Faculty Bibliography

Glutamate is the principal excitatory neurotransmitter in the central nervous system, and is thought to be involved in the process of memory encoding and storage. Glutamate disturbances have also been reported in psychiatric disorders, such as schizophrenia and major depressive disorder (MDD), and in Alzheimer's disease. In this paper, we set out to study the relationship between cerebrospinal fluid (CSF) glutamate levels and memory performance, which we believe has not been reported previously. In particular, we focused on recall performance broken down by serial position. Our prediction was that the recency ratio (Rr), a novel cognitive marker of intellectual impairment, would be linked with CSF glutamate levels. We studied data from a group of cognitively intact elderly individuals, 28 of whom had MDD, while 19 were controls. Study results indicated that Rr levels, but no other memory score, were inversely correlated with CSF glutamate levels, although this was found only in individuals with late-life MDD. For comparison, glutamine or GABA were not correlated with any memory performance measure.

Posttraumatic stress disorder (PTSD) has been regarded as a signature injury of war and elevated to one of the major behavioral health problems faced by military service members and veterans deployed to warzones. In PTSD diagnosis, self-report measures have often been used with a cutoff score to identify those with an elevated likelihood of having PTSD prior to conducting a second-tier diagnostic interview. With an attempt to guide the selection of cutoffs in self-report PTSD measures for various purposes, this study examined how five common criteria for establishing an optimal cutoff influenced the performance of self-report measures for warzone PTSD in relation to the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and whether the influence differed for the PTSD Checklist for DSM-5 and the Mississippi Scale for Combat-Related PTSD. Using a probability sample of Vietnam theater veterans in the National Vietnam Veterans Longitudinal Study, results showed that in both self-report measures, the Youden Index criterion yielded the optimal cutoff that led to better test performance. (PsycINFO Database Record

BACKGROUND: A growing body of evidence suggests that the ability to flexibly express and suppress emotions ("expressive flexibility") supports successful adaptation to trauma and loss. However, studies have yet to examine whether individuals that meet criteria for posttraumatic stress disorder (PTSD) or depression exhibit alterations in expressive flexibility. The present study aims to test whether lower levels of expressive flexibility are associated with PTSD and depression in combat-exposed veterans. METHODS: Fifty-nine combat veterans with and without PTSD completed self-report measures assessing symptoms of depression, PTSD, and combat exposure. Participants also completed an expressive flexibility task in which they were asked to either enhance or suppress their expressions of emotion while viewing affective images on a computer screen. Expressive flexibility was assessed by both expressive enhancement ability and expressive suppression ability. RESULTS: Repeated measures ANOVA's showed that both PTSD and depression were associated with lower levels of emotional enhancement ability. In addition, a series of linear regressions demonstrated that lower levels of emotional enhancement ability were associated with greater symptom severity of PTSD and depression. The ability to suppress emotional responses did not differ among individuals with and without PTSD or depression. LIMITATIONS: of the study include a cross-sectional design, precluding causality; the lack of a non-trauma exposed group and predominantly male participants limit the generalizability to other populations. CONCLUSIONS: Alterations in expressive flexibility is a previously unrecognized affective mechanism associated with PTSD and depression. Clinical strategies aimed at enhancing emotional expression may aid in the treatment of these disorders.

INTRODUCTION: Several lines of evidence indicate that increased inflammation is associated with Post-Traumatic Stress Disorder (PTSD). We have previously reported that peripheral inflammatory markers are significantly higher in combat-exposed veterans with than without PTSD. This study was designed to replicate these findings in a new study cohort using the same population and recruitment strategies. METHODS: Sixty-one male war veterans (31 PTSD and 30 control subjects) were included in this replication study. Levels of Interleukin-6, Tumor Necrosis Factor-alpha, Gamma interferon, and high-sensitivity C-reactive protein were quantified in blood samples. A standardized "total pro-inflammatory score" was calculated to limit the number of statistical comparisons. The Clinician Administered PTSD Scale (CAPS) rating scale was used to assess PTSD symptom severity. RESULTS: PTSD subjects had significantly higher total pro-inflammatory scores compared to non-PTSD subjects in unadjusted analysis (Cohen's d=0.75, p=0.005) as well as after adjusting for potentially confounding effects of age, BMI, smoking, and potentially interfering medications and somatic co-morbidities (p=0.023). There were no significant correlations between inflammatory markers and severity of symptoms within the PTSD group. CONCLUSIONS: We replicated, in a new sample, our previous finding of increased inflammatory markers in combat-exposed PTSD subjects compared to combat-exposed non-PTSD controls. These findings strongly add to the growing literature suggesting that immune activation may be an important aspect of PTSD pathophysiology, although not directly correlated with current PTSD symptom levels in the PTSD group.

