Localized Orbitofrontal and Subcortical Metabolic Changes and Predictors of Response to Paroxetine Treatment in Obsessive-Compulsive Disorder

Abstract

Previous positron emission tomography (PET) studies of patients with obsessive-compulsive disorder (OCD) have found elevated glucose metabolic rates in the orbitofrontalPrevious positron emission tomography (PET) studies of obsessive-compulsive disorder (OCD) have found elevated glucose metabolic rates in the orbitofrontal cortex (OFC), anterior cingulate gyrus (AC), caudate nuclei, and thalamus (Baxter et al. 1987(Baxter et al. , 1988Nordahl et al. 1989;Swerdlow 1995; see Saxena et al. 1998 for review) or cognitive-behavioral treatment (Baxter et al. 1992;Schwartz et al. 1996) NO . 6 that provoke OCD symptoms have been found to increase blood flow to similar brain regions (McGuire et al. 1994;Rauch et al. 1994;Breiter et al. 1996). These and other findings have led to the theory that the symptomatic expression of OCD is mediated by hyperactivity along specific, frontal-subcortical circuits (Alexander et al. 1986) connecting the OFC, ventromedial caudate, globus pallidus, and the medial dorsal nucleus of the thalamus (Modell et al. 1989;Baxter et al. 1992;Baxter 1995;Insel 1992). Some studies have also suggested that hyperactivity in the AC, which is also linked to basal ganglia structures and thalamus along a parallel circuit, may be involved in mediating some OCD symptoms (Rapaport and Wise 1988;Perani et al. 1995).The OFC is a cytoarchitecturally heterogeneous structure that changes from agranular cortical tissue in its posteromedial region to more granular cortical tissue in its anterolateral region. These subregions have distinct patterns of connectivity and seem to serve different functions (see Zald and Kim 1996a; 1996b for detailed review). Previous PET studies of OCD treatment and symptom provocation suggest that different subregions of the OFC may be differentially involved in the pathophysiology of OCD. Benkelfat et al. (1990) found that the OFC subregion with the largest metabolic change with clomipramine treatment of OCD was right anterior OFC. McGuire et al. (1994) reported that OCD symptom intensity correlated with increased blood flow to right lateral OFC during symptom provocation. Rauch et al. (1994) found two centroids of OFC activation with symptomatic treatment-left anterior and right posterior OFC. Of these, only activation in left anterior OFC was positively correlated with the intensity of OCD symptoms; whereas, activation of right posterior OFC was negatively correlated with symptom intensity, suggesting that the two regions might play opposing roles in mediating and suppressing OCD symptoms, respectively. We sought to determine the role of specific subregions of the OFC and associated basal ganglia structures in mediating OCD symptoms, by determining how glucose metabolic rates in these structures changed with treatment of OCD patients. We sought to confirm and extend earlier findings using paroxetine hydrochloride, an OCD treatment that differs from those used in previous PET studies. Based on the previous findings noted above, we hypothesized that glucose metabolism in anterolate...

Predictors of Fluvoxamine Response in Contamination-related Obsessive Compulsive Disorder A PET Symptom Provocation Study

“…Also, these same results were garnered regardless of whether imaging data were obtained during a symptomatic (Provoked) or control (Neutral) state. The inverse correlation between rCBF in OFC and subsequent symptomatic improvement with SRI treatment is consistent with results from three previous studies of OCD employing other SRIs, PET-FDG, and ROI-based analytic methods Saxena et al 1999;Swedo et al 1992). Taken together, these studies underscore the reliability of this finding in OCD, across SRIs, imaging modalities, and data analytic methods.…”

“…Based on previous OCD symptom provocation studies (Breiter et al 1996;McGuire et al 1994;Rauch et al 1994), we predicted activation in OFC, anterior cingulate cortex, and the caudate nucleus. Based on previous imaging studies of predictors of treatment response in OCD Rauch et al 2001b;Saxena et al 1999;Swedo et al 1992), we predicted correlations in OFC and PCC. Loci exhibiting effects of comparable statistical significance are also reported for completeness, and to obviate bias.…”

“…Three prospective studies of OCD patients have already found that pre-treatment positron emission tomography (PET) measurements of cerebral metabolic rates within OFC significantly predict subsequent response to treatment with serotonergic reuptake inhibitors (SRIs) Saxena et al 1999;Swedo et al 1992). Specifically, lower pre-treatment rates of metabolism within OFC have consistently been associated with better subsequent responses to SRIs.…”

Serotonin and Dopamine Transporter Availabilities Correlate with the Loudness Dependence of Auditory Evoked Potentials in Patients with Obsessive-Compulsive Disorder

“…In our patients with OCD, the LD of the right primary auditory cortex (tangential dipole) was associated with both serotonin and dopamine transporter availabilities. Brain functional abnormalities in patients with OCD have repeatedly been shown in imaging and neurophysiological studies, and many of these investigations revealed more pronounced right-sided alterations (Baxter et al, 1992;Saxena et al, 1999;Saxena and Rauch, 2000). This could explain that in our study only the right LD, representing the right primary auditory cortex, revealed significant correlations with the imaging data.…”

Review of structural neuroimaging in patients with refractory obsessivecompulsive disorder

“…Current knowledge from functional and structural neuroimaging emphasizes abnormalities of fronto-striatalthalamic-cortical circuits and orbitofronto-striato-thalamic circuits in the pathophysiology of OCD [9,10] . In this context, structural imaging studies have implicated the pathology of basal ganglia and frontal regions [11] .…”