Faculty Bibliography

Background: Several lines of evidence have implicated inflammatory pathways in major depressive disorder (MDD). These include reports of elevations in various pro-inflammatory cytokines including interleukin-6 (Il-6), interleukin-8 (IL-8), interleukin-1b (IL-1 beta). These cytokine elevations have also been reported in latelife depression and linked both to greater severity of baseline depressive symptoms and incident depression. A major drawback of existing cytokine studies is that they have been limited to determinations in plasma. Since these large molecules do not usually cross the blood-brain barrier, their relevance to neuroinflammation is not known. Most of these studies have also not included a neuroimaging component. This is particularly surprising, since white matter abnormalities implicated in depression may be especially sensitive to neuroinflammation. We examined a number of cytokines in both CSF and plasma in elderly individuals with MDD and healthy controls and hypothesized that elevations in certain cytokines would be found in MDD and would have a negative effect on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, IL-6, IL-8, IL-1 in were measured in CSF and plasma in 29 older subjects with MDD and 19 controls. MRI scans were performed to rule out structural brain abnormalities and to assess fractional anisotrophy (FA), a measure of white matter integrity. All had intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Results: Contrary to our prediction, there was no significant group difference in any of the CSF cytokines levels that we examined. However, consistent with previous reports, plasma IL-8 was elevated in individuals with MDD. Interestingly, in the entire sample, plasma IL-8 was negatively correlated with mean brain FA (r=-0.307; p=0.36). Conclusions: We found no evidence of CSF cytokine abnormalities in elderly subjects with MDD. However, there was an increase in plasma IL-8 in MDD, which merits further study because of its possible association with white matter pathology

In motor speech disorders, dysarthric features impacting intelligibility, articulation, fluency and voice emerge more saliently in conversation than in repetition, reading or singing. A role of the basal ganglia in these task discrepancies has been identified. Further, more recent studies of naturalistic speech in basal ganglia dysfunction have revealed that formulaic language is more impaired than novel language. This descriptive study extends these observations to a case of severely dysfluent dysarthria due to a parkinsonian syndrome. Dysfluencies were quantified and compared for conversation, two forms of repetition, reading, recited speech and singing. Other measures examined phonetic inventories, word forms and formulaic language. Phonetic, syllabic and lexical dysfluencies were more abundant in conversation than in other task conditions. Formulaic expressions in conversation were reduced compared to normal speakers. A proposed explanation supports the notion that the basal ganglia contribute to formulation of internal models for execution of speech.

OBJECTIVE: Major depressive disorder is common in the elderly, and symptoms are often not responsive to conventional antidepressant treatment, especially in the long term. Soluble oligomeric and aggregated forms of amyloid beta peptides, especially amyloid beta 42, impair neuronal and synaptic function. Amyloid beta 42 is the main component of plaques and is implicated in Alzheimer's disease. Amyloid beta peptides also induce a depressive state in rodents and disrupt major neurotransmitter systems linked to depression. The authors assessed whether major depression was associated with CSF levels of amyloid beta, tau protein, and F2-isoprostanes in elderly individuals with major depressive disorder and age-matched nondepressed comparison subjects. METHOD: CSF was obtained from 47 cognitively intact volunteers (major depression group, N=28; comparison group, N=19) and analyzed for levels of soluble amyloid beta, total and phosphorylated tau proteins, and isoprostanes. RESULTS: Amyloid beta 42 levels were significantly lower in the major depression group relative to the comparison group, and amyloid beta 40 levels were lower but only approaching statistical significance. In contrast, isoprostane levels were higher in the major depression group. No differences were observed in total and phosphorylated tau proteins across conditions. Antidepressant use was not associated with differences in amyloid beta 42 levels. CONCLUSIONS: Reduction in CSF levels of amyloid beta 42 may be related to increased brain amyloid beta plaques or decreased soluble amyloid beta production in elderly individuals with major depression relative to nondepressed comparison subjects. These results may have implications for our understanding of the pathophysiology of major depression and for the development of treatment strategies.

Connectivity analyses have become increasingly important in functional imaging. When used to describe the functional anatomy of a specific behavior, these analyses are generally applied to a subset of the data that demonstrate significant differences when experimental conditions are contrasted. Such data reduction is sub-optimal for a systems approach as it assumes that all data that survive the statistical contrast filter are related to the behavior and that none of the filtered data has a significant function. When such data filtering is applied to speech and language tasks, the resulting functional anatomy rarely reflects the brain lateralization established in over a century and a half of clinical studies. A two-step performance-based connectivity analysis is described in which the first step uses multiple linear regression to establish a direct relationship between regional brain activity and a measure of performance. The second step uses partial correlations to examine the functional relationships between the predictor regions and other brain regions. When applied to regional cerebral blood flow data obtained with positron emission tomography during a speech production task, the results demonstrate left lateralization of motor control areas, thalamic involvement in repetition rate, and auditory cortical suppression, all consistent with clinical observations. The integration of performance measures into the earliest stages of image analysis without reliance on data filtering based on decomposition may provide a path toward convergence with traditional descriptions of functional anatomy based on clinical studies.

