A preliminary study of resting brain metabolism in treatment-resistant depression before and after treatment with olanzapine-fluoxetine combination.

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.

Aging-Related Hypometabolism in the Anterior Cingulate Cortex of Cognitively Intact, Amyloid-Negative Seniors at Rest Mediates the Relationship between Age and Executive Function but Not Memory.

The anterior cingulate cortex (ACC) shows the most aging-related brain metabolic dysfunction that correlates with decreasing executive processing in otherwise healthy, cognitively intact volunteers. Here, data from ADNI are used to elucidate potential pathophysiological mechanisms involved in cognitive aging, that is, age-related decline in cognitive performance in the absence of known neurodegenerative disease. Amyloid-negative volunteers showed statistically significant mediation of ACC metabolism in the relationship between age and verbal fluency. A nonlinguistic task of executive function, Trails B, showed also negative correlation between performance and age, albeit weaker, but was not significant in the mediation analysis. Recall of story items, minimizing attentional demands compared with learning of word lists, did not correlate with age. ADNI subjects selected for low vascular risks also showed correlation between age and declining ACC metabolism. In the whole-brain amyloid-negative subset, ACC amyloid was not correlated with age. As expected, the metabolism in an arbitrary region such as motor cortex that was not expected to decline with cognitive aging showed no correlation with age or ACC metabolism suggesting regional specificity. These findings motivate the search for the pathophysiology of aging-related ACC dysfunction to prevent, diagnose, and treat the decline in executive function associated with cognitive aging.

Exposure to Cold Unmasks Potential Biomarkers of Fibromyalgia Syndrome Reflecting Insufficient Sympathetic Responses to Stress.

OBJECTIVES: Fibromyalgia syndrome (FMS) is a chronically painful condition whose symptoms are widely reported to be exacerbated by stress. We hypothesized that female patients with FMS differ from pain-free female controls in their sympathetic responses, a fact that may unmask important biomarkers and factors that contribute to the etiology of FMS. MATERIALS AND METHODS: In a pilot study, blood pressure (BP), skin temperature, thermogenic activity, circulating glucose, and pain sensitivity of 13 individuals with FMS and 11 controls at room temperature (24°C) were compared with that after exposure to cold (19°C). RESULTS: When measured at 24°C, BP, skin temperature, blood glucose, and brown adipose tissue (BAT) activity, measured using F-fluorodeoxyglucose positron-emission tomography/computed tomography, did not differ between controls and individuals with FMS. However, after cold exposure (19°C), BP and BAT activity increased in controls but not in individuals with FMS; skin temperature on the calf and arm decreased in controls more than in individiuals with FMS; and circulating glucose was lower in individiuals with FMS than in controls. Pain sensitivity did not change during the testing interval in response to cold. DISCUSSION: The convergence of the effect of cold on 4 relatively simple measures of thermogenic, cardiovascular, and metabolic activity, each regulated by sympathetic activity, strongly indicate that individuals with FMS have impaired sympathetic responses to stress that are observable and highly significant even when measured in extraordinarily small sample populations. If insufficient sympathetic responses to stress are linked to FMS, stress may unmask and maximize these potential clinical biomarkers of FMS and be related to its etiology.

Atypical Localization and Dissociation between Glucose Uptake and Amyloid Deposition in Cognitively Normal APOE*E4 Homozygotic Elders Compared with Patients with Late-Onset Alzheimer's Disease.

Alzheimer's disease (AD) progresses insidiously over decades. Therefore, study of preclinical AD is critical to identify early pathophysiological changes as potential targets for prevention or treatment. The brain processes at the preclinical stage remain minimally understood. Aside from age, the E4 allele of APOE flags a group at particularly high risk of late-onset AD (LOAD). Studies of these individuals could provide insights about the ontogenesis of AD offering clues for novel treatment strategies. To this end, cognitively normal, APOE*E4 homozygotes from the Alzheimer's Diseases Neuroimaging Research Initiative database (ADNI-LONI) provided fluorodeoxyglucose and amyloid (florbetapir) PET scans (n = 8 and 7, respectively; mean age 76 years). Their scans were compared to those of matched cognitively normal elders who were not E4 carriers. There was dissociation in the distribution between glucose uptake and amyloid deposition in the homozygotes. Peak hypometabolism localized bilaterally along the medial temporal cortex. In contrast, peak amyloid deposition localized principally to the putamen, a finding also seen in preclinical carriers of autosomal dominant AD mutations and preclinical AD associated with Down syndrome. Additional regions of amyloid deposition in homozygotes were medial prefrontal cortices including the anterior cingulate, middle and inferior frontal cortices, and middle and inferior occipital cortices. These findings contrast with those reported for LOAD. These data begin to characterize elders with normal cognition despite high AD risk in comparison to the known phenotypes of patients with LOAD.

