Kate D. Fitzgerald

Decrease in Caudate glutamatergic concentrations in pediatric obsessive-compulsive disorder patients taking paroxetine

OBJECTIVE To measure in vivo neurochemical changes in the caudate nucleus in pediatric obsessive-compulsive disorder (OCD) before and after treatment. METHOD Single-voxel proton magnetic resonance spectroscopic (1H-MRS) examinations of the left caudate were conducted in 11 psychotropic drug-naive children, aged 8 to 17 years, with OCD before and after 12 weeks of monotherapy with the selective serotonin reuptake inhibitor paroxetine (10-60 mg/day) and 11 healthy children aged 8 to 17 years. A different sample of 8 pediatric OCD patients and 8 healthy children had a 1H-MRS examination of occipital cortex. RESULTS Caudate glutamatergic concentrations (Glx) were significantly greater in treatment-naive OCD patients than in controls but declined significantly after paroxetine treatment to levels comparable with those of controls. Decrease in caudate Glx was associated with decrease in OCD symptom severity. Occipital Glx did not differ between OCD patients and controls. CONCLUSIONS These preliminary findings provide new evidence of Glx abnormalities in the caudate nucleus in pediatric OCD and suggest that paroxetine treatment may be mediated by a serotonergically modulated reduction in caudate Glx.

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.

A functional neuroimaging study of motivation and executive function.

Executive functions, such as working memory, must intersect with functions that determine value for the organism. Functional imaging work in humans and single-unit recordings in non-human primates provide evidence that PFC might integrate motivational context with working memory. With functional magnetic resonance imaging (fMRI), we addressed the question of motivation and working memory, using a trial-related design in an object-working memory task. The design permitted the analysis of BOLD signal at separate stages, corresponding to encoding, maintenance, and retrieval. Subjects were motivated by a financial incentive during the task, such that they could gain a high or a low reward. The two different levels of reward also entailed greater or lesser risk of losing money for incorrect responses. In the high, relative to the low, reward condition, subjects shifted response bias, and showed a trend to greater sensitivity. We found main effects in fMRI BOLD signal for reward, which overlapped with BOLD effects for maintenance of information, in the right superior frontal sulcus and bilateral intraparietal sulcus. We also found an interaction between reward and retrieval from working memory in the right dorsolateral prefrontal cortex. Main effects of load and reward occurred in adjacent regions of the ventrolateral PFC during retrieval. The data demonstrate that when subjects perform a simple working memory task, financial incentives motivate performance and interact with some of the same neural networks that process various stages of working memory. Areas of overlap and interaction may integrate information about value, or they may represent a general effect of motivation increasing neural effort.

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.

Proton spectroscopic imaging of the thalamus in treatment-naive pediatric obsessive–compulsive disorder∗

BACKGROUND Neurobiological abnormalities in the thalamus, particularly the dorsomedial nucleus of the thalamus, are believed to be involved in the pathophysiology of obsessive-compulsive disorder. Although obsessive-compulsive disorder commonly arises in childhood and adolescence, no prior study has examined the thalamus in pediatric obsessive-compulsive disorder patients. METHODS In this study, N-acetyl-aspartate, a putative marker of neuronal viability, creatine/phosphocreatine, and choline levels were measured in the lateral and medical subregions of the left and right thalami using a multislice proton magnetic resonance spectroscopic imaging sequence in 11 treatment-naive, nondepressed obsessive-compulsive disorder outpatients, 8-15 years old, and 11 case-matched control subjects. RESULTS A significant reduction in N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) was observed in both the right and left medial thalami in obsessive-compulsive disorder patients compared with control subjects. The N-acetyl-aspartate/choline and N-acetyl-aspartate/(creatine/phosphocreatine + choline) levels did not differ significantly between case-control pairs in either the left or the right lateral thalamus. Reduction in N-acetyl-aspartate levels in the left medial thalamus was inversely correlated with increased obsessive-compulsive disorder symptom severity. CONCLUSIONS These findings provide new evidence of localized functional neurochemical marker abnormalities in the thalamus in pediatric obsessive-compulsive disorder. Our results must be considered preliminary, however, given the small sample size.

