Sanjaya Saxena

FUNCTIONAL NEUROIMAGING AND THE NEUROANATOMY OF OBSESSIVE-COMPULSIVE DISORDER

Functional neuroimaging studies have advanced the understanding of the brain mediation of OCD by orbitofrontal-subcortical circuitry, but much is still unknown. Phenotypic heterogeneity could account for many of the inconsistencies among previous neuroimaging studies of OCD. Current studies are seeking to find the neurobiological basis of OCD symptom subtypes and predictors of treatment response. Future studies combining genetics and basic neuroanatomic research with neuroimaging may clarify the cause and pathophysiology of OCD. Although many lines of evidence point to dysfunction of orbitofrontal-subcortical circuitry in patients with OCD, many questions remain unanswered. Some have suggested that orbitofrontal-subcortical hyperactivity in OCD may be the result of abnormal neuroanatomic development of these structures or a failure of pruning of neuronal connections between them, as occurs in normal development, but no postmortem neuroanatomic studies of OCD exist to delineate its pathophysiology. Interventions that directly alter the indirect-direct pathway balance within frontal-subcortical circuits will allow for direct testing of the pathophysiologic hypotheses presented here. The roles of various neurochemical systems in OCD are similarly unclear. Although an abundance of indirect evidence suggests serotonergic abnormalities in patients with OCD, no direct evidence demonstrates what those abnormalities are or whether they are primary or secondary phenomena in patients with OCD. Ongoing studies of 5-HT synthesis in the brains of patients with OCD may shed light on this question.

Localized orbitofrontal and subcortical metabolic changes and predictors of response to paroxetine treatment in obsessive-compulsive disorder

Previous positron emission tomography (PET) studies of patients with obsessive-compulsive disorder (OCD) have found elevated glucose metabolic rates in the orbitofrontal cortex (OFC) and caudate nuclei that normalize with response to treatment. Furthermore, OCD symptom provocation differentially activates specific subregions of the OFC, which have distinct patterns of connectivity and serve different functions. Therefore, we sought to determine the role of specific subregions of the OFC and associated subcortical structures in mediating OCD symptoms, by determining how glucose metabolism in these structures changed with paroxetine treatment of OCD patients. We also sought to determine whether pretreatment OFC metabolism would predict response to paroxetine, as it has for other OCD treatments. Twenty subjects with OCD received [18F]-fluorodeoxyglucose (FDG)-PET scans before and after 8 to 12 weeks of treatment with paroxetine, 40 mg/day. In patients who responded to paroxetine, glucose metabolism decreased significantly in right anterolateral OFC and right caudate nucleus. Lower pretreatment metabolism in both left and right OFC predicted greater improvement in OCD severity with treatment. These results add to evidence indicating that orbitofrontal–subcortical circuit function mediates the symptomatic expression of OCD. Specific subregions of the OFC may be differentially involved in the pathophysiology of OCD and/or its response to pharmacotherapy.

FDG-PET predictors of response to behavioral therapy and pharmacotherapy in obsessive compulsive disorder

In subjects with obsessive-compulsive disorder (OCD), lower pre-treatment metabolism in the right orbitofrontal cortex (OFC) and anterior cingulate gyrus (AC) has been associated with a better response to clomipramine. We sought to determine pre-treatment metabolic predictors of response to behavioral therapy (BT) vs. pharmacotherapy in subjects with OCD. To do this, [18F]fluorodeoxyglucose positron emission tomography scans of the brain were obtained in subjects with OCD before treatment with either BT or fluoxetine. A Step-Wise Variable Selection was applied to normalized pre-treatment glucose metabolic rates in the OFC, AC, and caudate by treatment response (change in Yale-Brown Obsessive-Compulsive Scale) in the larger BT group. Left OFC metabolism (normalized to the ipsilateral hemisphere) alone was selected as predicting treatment response in the BT-treated group (F = 6.07, d.f. = 1,17, P = 0.025). Correlations between normalized left OFC metabolism and treatment response revealed that higher normalized metabolism in this region was associated with greater improvement in the BT-treated group (tau = 0.35, P = 0.04), but worse outcome (tau = -0.57, P = 0.03) in the fluoxetine-treated group. These results suggest that subjects with differing patterns of metabolism preferentially respond to BT vs. medication.