Automated quantitation of cold-inducible human brown adipose tissue with FDG PET/CT with application to fibromyalgia.

Increasing recognition of the importance of brown adipose tissue (BAT) motivates the development of reproducible and quantitative methods for measuring it. Positron emission tomography (PET)/computerized tomography (CT) with 18F-fluorodeoxyglucose (FDG) has become the principal method to non-invasively detect brown adipose tissue (BAT) in humans. Improvements in quantitation and standardization will drive further clinical application. One disorder hypothesized to involve dysregulation in thermoregulation and the processing of pain involving BAT is fibromyalgia syndrome (FMS). This report describes an approach with additional technical standardization to measure cold-inducible, BAT activity (ci-BAT) semi-quantitatively and reliably with minimal operator intervention with the FDG PET/CT technique. Ci-BAT was measured to test whether FMS patients have decreased BAT activation compared to normal controls. Threshold parameters to optimally separate ci-BAT from non-ci-BAT were developed based on the distribution of the pixel-wise parametric data from each merged PET/CT scan for each study session occurring on different days. BAT activity was the same under warm conditions in both control and FMS subjects attesting to reproducibility and reliability. However, considerable variability arose between groups at cool temperatures consistent with other literature. Increases in ci-BAT activity were significantly less in FMS patients than in controls, as hypothesized. Ci-BAT recruitment can be quantified non-invasively using FDG PET/CT using semi-automated techniques in human subjects across different diagnostic groups or within groups undergoing manipulations of interest.

Fluorodeoxyglucose positron emission tomography of mild cognitive impairment with clinical follow-up at 3 years.

BACKGROUND: Alzheimer's disease (AD) is the most common dementing illness. Development of effective treatments directed at AD requires an early diagnosis. Mild cognitive impairment (MCI) often heralds AD. Thus, characterizing MCI is fundamental to the early diagnosis of AD. METHODS: 19 MCI patients referred from a memory loss clinic and 27 healthy subjects, all followed up for 3 years. Metabolism scans (MCI minus controls) were compared voxel-wise after anatomic normalization and were examined both visually and with a computerized classifier. RESULTS: Agreement between raters as to whether the individual scans were normal or abnormal was high. Agreement between raters of the eventual clinical diagnosis and baseline metabolic pattern was poor. A computerized classifier was unsuccessful at classifying MCI from normal; however, its performance improved when using only prototypic AD-like MCI scans, indicating the classifier worked well when shared patterns existed in the data. Outcomes on follow-up were nine of 19 AD, five of 19 remained MCI, and five of 19 developed dementias other than AD. Both MCI cases of early Lewy body dementia (LBD) showed an AD-like metabolic pattern. CONCLUSIONS: Visual inspection proved reliable in determining normal from abnormal scans, but it proved unreliable at predicting diagnosis on follow-up. Computerized classification of MCI by using an AD-like metabolic template (such as derived from the averaged MCI images) showed potential to identify patients who will develop AD. However, the metabolic pattern in early LBD did not differ from that in AD.

Chronic vagus nerve stimulation for treatment-resistant depression decreases resting ventromedial prefrontal glucose metabolism.

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for treatment-resistant depression (TRD). Its mechanism of action is not fully understood. Longitudinal measurement of changes in brain metabolism associated with VNS can provide insights into this new treatment modality. Eight severely depressed outpatients who were highly treatment-resistant underwent electrical stimulation of the left vagus nerve for approximately one year. The main outcome measures were resting regional brain glucose uptake measured with positron emission tomography (PET) and the 24-item Hamilton Depression Scale. The most significant and extensive change over one year of chronic VNS localized to the ventromedial prefrontal cortex extending from the subgenual cingulate to the frontal pole. This region continued to decline in metabolism even toward the end of the study. Clinically, this cohort showed a trend for improvement. No correlations surfaced between change in glucose uptake and depression scores. However, the sample size was small; none remitted; and the range of depression scores was limited. Chronic VNS as adjunctive therapy in patients with severe TRD produces protracted and robust declines in resting brain activity within the ventromedial prefrontal cortex, a network with dense connectivity to the amygdala and structures monitoring the internal milieu.

Internet image viewer (iiV).