Altered function and connectivity of the medial frontal cortex in pediatric obsessive compulsive disorder

BACKGROUND Exaggerated concern for correct performance has been linked to hyperactivity of the medial frontal cortex (MFC) in adult obsessive-compulsive disorder (OCD), but the role of the MFC during the early course of illness remains poorly understood. We tested whether hyperactive MFC-based performance monitoring function relates to altered MFC connectivity within task control and default mode networks in pediatric patients. METHODS Eighteen pairs of OCD and matched healthy youth underwent functional magnetic resonance imaging during performance monitoring and at rest. Task-related hyperactivations in the posterior and ventral MFC were used as seeds for connectivity analyses during task and resting state. RESULTS In posterior MFC, patients showed greater activation of dorsal anterior cingulate cortex (dACC) than control subjects, with greater activation predicting worse performance. In ventral MFC, control subjects exhibited deactivation, whereas patients activated this region. Compared with control subjects, patients showed increased dACC-ventral MFC connectivity during task and decreased dACC-right anterior operculum and ventral MFC-posterior cingulate connectivity during rest. CONCLUSIONS Excessive activation and increased interactions of posterior and ventral MFC during performance monitoring may combine with reduced resting state connectivity of these regions within networks for task control and default mode to reflect early markers of OCD. Alteration of reciprocal interactions between these networks could potentiate the intrusion of ventral MFC-based affectively laden, self-referential thoughts, while disrupting posterior MFC-based performance-monitoring function in young patients.

Developmental Alterations of Frontal-Striatal-Thalamic Connectivity in Obsessive-Compulsive Disorder

OBJECTIVE Pediatric obsessive-compulsive disorder is characterized by abnormalities of frontal-striatal-thalamic circuitry that appear near illness onset and persist over its course. Distinct frontal-striatal-thalamic loops through cortical centers for cognitive control (anterior cingulate cortex) and emotion processing (ventral medial frontal cortex) follow unique maturational trajectories, and altered connectivity within distinct loops may be differentially associated with OCD at specific stages of development. METHOD Altered development of striatal and thalamic connectivity to medial frontal cortex was tested in 60 OCD patients compared with 61 healthy control subjects at child, adolescent, and adult stages of development, using resting-state functional connectivity MRI. RESULTS OCD in the youngest patients was associated with reduced connectivity of dorsal striatum and medial dorsal thalamus to rostral and dorsal anterior cingulate cortex, respectively. Increased connectivity of dorsal striatum to ventral medial frontal cortex was observed in patients at all developmental stages. In child patients, reduced connectivity between dorsal striatum and rostral anterior cingulate cortex correlated with OCD severity. CONCLUSIONS Frontal-striatal-thalamic loops involved in cognitive control are hypoconnected in young patients near illness onset, whereas loops implicated in emotion processing are hyperconnected throughout the illness.

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.

Paroxetine open-label treatment of pediatric outpatients with obsessive- compulsive disorder

OBJECTIVE Paroxetine is a selective serotonin reuptake inhibitor with demonstrated efficacy in treating obsessive-compulsive disorder (OCD) in adults. This study evaluates the safety and effectiveness of paroxetine in pediatric OCD patients. METHOD In a 12-week, open-label trial of paroxetine, 20 OCD outpatients, aged 8 to 17 years, were treated for OCD with daily doses ranging from 10 to 60 mg. Target symptoms were rated at regular intervals with the Childrens Yale-Brown Obsessive Compulsive Scale (CY-BOCS), the Childrens Global Assessment Scale, the Clinical Global Impression Scale, the Hamilton Anxiety Rating Scale, and the Yale Global Tic Severity Scale. RESULTS Paroxetine proved relatively safe in this brief trial with a small sample and appeared to be effective in patients with OCD; mean CY-BOCS scores decreased significantly (z = 3.49, p = .0005) from 30.6 +/- 3.5 to 21.6 +/- 6.8 on medication. The most common side effects (n > or = 2) were hyperactivity/behavioral activation, headache, insomnia, nausea, and anxiety. Paroxetine did not have to be discontinued in any of the patients because of side effects; the most serious side effects included hyperactivity/behavioral activation in 3 younger patients (< 10 years) necessitating dosage reduction but not discontinuation. CONCLUSIONS Preliminary evidence suggests that short-term treatment of pediatric OCD outpatients with paroxetine may be relatively safe and effective.

INCREASED ERROR-RELATED BRAIN ACTIVITY IN YOUTH WITH OBSESSIVE-COMPULSIVE DISORDER AND UNAFFECTED SIBLINGS

The pathophysiology of obsessive‐compulsive disorder (OCD) involves increased activity in cortico‐striatal circuits connecting the anterior cingulate cortex (ACC) with other brain regions. The error‐related negativity (ERN) is a negative deflection in the event‐related potential following an erroneous response and is thought to reflect ACC activity. This study was done to assess the ERN as a biomarker for OCD by comparing ERN amplitudes in pediatric OCD patients, unaffected siblings of pediatric OCD patients, and healthy controls.