Refining the diagnostic boundaries of compulsive hoarding: a critical review.

Like most human behaviors, saving and collecting possessions can range from totally normal and adaptive to excessive or pathological. Hoarding, or compulsive hoarding, are some of the more commonly used terms to refer to this excessive form of collectionism. Hoarding is highly prevalent and, when severe, it is associated with substantial functional disability and represents a great burden for the sufferers, their families, and society in general. It is generally considered difficult to treat. Hoarding can occur in the context of a variety of neurological and psychiatric conditions. Although it has frequently been considered a symptom (or symptom dimension) of obsessive-compulsive disorder, and is listed as one of the diagnostic criteria for obsessive-compulsive personality disorder, its diagnostic boundaries are still a matter of debate. Recent data suggest that compulsive hoarding can also be a standalone problem. Growing evidence from epidemiological, phenomenological, neurobiological, and treatment studies suggests that compulsive hoarding may be best classified as a discrete disorder with its own diagnostic criteria.

Cerebral metabolism in major depression and obsessive-compulsive disorder occurring separately and concurrently

BACKGROUND The frequent comorbidity of major depressive disorder (MDD) and obsessive-compulsive disorder (OCD) suggests a fundamental relationship between them. We sought to determine whether MDD and OCD have unique cerebral metabolic patterns that remain the same when they coexist as when they occur independently. METHODS [18F]-fluorodeoxyglucose positron emission tomography (PET) brain scans were obtained on 27 subjects with OCD alone, 27 with MDD alone, 17 with concurrent OCD+MDD, and 17 normal control subjects, all in the untreated state. Regional cerebral glucose metabolism was compared between groups. RESULTS Left hippocampal metabolism was significantly lower in subjects with MDD alone and in subjects with concurrent OCD+MDD than in control subjects or subjects with OCD alone. Hippocampal metabolism was negatively correlated with depression severity across all subjects. Thalamic metabolism was significantly elevated in OCD alone and in MDD alone. Subjects with concurrent OCD+MDD had significantly lower metabolism in thalamus, caudate, and hippocampus than subjects with OCD alone. CONCLUSIONS Left hippocampal dysfunction was associated with major depressive episodes, regardless of primary diagnosis. Other cerebral metabolic abnormalities found in OCD and MDD occurring separately were not seen when the disorders coexisted. Depressive episodes occurring in OCD patients may be mediated by different basal ganglia-thalamic abnormalities than in primary MDD patients.

Brain metabolic changes associated with symptom factor improvement in major depressive disorder

BACKGROUND Symptoms of major depressive disorder (MDD) have been linked to regional brain function through imaging studies of symptom provocation in normal control subjects and baseline studies of subjects with MDD. We examined associations between change in depressive symptom factors and change in regional brain metabolism from before to after treatment of MDD. METHODS Thirty-nine outpatients with MDD underwent 18F-fluorodeoxyglucose positron emission tomography scanning before and after treatment with either paroxetine or interpersonal psychotherapy. Associations were determined between changes in regional brain metabolism and changes in four Hamilton Depression Rating Scale factors (anxiety/somatization [ANX], psychomotor retardation [PR], cognitive disturbance [COGN], and sleep disturbance) and two corresponding Profile of Mood States subscales (tension [TENS] and fatigue [FATIG]). RESULTS Improvement in ANX, PR, TENS, and FATIG factors was associated with decreasing ventral frontal lobe metabolism. Improvement in ANX and TENS was also associated with decreasing ventral anterior cingulate gyrus (AC) and anterior insula activity, whereas improvement in PR was associated with increasing dorsal AC activity. COGN improvement was associated with increasing dorsolateral prefrontal cortex metabolism. CONCLUSIONS Brain regions that show significant relationships with symptom provocation in normal control subjects have similar relationships with MDD symptoms as they improve with treatment.

Age at onset and clinical features of late life compulsive hoarding

Compulsive hoarding is a debilitating, chronic disorder, yet we know little about its onset, clinical features, or course throughout the life span. Hoarding symptoms often come to clinical attention when patients are in late life, and case reports of elderly hoarders abound. Yet no prior study has examined whether elderly compulsive hoarders have early or late onset of hoarding symptoms, whether their hoarding symptoms are idiopathic or secondary to other conditions, or whether their symptoms are similar to compulsive hoarding symptoms seen in younger and middle‐aged populations. The objectives of this study were to determine the onset and illustrate the course and clinical features of late life compulsive hoarding, including psychiatric and medical comorbitities.

