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1.  Volumetric Parcellation Methodology of the Human Hypothalamus in Neuroimaging: Normative Data and Sex Differences 
NeuroImage  2012;69:1-10.
There is increasing evidence regarding the importance of the hypothalamus for understanding sex differences in relation to neurological, psychiatric, endocrine and sleep disorders. Although different in histology, physiology, connections and function, multiple hypothalamic nuclei subserve non-voluntary functions and are nodal points for the purpose of maintaining homeostasis of the organism. Thus, given the critical importance of hypothalamic nuclei and their key multiple roles in regulating basic functions, it is important to develop the ability to conduct in vivo human studies of anatomic structure, volume, connectivity, and function of hypothalamic regions represented at the level of its nuclei. The goals of the present study were to develop a novel method of semi-automated volumetric parcellation for the human hypothalamus that could be used to investigate clinical conditions using MRI and to demonstrate its applicability. The proposed new method subdivides the hypothalamus into five parcels based on visible anatomic landmarks associated with specific nuclear groupings and was confirmed using two ex vivo hypothalami that were imaged in a 7 Tesla (7T) scanner and processed histologically. Imaging results were compared with histology from the same brain. Further, the method was applied to 44 healthy adults (26 men; 18 women, comparable on age, handedness, ethnicity, SES) to derive normative volumes and assess sex differences in hypothalamic regions using 1.5 Tesla MRI. Men compared to women had a significantly larger total hypothalamus, relative to cerebrum size, similar for both hemispheres, a difference that was primarily driven by the tuberal region, with the sex effect size being largest in the superior tuberal region and, to a lesser extent, inferior tuberal region. Given the critical role of hypothalamic nuclei in multiple chronic diseases and the importance of sex differences, we argue that the use of the novel methodology presented here will allow for critical investigations of these disorders and further delineation of potential treatments, particularly sex-specific approaches to gene and drug discoveries that involve hypothalamic nuclei.
PMCID: PMC3575213  PMID: 23247186
structural MRI; volumetry; hypothalamus; hypothalamic nuclei; tuberal region; sex differences
Schizophrenia research  2012;141(1):10.1016/j.schres.2012.07.024.
The 3rd Schizophrenia International Research Society Conference was held in Florence, Italy, April 14-18, 2012.and this year had as its emphasis, “The Globalization of Research”. Student travel awardees served as rapporteurs for each oral session and focused their summaries on the most significant findings that emerged and the discussions that followed. The following report is a composite of these summaries. We hope that it will provide an overview for those who were present, but could not participate in all sessions, and those who did not have the opportunity to attend, but who would be interested in an update on current investigations ongoing in the field of schizophrenia research.
PMCID: PMC3877922  PMID: 22910407
schizophrenia; genetics; gene-environment interaction; brain imaging; treatment; conference
3.  Covariance Modeling of MRI Brain Volumes in Memory Circuitry in Schizophrenia: Sex Differences are Critical 
NeuroImage  2011;56(4):1865-1874.
Women have consistently demonstrated better verbal memory on tests that evaluate immediate and delayed free recall. In patients with schizophrenia, these verbal memory processes are relatively more preserved in women than men. However an understanding of the brain anatomy of the female advantage for verbal memory is still unclear.
29 females and 59 males with schizophrenia made comparable to 21 female and 27 male healthy volunteers were scanned using structural magnetic resonance imaging (sMRI) in order to assess volumes of regions across the entire brain. Sex differences within and between groups in the covariance structure of memory circuitry regions were evaluated using a novel approach to covariance analysis (the Box M Test). Brain areas of interest included prefrontal cortex (PFC), inferior parietal lobule (iPAR), anterior cingulate gyrus (ACG), parahippocampus, and hippocampus (HIPP).
Results showed significant differences in the covariance matrices of females and males with schizophrenia compared with their healthy counterparts, in particular the relationships between iPAR-PFC, iPAR-ACG, and HIPP-PFC. Sex differences in the iPAR-PFC relationship were significantly associated with sex differences in verbal memory performance. In control women, but not in men ACG volume correlated strongly with memory performance. In schizophrenia, ACG volume was reduced in females, but not in men, relative to controls.
Findings suggest that the relationship between iPAR and PFC is particularly important for understanding the relative preservation of verbal memory processing in females with schizophrenia and may compensate for ACG volume reductions. These results illustrate the utility of a unique covariance structure modeling approach that yields important new knowledge for understanding the nature of schizophrenia.
