Leah H. Rubin

Peripheral oxytocin is associated with reduced symptom severity in schizophrenia

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 (ps<0.01). Oxytocin did not fluctuate across phases, but in female patients (ps<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). CONCLUSION Consistent with previous findings in acutely ill patients, our results suggest that clinical symptoms vary across the menstrual cycle in patients with chronic schizophrenia. Similar to recent findings regarding benefits of intranasal oxytocin, these new findings indicate that high levels of endogenous oxytocin might improve positive symptom severity and general psychopathology in women and social behaviors in both sexes.

Effects of menstrual cycle phase and oral contraceptive use on verbal memory

Surgical or pharmacological suppression of ovarian hormones leads to declines in verbal memory, and estrogen treatment reverses these deficits. In the current study, we investigated the effects of menstrual cycle phase and oral contraceptives on verbal memory, as measured by the California Verbal Learning Test, in two groups of premenopausal women - 16 naturally cycling women and 20 current users of estrogen-based oral contraceptives (OCs). Naturally cycling women were assessed twice - once during the early follicular phase (Days 2-4) and once during the midluteal phase (Days 20-22) of the menstrual cycle. OC users were tested on the same cycle days, corresponding to inactive and active pill phases, respectively. We predicted that naturally cycling women would show improved verbal memory during the midluteal phase, when estradiol levels are high, compared with the follicular phase, when estradiol levels are low. We also predicted that OC users, who show no change in endogenous estradiol across the cycle, would show no change in verbal memory. Contrary to predictions, naturally cycling women showed no changes in verbal memory across the cycle, whereas OC users showed enhanced memory during the active pill phase (p<.05). None of the secondary cognitive outcome measures varied with cycle phase or OC use including measures of visuospatial memory, verbal fluency, visuospatial abilities, and attention. Overall, these results suggest that verbal memory performance in premenopausal women varies across the cycle with OC use, but does not vary systematically with changes in endogenous estradiol.

Impairments in memory and hippocampal function in HIV-positive vs HIV-negative women: a preliminary study.

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 HIV+ men, though HIV+ 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 HIV+ and 12 HIV− women (mean age = 43 years; 86% African American) recruited from the Chicago site of the Womens 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 HIV+ 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 HIV+ women and may be associated with hippocampal dysfunction at both encoding and retrieval.

Objective hot flashes are negatively related to verbal memory performance in midlife women.

Objective: To test the hypothesis that hot flashes specifically relate to verbal memory performance by examining the relationship between objective hot flashes and cognitive test performance in women with moderate to severe vasomotor symptoms. Design: In an observational study, 29 midlife women (mean age, 53 y) with moderate to severe hot flashes provided measures of objective hot flashes with an ambulatory hot flash monitor, subjective hot flashes with a diary and questionnaire, and objective measures of verbal memory and other cognitive functions with standardized neuropsychological tests. Results: The mean number of objective hot flashes was 19.5 per day (range, 6 to 35), including 15.3 (range, 6 to 35) during waking hours and 4.2 (range, 0 to 9) during sleep. The mean sensitivity (ie, subjective detection of objectively measured hot flashes) was 60%. Regression analyses revealed that total number of objective hot flashes, sleep duration, and verbal knowledge were significant predictors of delayed verbal memory. