Background-Emerging evidence from clinical trials suggests that oral estrogen and intranasal oxytocin might reduce symptom severity in schizophrenia. Whether increases in endogenous hormones are similarly associated with improved symptoms is unknown. We investigated the effects of menstrual cycle phase and related fluctuations in peripheral hormone levels on clinical symptoms in women with chronic schizophrenia.Method-Twenty-three women with schizophrenia were administered the Positive and Negative Syndrome Scale (PANSS), a measure of clinical symptom severity, at two menstrual cycle phases: 1) early follicular (Days 2-4; low estrogen/progesterone) and 2) midluteal (Days 20-22; high estrogen/progesterone). Twenty-seven males with schizophrenia and 58 controls (31 female) completed testing at comparable intervals. Men were included to examine whether the relationships between clinical symptoms and hormone levels in women generalize to men. Plasma hormone assays of estrogen, oxytocin, progesterone, and testosterone were obtained.Results-Female patients showed less severe symptoms during the midluteal versus early follicular phase (p's<0.01). Oxytocin did not fluctuate across phases, but in female patients (p's<0.01) higher oxytocin levels were associated with less severe positive symptoms and overall psychopathology. In both sexes, higher oxytocin levels were associated with more prosocial behaviors (p<0.05).Requests for reprints and correspondences should be addressed to: Leah H. Rubin, Ph.D., University of Illinois at Chicago, Department of Psychiatry, 912 S. Wood St. (MC 913), Chicago, Illinois 60612, (312) 355-5017 (phone), (312) 413-7856 (fax), lrubin@psych.uic.edu. Contributors Drs. Rubin and Maki conceived the idea and methodology for the study. Dr. Carter developed the methodology to explore oxytocin and served as an advisor and resource on this project for understanding oxytocin. Dr. Sweeney served as an advisor on this project and provided his expertise in schizophrenia. Dr. Pournajafi-Nazarloo and Ms. Drogos ran the oxytocin assays. Dr. Rubin, Dr. Maki's lab, and the Center for Cognitive Medicine were involved in recruitment and clinical assessments. Dr. Rubin conducted the statistical analyses and wrote the first draft. Drs. Rubin, Maki, Carter, and Sweeney exchanged multiple versions of the manuscript. All authors contributed to the writing of the manuscript and approval of the final version. Conflict of interestDr. Sweeney is a consultant to Pfizer and has a research grant from Janssen. Dr. Maki received honoraria from the American Nutraceutical Association and research support from the Soy Health Research Program. All other authors declare that, except for income received from their primary employer, no financial support or compensation has been received from any individual or corporate entity over the past 3 years for research or professional service, and there are no personal financial holdings that could be perceived as constituting a potential conflict of interest.Publisher's Disclaimer:...

Objective: In the largest cohort study of neuropsychological outcomes among HIV-infected women to date, we examined the association between HIV status and cognition in relation to other determinants of cognitive function (aim 1) and the pattern and magnitude of impairment across cognitive outcomes (aim 2).Methods: From 2009 participants from the Women's Interagency HIV Study (WIHS) completed a comprehensive neuropsychological test battery. We used multivariable regression on raw test scores for the first aim and normative regression-based analyses (t scores) for the second aim. The design was cross-sectional. Results:The effect sizes for HIV status on cognition were very small, accounting for only 0.05 to 0.09 SD units. The effect of HIV status was smaller than that of years of education, age, race, income, and reading level. In adjusted analyses, HIV-infected women performed worse than uninfected women on verbal learning, delayed recall and recognition, and psychomotor speed and attention. The largest deficit was observed in delayed memory. The association of low reading level with cognition was greater in HIV-infected compared to HIV-uninfected women. HIV biomarkers (CD4 count, history of AIDS-defining illness, viral load) were associated with cognitive dysfunction. Conclusions:The effect of HIV on cognition in women is very small except among women with low reading level or HIV-related comorbidities. Direct comparisons of rates of impairment in wellmatched groups of HIV-infected men and women are needed to evaluate possible sex differences in cognition. Compared to HIV-infected men, HIV-infected women may be at greater risk for cognitive decline due to a higher prevalence of risk factors common in predominantly minority, urbandwelling women, such as poverty, low literacy levels, low education, substance abuse, poor mental health, early life stressors and trauma, barriers to health care service utilization, and environmental exposures.1,2 These factors might contribute to low cognitive reserve and confer increased risks of cognitive dysfunction. Several studies have examined cognition in HIVinfected women, 3-11 but the maximum sample size has been 237. Larger studies are needed to understand the determinants and patterns of cognitive function in HIV-infected women.The Women's Interagency HIV Study (WIHS) is the largest longitudinal study of the natural and treated history of HIV infection and clinical outcomes in women residing in the United States.12,13 Here we present the first findings from the largest comprehensive cohort study of cognitive function in HIV-infected (n 5 1,019) and demographically similar HIVuninfected women (n 5 502). Our first aim was to investigate the association between HIV status and cognition in relation to other determinants of cognition. We predicted that low socioeconomic status, low reading level, illicit substance use, and depressive symptoms would contribute to decrements across a range of cognitive domains, and would more strongly influence cognition in HIV-infected wo...