PMCID: PMC3113542  PMID: 21497198
Verbal memory; sex differences; schizophrenia; magnetic resonance imaging; brain morphometry; covariance
4.  Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry 
The amygdala, hippocampus, medial prefrontal cortex (mPFC) and brain-stem subregions are implicated in fear conditioning and extinction, and are brain regions known to be sexually dimorphic. We used functional magnetic resonance imaging (fMRI) to investigate sex differences in brain activity in these regions during fear conditioning and extinction.
Subjects were 12 healthy men comparable to 12 healthy women who underwent a 2-day experiment in a 3 T MR scanner. Fear conditioning and extinction learning occurred on day 1 and extinction recall occurred on day 2. The conditioned stimuli were visual cues and the unconditioned stimulus was a mild electric shock. Skin conductance responses (SCR) were recorded throughout the experiment as an index of the conditioned response. fMRI data (blood-oxygen-level-dependent [BOLD] signal changes) were analyzed using SPM8.
Findings showed no significant sex differences in SCR during any experimental phases. However, during fear conditioning, there were significantly greater BOLD-signal changes in the right amygdala, right rostral anterior cingulate (rACC) and dorsal anterior cingulate cortex (dACC) in women compared with men. In contrast, men showed significantly greater signal changes in bilateral rACC during extinction recall.
These results indicate sex differences in brain activation within the fear circuitry of healthy subjects despite similar peripheral autonomic responses. Furthermore, we found that regions where sex differences were previously reported in response to stress, also exhibited sex differences during fear conditioning and extinction.
PMCID: PMC3416700  PMID: 22738021
Sex differences; Fear extinction; Fear conditioning; fMRI; Stress response circuitry
5.  Implications of Cognitive Load for Hypothesis Generation and Probability Judgment 
We tested the predictions of HyGene (Thomas et al., 2008) that both divided attention at encoding and judgment should affect the degree to which participants’ probability judgments violate the principle of additivity. In two experiments, we showed that divided attention during judgment leads to an increase in subadditivity, suggesting that the comparison process for probability judgments is capacity limited. Contrary to the predictions of HyGene, a third experiment revealed that divided attention during encoding leads to an increase in later probability judgment made under full attention. The effect of divided attention during encoding on judgment was completely mediated by the number of hypotheses participants generated, indicating that limitations in both encoding and recall can cascade into biases in judgments.
PMCID: PMC3120978  PMID: 21734897
working memory; probability judgment; hypothesis generation; support theory
6.  Sex Differences in Stress Response Circuitry Activation Dependent on Female Hormonal Cycle 
Understanding sex differences in stress regulation has important implications for understanding basic physiological differences in the male and female brain and their impact on vulnerability to sex differences in chronic medical disorders associated with stress response circuitry. In this fMRI study, we demonstrated that significant sex differences in brain activity in stress response circuitry were dependent on women's menstrual cycle phase. Twelve healthy Caucasian premenopausal women were compared to a group of healthy men from the same population, based on age, ethnicity, education, and right-handedness. Subjects were scanned using negative valence/high arousal versus neutral visual stimuli that we demonstrated activated stress response circuitry (amygdala, hypothalamus, hippocampus, brainstem, orbitofrontal and medial prefrontal cortices (OFC and mPFC), and anterior cingulate gyrus (ACG). Women were scanned twice based on normal variation in menstrual cycle hormones (i.e., early follicular (EF) compared with late follicular-midcycle menstrual phases (LF/MC)). Using SPM8b, there were few significant differences in BOLD signal changes in men compared to EF women, except ventromedial (VMN) and lateral (LHA) hypothalamus, left amygdala, and ACG. In contrast, men exhibited significantly greater BOLD signal changes compared to LF/MC women on bilateral ACG and OFC, mPFC, LHA, VMN, hippocampus, and periaqueductal gray, with largest effect sizes in mPFC and OFC. Findings suggest that sex differences in stress response circuitry are hormonally regulated via the impact of subcortical brain activity on the cortical control of arousal, and demonstrate that females have been endowed with a natural hormonal capacity to regulate the stress response that differs from males.
PMCID: PMC2827936  PMID: 20071507
fMRI; Stress; Sex difference; Arousal; Hypothalamus; Amygdala; HPA axis

Results 1-6 (6)