functional magnetic resonance imaging (fMRI) study, we sought to further localize error-processing differences within the ACC of OCD patients compared with healthy subjects. METHODS Event-related fMRI data were collected for eight OCD patients and seven healthy subjects during the performance of a simple cognitive task designed to elicit errors but not OCD symptoms. RESULTS Both OCD patients and healthy subjects demonstrated dorsal ACC activation during error commission. The OCD patients exhibited significantly greater error-related activation of the rostral ACC than comparison subjects. Activity in this region was positively correlated with symptom severity in the patients. CONCLUSIONS Error-processing abnormalities within the rostral anterior cingulate occur in the absence of symptom expression in patients with OCD.

Serotonin transporter and seasonal variation in blood serotonin in families with obsessive-compulsive disorder.

The serotonin transporter (HTT) is a candidate gene for obsessive-compulsive disorder (OCD) that has been associated with anxiety-related traits. The long (l) and short (s) variants of the HTT promoter have different transcriptional efficiencies. HTT promoter genotype and blood 5-HT concentration were examined in 70 subjects from 20 families ascertained through children and adolescents with a DSM-III-R diagnosis of OCD. The HTT promoter variant had a significant effect on blood 5-HT content. Subjects with the l/l and l/s genotypes had significantly higher blood 5-HT levels than did those with the s/s genotype. There was a significant interaction between HTT promoter genotype and seasonal variation in blood 5-HT content, with significant seasonal differences in 5-HT occurring only in the subjects with thel/l genotype. Further studies of the regulation of HTT gene expression are indicated.

A family study of obsessive-compulsive disorder with pediatric probands

Obsessive‐compulsive disorder (OCD) is a heterogeneous disorder of unknown etiology. We examined the lifetime history of obsessions, compulsions, and OCD in the first‐ and second‐degree relatives of 35 pediatric probands with OCD and 17 controls with no psychiatric diagnosis. All available first‐degree relatives were directly interviewed blind to proband status with two semi‐structured interviews. Parents were also interviewed to systematically assess the family psychiatric history of first‐ and second‐degree relatives. Best‐estimate lifetime diagnoses were made using all available sources of information. Data were analyzed with logistic regression by the generalized estimating equation method and with robust Cox regression models. The lifetime prevalence of definite OCD was significantly higher in case than control first‐degree relatives (22.5% vs. 2.6%, P < 0.05). Compared to controls, case first‐degree relatives also had significantly higher lifetime rates of obsessions and compulsions (both P < 0.05). There was no significant difference between case and control second‐degree relatives in lifetime rates of OCD. First‐degree relatives of case probands with ordering compulsions had a significantly higher lifetime rate of definite and subthreshold OCD than relatives of case probands without ordering compulsions (45.4% vs. 18.8%, P < 0.05). The lifetime prevalence of definite OCD was significantly higher in case first‐degree relatives with a history of tics than in case first‐degree relatives without a tic history (57.1% vs. 20.9%, P < 0.01). The results provide further evidence that early‐onset OCD is highly familial and suggest that two clinical variables are associated with its familial aggregation.

Medial Frontal Cortex Activity and Loss-Related Responses to Errors

Making an error elicits activity from brain regions that monitor performance, especially the medial frontal cortex (MFC). However, uncertainty exists about whether the posterior or anterior/rostral MFC processes errors and to what degree affective responses to errors are mediated in the MFC, specifically the rostral anterior cingulate cortex (rACC). To test the hypothesis that rACC mediates a type of affective response, we conceptualized affect in response to an error as a reaction to loss and amplified this response with a monetary penalty. While subjects performed a cognitive interference task during functional magnetic resonance imaging, hemodynamic activity in the rACC was significantly greater when subjects lost money as a result of an error compared with errors that did not lead to monetary loss. A significant interaction between the incentive conditions and error events demonstrated that the effect was not merely attributable to working harder to win (or not lose) money, although an effect of motivation was noted in the mid-MFC. Activation foci also occurred in similar regions of the posterior MFC for error and interference processing, which were not modulated by the incentive conditions. However, at the level of the individual subject, substantial functional variability occurred along the MFC during error processing, including foci in the rostral/anterior extent of the MFC not appearing in the group analysis. The findings support the hypothesis that the rostral extent of the MFC (rACC) processes loss-related responses to errors, and individual differences may account for some of the reported variation of error-related foci in the MFC.

