Faculty Bibliography

Anxiety-related disorders are among the most common psychiatric illnesses, thought to have both genetic and environmental causes. Early-life trauma, such as abuse from a caregiver, can be predictable or unpredictable, each resulting in increased prevalence and severity of a unique set of disorders. In this study, we examined the influence of early unpredictable trauma on both the behavioral expression of adult anxiety and gene expression within the amygdala. Neonatal rats were exposed to unpaired odor-shock conditioning for 5days, which produces deficits in adult behavior and amygdala dysfunction. In adulthood, we used the Light/Dark box test to measure anxiety-related behaviors, measuring the latency to enter the lit area and quantified urination and defecation. The amygdala was then dissected and a microarray analysis was performed to examine changes in gene expression. Animals that had received early unpredictable trauma displayed significantly longer latencies to enter the lit area and more defecation and urination. The microarray analysis revealed over-represented genes related to learning and memory, synaptic transmission and trans-membrane transport. Gene ontology and pathway analysis identified highly represented disease states related to anxiety phenotypes, including social anxiety, obsessive-compulsive disorders, post-traumatic stress disorder and bipolar disorder. Addiction-related genes were also overrepresented in this analysis. Unpredictable shock during early development increased anxiety-like behaviors in adulthood with concomitant changes in genes related to neurotransmission, resulting in gene expression patterns similar to anxiety-related psychiatric disorders.

We propose a fused lasso logistic regression to analyze callosal thickness profiles. The fused lasso regression imposes penalties on both the l1-norm of the model coefficients and their successive differences, and finds only a small number of non-zero coefficients which are locally constant. An iterative method of solving logistic regression with fused lasso regularization is proposed to make this a practical procedure. In this study we analyzed callosal thickness profiles sampled at 100 equal intervals between the rostrum and the splenium. The method was applied to corpora callosa of elderly normal controls (NCs) and patients with very mild or mild Alzheimer's disease (AD) from the Open Access Series of Imaging Studies (OASIS) database. We found specific locations in the genu and splenium of AD patients that are proportionally thinner than those of NCs. Callosal thickness in these regions combined with the Mini Mental State Examination scores differentiated AD from NC with 84% accuracy.

Tourette syndrome (TS) is characterized by tics, sensorimotor gating deficiencies, and abnormalities of cortico-basal ganglia circuits. A mutation in histidine decarboxylase (Hdc), the key enzyme for the biosynthesis of histamine (HA), has been implicated as a rare genetic cause. Hdc knockout mice exhibited potentiated tic-like stereotypies, recapitulating core phenomenology of TS; these were mitigated by the dopamine (DA) D2 antagonist haloperidol, a proven pharmacotherapy, and by HA infusion into the brain. Prepulse inhibition was impaired in both mice and humans carrying Hdc mutations. HA infusion reduced striatal DA levels; in Hdc knockout mice, striatal DA was increased and the DA-regulated immediate early gene Fos was upregulated. DA D2/D3 receptor binding was altered both in mice and in humans carrying the Hdc mutation. These data confirm histidine decarboxylase deficiency as a rare cause of TS and identify HA-DA interactions in the basal ganglia as an important locus of pathology.

Neurocognitive aging studies have focused on age-related changes in neural activity or neural structure but few studies have focused on relationships between the two. The present study quantitatively reviewed 24 studies of age-related changes in fMRI activation across a broad spectrum of executive function tasks using activation likelihood estimation (ALE) and 22 separate studies of age-related changes in gray matter using voxel-based morphometry (VBM). Conjunction analyses between functional and structural alteration maps were constructed. Overlaps were only observed in the conjunction of dorsolateral prefrontal cortex (DLPFC) gray matter reduction and functional hyperactivation but not hypoactivation. It was not evident that the conjunctions between gray matter and activation were related to task performance. Theoretical implications of these results are discussed.

While it is common to think that neuroscientists are proponents of basic emotions theory, this is not necessarily the case. My ideas, for example are more aligned with cognitive than basic emotions theories.

While researchers have for decades considered the role of social factors, endocrinology, neural function, hippocampal integrity, and cognition in the development of schizophrenia, there has been a relative paucity of studies considering the participation of the stress cascade in the interplay of these elements. As described in this review, stressful exposures and stress sensitivity may plausibly be argued to play a role in the etiology, neurobiology, and course of schizophrenia and related psychotic disorders. Notably, research conducted over the last decade has made it increasingly clear that childhood traumatic experiences represent a prominent risk factor for the development of psychotic disorders, including schizophrenia. Accumulating evidence suggests that this relationship is mediated by the development of a neuropathological stress response, involving HPA axis dysregulation, aberrant functioning of different neurotransmitter systems, hippocampal damage, and memory deficits. However, it remains difficult to identify exact causal pathways linking early trauma to schizophrenia, including to the individual symptoms associated with the disorder. In addition to the strong association among early trauma, stress sensitization, and positive symptoms in schizophrenia, there is also evidence indicating that the negative and cognitive symptoms are related to these factors. However, the emergence of these symptoms may lie on a distinct and non-interacting pathway in relation to the development of the positive symptoms. The natural increases in stress sensitivity and HPA axis activity during adolescence may act on already maladaptive stress circuitry resulting from early trauma and/or a genetic predisposition to produce full blown stress sensitization and cause epigenetic effects, such as the altered methylation of different genes, that lead to schizophrenia or other psychiatric illnesses.

We propose a penalized spline approach to performing large numbers of parallel non-parametric analyses of either of two types: restricted likelihood ratio tests of a parametric regression model versus a general smooth alternative, and nonparametric regression. Compared with naively performing each analysis in turn, our techniques reduce computation time dramatically. Viewing the large collection of scatterplot smooths produced by our methods as functional data, we develop a clustering approach to summarize and visualize these results. Our approach is applicable to ultra-high-dimensional data, particularly data acquired by neuroimaging; we illustrate it with an analysis of developmental trajectories of functional connectivity at each of approximately 70000 brain locations. Supplementary materials, including an appendix and an R package, are available online.