This study examined whether reduced performance on two neuropsychological tasks, cognitive flexibility and working memory, were associated with higher levels of trauma centrality. A growing body of research has shown that trauma centrality, the extent to which a person believes a potentially traumatic event has become central to their self-identity and life story, is associated with post-traumatic stress disorder (PTSD). Furthermore, PTSD is often associated with alterations in neuropsychological functioning. The relationship between neuropsychological processes and trauma centrality, however, has yet to be explored. OEF/OIF combat veterans (N = 41) completed the Post-traumatic Diagnostic Scale (PDS), the Beck Depression Inventory-II (BDI-II), the Centrality of Event Scale (CES), and on-line measures of cognitive flexibility and working memory assessed via WebNeuro. Bivariate Pearson correlations showed that CES scores were positively correlated with PDS and BDI scores, and negatively correlated with cognitive flexibility and working memory. Linear regressions revealed that working memory significantly predicted CES when controlling for depression and PTSD severity while cognitive flexibility approached significance when controlling for these same variables. This study employed a cross-sectional design, precluding causality. The small sample size, entirely male sample, and use of an online neuropsychological assessment warrant follow-up research. Although numerous studies have found an association between CES and PTSD, this is the first to suggest that neuropsychological processes underlie the construct of trauma centrality. Given the importance of maladaptive cognitive processes underlying the pathogenesis of PTSD, these data suggest that future studies aimed at examining the link between neuropsychological processes and maladaptive cognitive processes, such as trauma centrality, may help to characterize and treat PTSD.

Introduction AL patients may experience severe physical and psychological distress. To address this, we developed a novel intervention called EASE, which includes: 1) tailored psychotherapy; and 2) physical symptom screening, with distressing symptoms triggering early involvement of palliative care. Objectives To assess the feasibility and preliminary efficacy of EASE. Methods Patients were recruited within 2 weeks of admission to a comprehensive cancer center and randomized to receive either EASE or usual care (UC). Physical and psychological symptoms were assessed at baseline, 4, 8 (primary endpoint), and 12 weeks. Intervention patients received 6-10 psychotherapy sessions over 8 weeks, weekly assessment of physical symptoms, and referral to palliative care, triggered by symptoms. Oneway ANOVA was performed to assess mean change scores over time between groups. Results Forty-two patients were randomized to EASE (n=22) or UC (n=20). Predefined feasibility outcomes were met: 86% (19/22) of EASE partic-ipants (goal >64%) completed >50% of psychotherapy sessions; 64% (14/22) completed symptom screenings (goal >50%); and 100% of those with distressing symptoms had >1 meeting with palliative care (goal 100%). There were statistically significant findings favoring EASE for satisfaction with care at 8 (DELTA: 7.39 vs-3.12, p<0.04) and 12 (DELTA: 0.01 vs-6.19, p<0.03) weeks and trends favoring EASE for traumatic stress, depression, quality of life, attachment security, and number, severity, and distress related to physical symptoms at 4, 8, and 12 weeks. Conclusions This randomized pilot trial of EASE showed promising reductions in psychological and physical distress and supports feasibility and need for a larger randomized controlled trial