Anxiety disorders among African Americans, blacks of Caribbean descent, and non-Hispanic whites in the United States

The central aim of this study is to estimate prevalence, ages of onset, severity, and associated disability of anxiety disorders among African Americans, Caribbean Blacks, and non-Hispanic whites in the U.S. Results indicated that whites were at elevated risk for generalized anxiety disorder, panic disorder, and social anxiety compared to Caribbean Blacks and African Americans. Black respondents were more likely to meet criteria for PTSD. When African American and Caribbean Black respondents met criteria for an anxiety disorder, they experienced higher levels of overall mental illness severity and functional impairment compared to whites. White respondents were at greater risk to develop generalized anxiety, social anxiety, and panic disorders late in life. Risk of developing PTSD endured throughout the life course for blacks whereas whites rarely developed PTSD after young adulthood. These results can be used to inform targeted interventions to prevent or remediate anxiety disorders among these diverse groups.

Blood-injury-illness phobia: A review

The empirical literature that pertains to phobias of blood, injury, or illness (BII) is surveyed. BII phobia is selectively associated with a vasovagal fainting response upon exposure to phobic stimuli, and the clinical entity may represent an exaggeration of a response that is relatively prevalent in the general population. Clinical, demographic and etiological information obtained from a series of 15 BII phobics is presented, and the suggestion is made that this disorder warrants a diagnostic category separate from simple phobia.

Association studies of serotonin system candidate genes in early-onset obsessive-compulsive disorder.

BACKGROUND Family-based evidence for association at serotonin system genes SLC6A4, HTR1B, HTR2A, and brain-derived neurotrophic factor (BDNF) has been previously reported in obsessive-compulsive disorder (OCD). Early-onset OCD is a more familial form of the disorder. METHODS We used the transmission-disequilibrium test of association at common polymorphisms in each of these genes in 54 parent-child trios ascertained through probands with early-onset OCD. RESULTS No evidence for association was detected at any of the polymorphisms in the entire set of subjects. Nominally significant association was found at the HTR2A rs6311 polymorphism in subjects with tic disorder and OCD (p = .05), replicating a previous finding in Tourette syndrome and OCD. Nominally significant association was also found for the SLC6A4 HT transporter gene-linked polymorphic region (5-HTTLPR) polymorphism for female subjects (p = .03). Neither association would remain significant after statistical correction for multiple testing. Despite no individual study reporting replication, a pooled analysis of five replication studies of the SLC6A4 5-HTTLPR polymorphism supports association (p = .02). CONCLUSIONS Low power across individual association studies in OCD may lead to a false acceptance of the null hypothesis. Accumulation of evidence from multiple studies will be necessary to evaluate the potential role for these genes in contributing to susceptibility to OCD.

Hyperactive Error Responses and Altered Connectivity in Ventromedial and Frontoinsular Cortices in Obsessive-Compulsive Disorder

BACKGROUND Patients with obsessive-compulsive disorder (OCD) show abnormal functioning in ventral frontal brain regions involved in emotional/motivational processes, including anterior insula/frontal operculum (aI/fO) and ventromedial frontal cortex (VMPFC). While OCD has been associated with an increased neural response to errors, the influence of motivational factors on this effect remains poorly understood. METHODS To investigate the contribution of motivational factors to error processing in OCD and to examine functional connectivity between regions involved in the error response, functional magnetic resonance imaging data were measured in 39 OCD patients (20 unmedicated, 19 medicated) and 38 control subjects (20 unmedicated, 18 medicated) during an error-eliciting interference task where motivational context was varied using monetary incentives (null, loss, and gain). RESULTS Across all errors, OCD patients showed reduced deactivation of VMPFC and greater activation in left aI/FO compared with control subjects. For errors specifically resulting in a loss, patients further hyperactivated VMPFC, as well as right aI/FO. Independent of activity associated with task events, OCD patients showed greater functional connectivity between VMPFC and regions of bilateral aI/FO and right thalamus. CONCLUSIONS Obsessive-compulsive disorder patients show greater activation in neural regions associated with emotion and valuation when making errors, which could be related to altered intrinsic functional connectivity between brain networks. These results highlight the importance of emotional/motivational responses to mistakes in OCD and point to the need for further study of network interactions in the disorder.

Alcohol abuse and the anxiety disorders: Evidence from the epidemiologic catchment area survey

This study examined the prevalence of alcohol abuse and/or dependence in a sample of patients with anxiety disorders gathered from the Epidemiologic Catchment Area Study. Prior research had indicated that anxiety disorders are preva- lent among alcoholics and also that alcoholism is prevalent among samples of anxiety disorder patients. The sample included 2471 individuals who met a lifetime diagnosis of agoraphobia, panic disorder, agoraphobia with panic attacks, social phobia, simple phobia, or obsessive-compulsive disorder. About 12% of these individuals met criteria for a lifetime history of alcohol abuse and/or dependence. Relative odds ratios were calculated for the risk of alcohol use disorder, correcting for the effects of site, age, race, and gender. Among those individuals with a history of both anxiety and alco- holism disorders, the highest risk of alcohol use disorder was found in the agorapho- bia with panic group. Lowest risk was found among those with a single diagnosis of simple phobia or agoraphobia without panic attacks. Clinical implications of these results are discussed.