BACKGROUND: Visualizing 3-dimensional (3-D) datasets is an important part of modern neuroimaging research. Many tools address this problem; however, they often fail to address specific needs and flexibility, such as the ability to work with different data formats, to control how and what data are displayed, to interact with values, and to undo mistakes. RESULTS: iiV, an interactive software program for displaying 3-D brain images, is described. This tool was programmed to solve basic problems in 3-D data visualization. It is written in Java so it is extensible, is platform independent, and can display images within web pages.iiV displays 3-D images as 2-dimensional (2-D) slices with each slice being an independent object with independent features such as location, zoom, colors, labels, etc. Feature manipulation becomes easier by having a full set of editing capabilities including the following: undo or redo changes; drag, copy, delete and paste objects; and save objects with their features to a file for future editing. It can read multiple standard positron emission tomography (PET) and magnetic resonance imaging (MRI) file formats like ECAT, ECAT7, ANALYZE, NIfTI-1 and DICOM. We present sample applications to illustrate some of the features and capabilities. CONCLUSION: iiV is an image display tool with many useful features. It is highly extensible, platform independent, and web-compatible. This report summarizes its features and applications, while illustrating iiV's usefulness to the biomedical imaging community.

Bringing functional brain image analysis to the clinician: initial assessment of an online interactive diagnostic aide.

Image database extensions for functional brain images were assessed by asking clinicians questions about (i) diagnosis confidence level before and after using the software; (ii) expected and unexpected differences between patient and control images; and (iii) an overall rating of the future usefulness of this application in an everyday clinical setting. Examining the difference image of a patient compared to a normative group affects the clinicians' initial diagnosis of the patient in two-thirds of the cases. All three clinicians stated that the interface would be a useful tool when added to the clinical workup of a patient.

Where the brain grows old: decline in anterior cingulate and medial prefrontal function with normal aging.

Even healthy adults worry about declines in mental efficiency with aging. Subjective changes in mental flexibility, self-regulation, processing speed, and memory are often cited. We show here that focal decreases in brain activity occur with normal aging as measured with fluorodeoxyglucose and positron emission tomography. The largest declines localize to a medial network including the anterior cingulate/medial prefrontal cortex, dorsomedial thalamus, and sugenual cingulate/basal forebrain. Declining metabolism in this network correlates with declining cognitive function. The medial prefrontal metabolic changes with aging are similar in magnitude to the hypometabolism found in Mild Cognitive Impairment or Alzheimer's disease. These results converge with data from healthy elderly indicating dysfunction in the anterior attention system. The interaction of attention in the anterior cingulate cortex with memory in the medial temporal lobe may explain the global impairment that defines dementia. Despite the implications for an aging population, the neurophysiologic mechanisms of these metabolic decreases remain unknown.

About the mechanisms of auditory verbal hallucinations: a positron emission tomographic study.

OBJECTIVE: Auditory verbal hallucinations (AVHs) likely result from disorders, as yet unspecified, of the neural mechanisms of language. Here we examine the functional neuroanatomy of single-word reading in patients with and without a history of AVH. METHOD: Eighteen medicated schizophrenia patients (8 with AVH and 10 without AVH) and 12 healthy control subjects were scanned with PET (15)O-water technique under 2 conditions: reading aloud English nouns and passively looking at English nouns without reading them. RESULTS: The contrast between the 2 conditions shows higher activation in Wernicke's area during the reading condition in the patient group and a reversed laterality index for the supplementary motor area in the AVH group. CONCLUSIONS: These findings provide indications about the possible mechanisms of AVH. We suggest that the abnormal laterality of the supplementary motor area activity accounts for the failure to attribute speech generated by one's own brain to one's self and that the activation of Wernicke's area accounts for the perceptual nature (hearing) of the patient's experience.

Functional neuroanatomy of the human near/far response to blur cues: eye-lens accommodation/vergence to point targets varying in depth.

The purpose of this study was to identify the networks involved in the regulation of visual accommodation/vergence by contrasting the cortical functions subservient to eye-lens accommodation with those evoked by foveal fixation. Neural activity was assessed in normal volunteers by changes in rCBF measured with PET. Thirteen right-handed subjects participated in three monocular tasks: (i) resting with eyes closed; (ii) sustained foveal fixation upon a LED at 1.2 m (0.83 D); and (iii) accommodating alternately on a near (24 cm, 4.16 D) vs. a far (3.0 m, 0.33 D) LED alternately illuminated in sequential 2 s epochs. The contrast between the conditions of near/far accommodation and of constant foveal fixation revealed activation in cerebellar hemispheres and vermis; middle and inferior temporal cortex (BA 20, 21, 37); striate cortex and associative visual areas (BA 17/18). Comparison of the condition of constant fixation with the condition of resting with closed eyes indicated activation of cerebellar hemispheres and vermis; visual cortices (BA 17/18); a right hemisphere dominant network encompassing prefrontal (BA 6, 9, 47), superior parietal (BA 7), and superior temporal (BA 40) cortices; and bilateral thalamus. The contrast between the conditions of near/far accommodation with closed-eye rest reflected an incremental summation of the activations found in the previous comparisons (i.e. activations associated with constant fixation). Neural circuits activated selectively during the near/far response to blur cues over those during constant visual fixation, occupy posterior structures that include occipital visual regions, cerebellar hemispheres and vermis, and temporal cortex.