Background: Entropy has a fundamental relationship with information and the functioning of all computational systems. Entropy is defined as the number of states available to a system. A system with low entropy has access to fewer states than does one with high entropy. A system with low entropy is more ordered and more predicable than a system with high entropy. Since entropy is related to the functioning of computational systems, there is an emerging theoretical and empirical literature about its role in brain function and dysfunction. We present the results of three integrated studies applying resting state fMRI entropy measurement to understand intelligence, personality, and psychopathology. Brain entropy is an index of an individual's access to brain states at a given time and is measured through the predictivity of brain state over time. Thus, we would expect to observe brain entropic differences between conditions known to be associated with high flexibility (e.g. high intelligence, creativity, novelty seeking) vs. conditions associated with high rigidity (e.g. anxiety, depression, Posttraumatic Stress). The three studies are: Brain entropy and intelligence in 926 adults from the Brain Genomic Superstruct Project, 2. Brain entropy and personality in 926 adults from the Brain Genomic Superstruct Project, and 3. Brain entropy and PTSD in 95 veterans from the NYU Cohen Veterans Data Set. Methods: Subjects: Study 1 (Entropy and Intelligence) and Study 2 (Entropy and Personality) were conducted with data from the Brain Genomics Superstruct Project (BGSP). The BGSP includes 1570 healthy adult participants between the ages of 18 and 35. The current study utilized data from the 926 participants who completed intelligence and personality assessments. Study 3 (Entropy and PTSD) was conducted with data from the NYU Cohen Veterans Data Set. This data set includes 95 combat veterans, 46 with PTSD and 49 without PTSD. fMRI Procedures: Brain Genomics Superstruct Project (BGSP). All MRI data were obtained with 3T Trio scanners (Siemens Healthcare, Erlangen, Germany) at Harvard University and Massachusetts General Hospital. MRI scans for each participant included a high resolution structural scan (T1-weighted multi-echo MPRAGE, TR = 2.2 sec, TE = 1.5/3.4/5.2/7.0 msec, slices = 144, resolution = 1.2 x 1.2 x 1.2 mm) and a resting-state functional scan sensitive to blood oxygenation level-dependent (BOLD) contrast (TR = 3.0 sec, TE = 30 msec, slices = 47, resolution = 3.0 x 3.0 x 3.0 mm, 120 measurements). NYU Cohen Veterans Data Set: All MRI data were obtained with a 3T Trio scanner (Siemens AG, Erlangen Germany). Anatomical images were acquired with magnetization prepared rapid gradient echo sequence with TE/TI/TR = 2.98/900/2300 ms, 256 x 240 matrix, 256 mm x 240 mm fieldof-view, flip angle = 9degree, slice thickness = 1 mm and total slice number = 191; resting state fMRI was obtained using an echo-planar imaging sequence (TR/TE = 2000/29 ms, flip angle = 90degree), 64 x 64 matrix, pixel size 3.125 mm x 3.125 mm, total slice number = 32, slice thickness = 3.5 mm (without gaps), total volume number = 200. fMRI Entropy Analysis: Brain entropy was calculated using the Brain Entropy Mapping Toolbox (BENtbx) (Wang et al, 2014) for MATLAB (MATLAB Release R2015b, The MathWorks Inc., Natick, MA, United States). The BENtbx utilizes Sample Entropy (SampEn). For a given time series, SampEn is a single number representing the predictability of the series. The entropy of highly predictable series is small, close to 0, indicating a lack of variation or disorder. The entropy of unpredictable series is large, indicating a high amount of variation or disorder. The Sample Entropy process first breaks a series into smaller sets of size m. For example, for m = 2, and the BOLD time series is broken into pairs of consecutive values. Each pair is then compared with every other pair to find the maximum distance (absolute value difference) between any number in the first pair and any number in the second pair. If the distance is less than the threshold r, the two pairs are considered a 'match.' This process is then repeated for sets of size m + 1. Sample Entropy is then the ratio: SampEn =-log A/B: Where, A = number of matches using sets of size m+1 and B = number of matches using sets of size m. For perfectly predictable series, A and B will be equal, and entropy will be 0. As disorder in a series increases, B will become greater than A, and the equation will yield an increasingly large positive number. Psychometric Measurement: Study 1: Intelligence was measured with the Shipley Estimated IQ, Vocabulary, and Matrix Reasoning scales. Study 2: Personality was measured for Behavioral Inhibition, Harm Avoidance, Risk Taking, and Novelty Seeking. Study 3: PTSD was measured with the Clinician Administered PTSD Scale (CAPS). Results: Study 1: Shipley Estimated IQ, Vocabulary, and Matrix Reasoning were all associated with higher brain entropy. In particular, Vocabulary was related to higher entropy in the L fusiform gyrus, inferior temporal gyrus, parahippocampal gyrus. Matrix Reasoning was associated with higher entropy in the bilateral superior, medial, inferior frontal gyrus, bilateral orbital gyrus, and R middle frontal gyrus. Study 2: Harm avoidance and Behavioral Inhibition were associated with lower entropy and Novelty Seeking and Risk Taking were associated with higher entropy. Study 3: PTSD was associated with lower entropy, particularly in the L hippocampus and parahippocampal gyrus, inferior and middle temporal lobes: and higher entropy in the R precuneus, and R parietal lobe. Conclusions: Brain entropy may provide a novel approach to understand intelligence, personality, and psychopathology such as PTSD