Ventral Striatal Dopamine Release in Response to Smoking a Regular vs a Denicotinized Cigarette

Prior studies have demonstrated that both nicotine administration and cigarette smoking lead to dopamine (DA) release in the ventral striatum/nucleus accumbens. In tobacco-dependent individuals, smoking denicotinized cigarettes leads to reduced craving, but less pleasure, than smoking regular cigarettes. Using denicotinized cigarettes and 11C-raclopride positron emission tomography (PET) scanning, we sought to determine if nicotine is necessary for smoking-induced DA release. Sixty-two tobacco-dependent smokers underwent 11C-raclopride PET scanning, during which they smoked either a regular or denicotinized cigarette (double-blind). Change in 11C-raclopride binding potential (BP) in the ventral striatum from before to after smoking was determined as an indirect measure of DA release. Cigarette craving, anxiety, and mood were monitored during scanning. Smoking a regular cigarette resulted in a significantly greater mean reduction in ventral striatal 11C-raclopride BP than smoking a denicotinized cigarette. Although both groups had reductions in craving and anxiety with smoking, the regular cigarette group had a greater improvement in mood. For the total group, change in BP correlated inversely with change in mood, indicating that greater smoking-induced DA release was associated with more smoking-related mood improvement. Thus, nicotine delivered through cigarette smoking appears to be important for ventral striatal DA release. Study findings also suggest that mood improvement from smoking is specifically related to ventral striatal DA release.

Rapid effects of brief intensive cognitive-behavioral therapy on brain glucose metabolism in obsessive-compulsive disorder

Brief intensive cognitive-behavioral therapy (CBT) using exposure and response prevention significantly improves obsessive-compulsive disorder (OCD) symptoms in as little as 4 weeks. However, it has been thought that much longer treatment was needed to produce the changes in brain function seen in neuroimaging studies of OCD. We sought to elucidate the brain mediation of response to brief intensive CBT for OCD and determine whether this treatment could induce functional brain changes previously seen after longer trials of pharmacotherapy or standard CBT. [18F]-fluorodeoxyglucose positron emission tomography brain scans were obtained on 10 OCD patients before and after 4 weeks of intensive individual CBT. Twelve normal controls were scanned twice, several weeks apart, without treatment. Regional glucose metabolic changes were compared between groups. OCD symptoms, depression, anxiety and overall functioning improved robustly with treatment. Significant changes in normalized regional glucose metabolism were seen after brief intensive CBT (P=0.04). Compared to controls, OCD patients showed significant bilateral decreases in normalized thalamic metabolism with intensive CBT but had a significant increase in right dorsal anterior cingulate cortex activity that correlated strongly with the degree of improvement in OCD symptoms (P=0.02). The rapid response of OCD to intensive CBT is mediated by a distinct pattern of changes in regional brain function. Reduction of thalamic activity may be a final common pathway for improvement in OCD, but response to intensive CBT may require activation of dorsal anterior cingulate cortex, a region involved in reappraisal and suppression of negative emotions.

Early detection of Alzheimer's disease by combining apolipoprotein E and neuroimaging

New treatments for Alzheimers disease (AD) are more likely to slow or halt disease progression rather than to reverse existing neuronal damage. Identifying persons with mild cognitive complaints who are at risk for AD will allow investigators to apply anti-dementia treatments before extensive brain damage develops. The discovery of the apolipoprotein E epsilon 4 allele (APOE epsilon 4) as a major risk factor for AD offers promise of assisting in early detection and prediction of Alzheimers disease, particularly when genetic assessments are combined with other biomarkers such as neuroimaging. Studies of relatives at risk for familial AD using neuroimaging (positron emission tomography [PET]) and genetic assessments of APOE suggest that at-risk relatives with APOE epsilon 4 have lower parietal metabolism than those without APOE epsilon 4. Additional techniques that might increase sensitivity and specificity include longitudinal assessment of clinical and brain functional change, pharmacological challenges of short-acting anticholinergic agents, and memory activation paradigms during functional scanning. Such strategies should eventually assist in early detection of AD and in vivo therapeutic monitoring of brain function during experimental anti-dementia treatment trials.