Chronic, high-frequency electrical stimulation of the subthalamic nuclei (STNs) has become an effective and widely used therapy in Parkinson's disease (PD), but the therapeutic mechanism is not understood. Stimulation of the STN is believed to reorganize neurophysiological activity patterns within the basal ganglia, whereas local field effects extending to tracts adjacent to the STN are viewed as sources of nontherapeutic side effects. This study is part of a larger project investigating the effects of STN stimulation on speech and regional cerebral blood flow (CBF) in human subjects with PD. While generating measures of global CBF (gCBF) to normalize regional CBF values for a subsequent combined analysis of regional CBF and speech data, we observed a third effect of this therapy: a gCBF increase. This effect was present across three estimates of gCBF ranging from values based on the highest activity voxels to those based on all voxels. The magnitude of the gCBF increase was related to the subject's duration of PD. It is not clear whether this CBF effect has a therapeutic role, but the impact of deep brain stimulation on cerebrovascular control warrants study from neuroscience, pathophysiological, and therapeutic perspectives.

The National Institute of Mental Health strategic plan for advancing psychiatric neuroscience calls for an acceleration of discovery and the delineation of developmental trajectories for risk and resilience across the lifespan. To attain these objectives, sufficiently powered datasets with broad and deep phenotypic characterization, state-of-the-art neuroimaging, and genetic samples must be generated and made openly available to the scientific community. The enhanced Nathan Kline Institute-Rockland Sample (NKI-RS) is a response to this need. NKI-RS is an ongoing, institutionally centered endeavor aimed at creating a large-scale (N > 1000), deeply phenotyped, community-ascertained, lifespan sample (ages 6-85 years old) with advanced neuroimaging and genetics. These data will be publically shared, openly, and prospectively (i.e., on a weekly basis). Herein, we describe the conceptual basis of the NKI-RS, including study design, sampling considerations, and steps to synchronize phenotypic and neuroimaging assessment. Additionally, we describe our process for sharing the data with the scientific community while protecting participant confidentiality, maintaining an adequate database, and certifying data integrity. The pilot phase of the NKI-RS, including challenges in recruiting, characterizing, imaging, and sharing data, is discussed while also explaining how this experience informed the final design of the enhanced NKI-RS. It is our hope that familiarity with the conceptual underpinnings of the enhanced NKI-RS will facilitate harmonization with future data collection efforts aimed at advancing psychiatric neuroscience and nosology.

Background: Reductions in brain-derived neurotrophic factor (BDNF) have been implicated in the pathophysiology of Alzheimer's disease (AD). Nevertheless, the factors influencing central and peripheral BDNF levels are still poorly understood. Cerebral microvascular endothelial cells are known to be a major source of BDNF with a rate of production by far exceeding that of cortical neurons. Exposure of these cells to amyloid beta (Ab), results in cell death or injury with significant reductions in BDNF secretion. Moreover, in rodents, infusion of Ab40 into the carotid resulted in a disruption of endothelial cells, which was not observed with Ab42. Plasma Ab40 levels have also been associated with white matter hyperintense lesions (WMHI) on MRI scans in AD, an effect that may be mediated by the toxic effects of soluble Ab40 on small cerebral blood vessels and endothelial cells. Therefore, we hypothesized that concentrations of plasma Ab40, but not Ab42, would have a negative effect on plasma BDNF and on measures of white matter integrity as determined by Diffusion Tensor Imaging (DTI). Methods: To test this hypothesis, we examined BDNF and Ab levels in plasma from 119 subjects with intact cognition (no dementia and a Mini-Mental State Exam score of at least 28) and no gross MRI abnormalities other than white matter hyperintensities. Of these, 88 subjects also had BDNF in plasma determined. Results: Consistent with our prediction, Ab40 was inversely correlated with BDNF concentrations (P <.001), whereas Ab42 was independent (P = .231). Fractional anisotropy (FA; a measure of white matter integrity in DTI) was also inversely correlated with Ab40 (P = .001) and so was performance in delayed recall (P = .029). Conclusions: In cognitively intact individuals, circulating Ab40 results in reduction in plasma BDNF, white matter integrity (FA), and memory performance. As such, it may have prognostic significance