Lewis R. Baxter

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.

Reduced Cerebral Glucose Metabolism in Asymptomatic Subjects at Risk for Huntington's Disease

Symptomatic patients with Huntingtons disease may have reduced glucose metabolism in the caudate nuclei. We used positron emission tomography and [18F]fluorodeoxyglucose to study cerebral glucose metabolism in 95 subjects: 58 clinically asymptomatic (chorea-free) subjects at risk for Huntingtons disease, 10 symptomatic patients with the disease, and 27 controls. All the symptomatic patients had marked reductions in caudate glucose metabolism. Despite a normal structural appearance on computed tomography, caudate glucose metabolism was bilaterally reduced in 31 percent of the subjects at risk (18 of 58). Using each at-risk subjects age and the sex of the affected parent, we averaged individual risk estimates for the development of Huntingtons disease for this group and predicted that the probability of having the clinically unexpressed Huntingtons disease gene should be 33.9 +/- 6.0 percent for the group. Thus, there was excellent agreement between the predicted percentage of carriers of the Huntingtons disease gene (33.9 +/- 6.0 percent) and the percentage with metabolic abnormalities of the caudate nuclei (31 percent). These results indicate that the measurement of glucose metabolism may allow the observation of the pathophysiologic effects of the Huntingtons disease gene during the natural development of the disease. It may also provide a direct means to monitor the response to experimental treatments during both the clinically asymptomatic and the symptomatic phases of the disorder.

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.

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.

Cerebral glucose metabolic rates in normal human females versus normal males

Sex-related differences have been reported for some brain neuroanatomical structures and several measures of brain function. We studied the cerebral glucose metabolic rates of normal men (n = 7) and women (n = 7) with positron emission tomography and the fluorodeoxyglucose method. Women were studied between days 5 and 15 of the menstrual cycle. Women had whole brain glucose metabolic rates that were 19% higher than those of men. All neuroanatomical structures surveyed showed significant female greater than male rates, with no particular regions being outstanding. The higher cerebral glucose metabolic rates we observed in women may have been related to the effects of the high estrogen levels that can obtain in the phase of the menstrual cycle during which we tested our female subjects.

Prolongation of the antidepressant response to partial sleep deprivation by lithium

Depressed patients given a loading dose of lithium on the first of 2 successive days of partial sleep deprivation (PSD), and kept at maintenance levels thereafter, showed significantly greater prolongation of the antidepressant effects of PSD than patients treated with PSD and placebo, even though the acute elevation in mood derived from PSD was as great on placebo as on lithium. Depression was assessed 3 days after PSD with an augmented version of the Hamilton Rating Scale for Depression. Patients on lithium alone, without PSD, did not have the acute elevation in mood seen in the two PSD groups and had significantly less improvement in depression than those who received PSD with lithium.

Effects of partial sleep deprivation on the diurnal variation of mood and motor activity in major depression

Partial sleep deprivation (PSD), keeping a subject awake from 2 AM to 9 PM produces an acute mood improvement in 60% of patients with major depression. We sought to characterize the timing, subcomponent mood, and motor activity changes of this response. Thirty-seven subjects with major depression were rated with the 6-item Hamilton Depression Scale (HAM-6) at 1 PM and completed the Profile of Mood States (POMS) every 2 hr on the day before and day of PSD. Locomotor activity was monitored continuously during the trial with an automated device. Bipolar I patients responded more frequently than other groups. Positive mood responders had greater improvement than nonresponders in POMS subscales of depression, tension, confusion, and anger. The mood improvement increased steadily during the day, peaked in late afternoon, and declined thereafter. Responders showed significantly higher levels of locomotor activity on the baseline pre-PSD day than did nonresponders. All subjects increased motor activity following sleep deprivation, however.

A general technique for interstudy registration of multifunction and multimodality images

A technique that can register anatomic/structural brain images (e.g., MRI) with various functional images (e.g., PET-FDG and PET-FDOPA) of the same subject has been developed. The procedure of this technique includes the following steps: (1) segmentation of MRI brain images into gray matter (GM), white matter (WM), cerebral spinal fluid (CSF), and, muscle (MS) components, (2) assignment of appropriate radio-tracer concentrations to various components depending on the kind of functional image that is being registered, (3) generation of simulated functional images to have a spatial resolution that is comparable to that of the measured ones, (4) alignment of the measured functional images to the simulated ones that are based on MRI images. A self-organization clustering method is used to segment the MRI images. The image alignment is based on the criterion of least squares of the pixel-by-pixel differences between the two sets of images that are being matched and on the Powells algorithm for minimization. The technique was applied successfully for registering the MRI, PET-FDG, and PET-FDOPA images. This technique offers a general solution to the registration of structural images to functional images and to the registration of different functional images of markedly different distributions. >

Lithium sustains the acute antidepressant effects of sleep deprivation: Preliminary findings from a controlled study

Early morning sleep deprivation (patient awake from 0200 to 2200 hours) produces a same-day antidepressant effect in approximately one-half of patients with major depression. Unfortunately, these antidepressant effects are short-lived and patients usually relapse to baseline depression levels within 48 hours. Recent work suggests, however, that the use of lithium with early morning sleep deprivation sustains this rapid antidepressant effect and makes it clinically useful. In a 30-day study, we compared the abilities of four different treatments (lithium plus early morning sleep deprivation, lithium plus a control sleep deprivation procedure, and desipramine with either of the two sleep manipulations) to induce a rapid (next-day) and sustained antidepressant response in 16 depressed patients. Lithium plus early morning sleep deprivation produced a quicker response than lithium with the control sleep deprivation, and the response was sustained for at least 30 days. In this design, however, lithium/early morning sleep deprivation was no faster than either of the two desipramine/sleep deprivation conditions in inducing remission. These results support the results of previous studies and suggest further investigation of this novel sleep/pharmacologic intervention is warranted.