Background: Numerous studies have linked depressive symptoms, or syndromal depression, to increased risk for Alzheimer's disease (AD) irrespective of its onset age. The neurobiological basis for this association, however, remains poorly understood. Studies which have examined biomarkers of AD in peripheral and central tissues in depression, including CSF Abeta42 (Abeta42) and brain amyloid using PET ligands, have provided conflicting results. These discrepant results may have been due to methodological differences across studies, including heterogeneity in study populations (e.g., inclusion of individuals with mild cognitive impairment) and the use of approaches for detecting depression (e.g., patients' self-ratings) that lack diagnostic specificity. In addition, only a few studies have employed structured interviews based on DSM diagnostic criteria or standardized pre-analytical and laboratory procedures for quantifying Abeta. Finally, all of the existing studies have been limited to cross sectional comparisons based on a single Abeta determination; thus, it is not known if these abnormalities persist over time and if depressive symptoms influence Abeta levels. The current study was conducted to address the aforementioned limitations. Methods: Our baseline sample consisted of 47 subjects aged 60 years and older; 28 with LMDD and 19 controls. Of the 47 older subjects, 31 were e4 non-carriers and 16 were e4 carriers. All subjects were cognitively-intact and had a) no evidence of dementia, b) a Mini-Mental State Exam score of at least 28, and c) no gross MRI abnormalities other than white matter hyperintensities. CSF collection was repeated after 3 years for 36 of these individuals: 19 with LLMD and 17 controls. We evaluated the effects of diagnosis and time on Abeta42 levels with 2 x 2 repeated measures ANOVA. Results: Longitudinal comparisons of controls and LLMD revealed that the LLMD group was significantly less depressed at follow up than at baseline, as determined by the HAM-D, whereas controls remained unchanged. There was a significant interaction between diagnosis and time on CSF Abeta42 levels. Importantly, the reductions in depressive symptoms observed over time were significantly correlated with increases in CSF Abeta42 levels, both in the entire cohort (r =-.451, p =.006) and within the LLMD group (r =-.547, p =.015), but not in the control group (p =.809). The same relationship was not significant with Abeta40 (Pomara et al., 2016). Performance on cognitive indices remained unchanged and was not significantly correlated with changes in AD Biomarkers. Conclusions: Cognitively-intact, elderly individuals with LLMD, who were more depressed at baseline, but less depressed at the 3 year follow-up, showed both a reduction in baseline CSF Abeta42 (Pomara et al., 2012) and elevation in Abeta42 at 3 year follow-up. In addition, changes in CSF Abeta42 were correlated with changes in depressive symptoms. Future studies should determine if these state-dependent changes in Abeta42 mediate the increased risk of AD contributed by LLMD. If this is the case, the need for more aggressive treatment of LLMD cannot be underestimated