Objective: To examine sex differences in the relationship between clinical symptoms related to Alzheimer disease (AD) (verbal memory deficits) and neurodegeneration (hippocampal volume/ intracranial volume ratio [HpVR]) across AD stages. Methods:The sample included 379 healthy participants, 694 participants with amnestic mild cognitive impairment (aMCI), and 235 participants with AD and dementia from the Alzheimer's Disease Neuroimaging Initiative who completed the Rey Auditory Verbal Learning Test (RAVLT). Cross-sectional analyses were conducted using linear regression to examine the interaction between sex and HpVR on RAVLT across and within diagnostic groups adjusting for age, education, and APOE e4 status.Results: Across groups, there were significant sex 3 HpVR interactions for immediate and delayed recall (p , 0.01). Women outperformed men among individuals with moderate to larger HpVR, but not among individuals with smaller HpVR. In diagnosis-stratified analyses, the HpVR 3 sex interaction was significant in the aMCI group, but not in the control or AD dementia groups, for immediate and delayed recall (p , 0.01). Among controls, women outperformed men on both outcomes irrespective of HpVR (p , 0.001). In AD dementia, better RAVLT performance was independently associated with female sex (immediate, p 5 0.04) and larger HpVR (delayed, p 5 0.001). The cognitive reserve theory posits that favorable premorbid factors including higher education and IQ delay the onset of clinical deficits despite Alzheimer disease (AD)-related neurodegeneration because compensatory mechanisms are more readily engaged (e.g., alternate brain networks or cognitive strategies). Conclusion:1-3 The theory predicts that the onset of accelerated cognitive decline is closer in time to AD dementia diagnosis in individuals with greater cognitive reserve; however, after onset, their decline is more rapid because neurodegeneration is more advanced at that point. [4][5][6] Throughout life, women outperform men on verbal memory tasks. [7][8][9] We predict that this female advantage may reflect a sex-specific form of cognitive reserve resulting in a delay in the clinical manifestation of memory impairment until more advanced neurodegeneration overwhelms the female advantage and decline begins. Thereafter, we predict that women decline From the Einstein Aging Study and the

Objective: Neurocognitive studies of HIV typically target executive functions dependent on frontostriatal circuitry. The integrity of medial temporal systems has received considerably less attention despite high hippocampal viral load. Studies also predominately involve HIVϩ men, though HIVϩ women may be at increased risk for cognitive dysfunction due to the high prevalence of psychosocial/mental health problems and lower educational attainment. Our aim was to conduct a preliminary investigation of episodic memory and its neural correlates in HIV-infected and at-risk uninfected women.Methods: Participants included 54 HIVϩ and 12 HIVϪ women (mean age ϭ 43 years; 86% African American) recruited from the Chicago site of the Women's Interagency HIV Study. Participants completed standardized tests of verbal and visual episodic memory, working memory, and executive function. A subset of 11 women also underwent functional MRI during a delayed verbal episodic memory task.Results: HIV serostatus predicted significantly lower immediate and delayed verbal episodic memory, working memory, and visual memory. Preliminary neuroimaging findings revealed group differences in bilateral hippocampal function, with HIVϩ women showing decreased activation during encoding and increased activation during delayed recognition. These alterations correlated with worse episodic verbal memory. Conclusions:Verbal episodic memory deficits are evident in HIVϩ women and may be associated with hippocampal dysfunction at both encoding and retrieval. Neurology Until recently, the functional integrity of medial temporal systems in neuroAIDS has received little attention despite considerable evidence of hippocampal injury associated with HIV. Brain viral loads of HIV are particularly high in the hippocampus.1,2 Postmortem evidence of neuroinflammation by microglial/macrophage activation was found to be high in the hippocampus of HIVϩ individuals treated with highly active antiretroviral therapy (HAART), higher even than levels found in pre-HAART neuropathologic studies.3 Regional neurodegeneration of hippocampus and putamen each contributed unique variance in prediction of antemortem neurocognitive status in HIV. 4 A functional MRI (fMRI) study of well-educated HIVϩ men demonstrated reduced signal intensity in right posterior hippocampus, right inferior frontal gyrus, and left lingual gyrus during encoding of scenes.5 Further detailed multimodal investiga-

There is a new appreciation of the perimenopause - defined as the early and late menopause transition stages as well as the early postmenopause - as a window of vulnerability for the development of both depressive symptoms and major depressive episodes. However, clinical recommendations on how to identify, characterize and treat clinical depression are lacking. To address this gap, an expert panel was convened to systematically review the published literature and develop guidelines on the evaluation and management of perimenopausal depression. The areas addressed included: 1) epidemiology; 2) clinical presentation; 3) therapeutic effects of antidepressants; 4) effects of hormone therapy; and 5) efficacy of other therapies (eg, psychotherapy, exercise, and natural health products). Overall, evidence generally suggests that most midlife women who experience a major depressive episode during the perimenopause have experienced a prior episode of depression. Midlife depression presents with classic depressive symptoms commonly in combination with menopause symptoms (ie, vasomotor symptoms, sleep disturbance), and psychosocial challenges. Menopause symptoms complicate, co-occur, and overlap with the presentation of depression. Diagnosis involves identification of menopausal stage, assessment of co-occurring psychiatric and menopause symptoms, appreciation of the psychosocial factors common in midlife, differential diagnoses, and the use of validated screening instruments. Proven therapeutic options for depression (ie, antidepressants, psychotherapy) are the front-line treatments for perimenopausal depression. Although estrogen therapy is not approved to treat perimenopausal depression, there is evidence that it has antidepressant effects in perimenopausal women, particularly those with concomitant vasomotor symptoms. Data on estrogen plus progestin are sparse and inconclusive.

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IMPORTANCE An increased understanding of the relationship between subconcussive head impacts and near point of convergence (NPC) ocular-motor function may be useful in delineating traumatic brain injury.OBJECTIVE To investigate whether repetitive subconcussive head impacts during preseason football practice cause changes in NPC. DESIGN, SETTING, AND PARTICIPANTSThis prospective, observational study of 29 National Collegiate Athletic Association Division I football players included baseline and preseason practices (1 noncontact and 4 contact), and postseason follow-up and outcome measures were obtained for each time. An accelerometer-embedded mouthguard measured head impact kinematics. Based on the sum of head impacts from all 5 practices, players were categorized into lower (n = 7) or higher (n = 22) impact groups.EXPOSURES Players participated in regular practices, and all head impacts greater than 10g from the 5 practices were recorded using the i1Biometerics Vector mouthguard (i1 Biometrics Inc). MAIN OUTCOMES AND MEASURES Near point of convergence measures and symptom scores.RESULTS A total of 1193 head impacts were recorded from 5 training camp practices in the 29 collegiate football players; 22 were categorized into the higher-impact group and 7 into the lower-impact group. There were significant differences in head impact kinematics between lower-and higher-impact groups (number of impacts, 6 vs 41 [lower impact minus higher impact = 35; 95% CI, 21-51; P < .001]; linear acceleration, 99g vs 1112g [lower impact minus higher impact= 1013; 95% CI, 621 -1578; P < .001]; angular acceleration, 7589 radian/s 2 vs 65 016 radian/s 2 [lower impact minus higher impact= 57 427; 95% CI , 31 123-80 498; P < .001], respectively). The trajectory and cumulative burden of subconcussive impacts on NPC differed by group (F for group × linear trend 1, 238 = 12.14, P < .001 and F for group × quadratic trend 1, 238 = 12.97, P < .001). In the higher-impact group, there was a linear increase in NPC over time (B for linear trend, unstandardized coefficient [SE]: 0.76 [0.12], P < .001) that plateaued and resolved by postseason follow-up (B for quadratic trend [SE]: −0.06 [0.008], P < .001). In the lower-impact group, there was no change in NPC over time. Group differences were first observed after the first contact practice and remained until the final full-gear practice. No group differences were observed postseason follow-up. There were no differences in symptom scores between groups over time. CONCLUSIONS AND RELEVANCEAlthough asymptomatic, these data suggest that repetitive subconcussive head impacts were associated with changes in NPC. The increase in NPC highlights the vulnerability and slow recovery of the ocular-motor system following subconcussive head impacts. Changes in NPC may become a useful clinical tool in deciphering brain injury severity.

Background We previously reported that higher levels of peripheral oxytocin are associated with lower levels of positive, general, and overall symptoms in women but not men with schizophrenia. Here we investigate the influence of sex, sex steroid hormone fluctuations, and peripheral oxytocin levels on emotional processing in men and women with schizophrenia. Method Twenty-two women with schizophrenia and 31 female controls completed the Penn Emotion Acuity Test (PEAT), a facial emotion recognition and perception task, during two menstrual cycle phases: 1) early follicular (Days 2–4; low estrogen/progesterone) and 2) midluteal (Days 20–22; high estrogen/progesterone). Twenty-six males with schizophrenia and 26 male controls completed testing at comparable intervals. We obtained plasma hormone assays of estrogen, progesterone, testosterone, and oxytocin. Results No sex differences were noted on the PEAT. Plasma oxytocin levels did not fluctuate across phases of the menstrual cycle. However, female patients and controls more accurately identified facial emotions during the early follicular versus midluteal phase (p<0.05). Higher oxytocin levels related to perceiving faces as happier in both female patients (r=−0.46, p=0.04) and controls (r=−0.40, p=0.04) but not in men. Conclusion Like healthy women, women with schizophrenia demonstrate menstrual-cycle dependent fluctuations in recognizing emotional cues. Like healthy women, female patients with higher levels of oxytocin perceived faces as happier. Future studies need to address whether this sex-specific relationship is associated with trust and other positive emotions, and whether exogenous oxytocin might enhance mood states and social interaction in female or all schizophrenia patients.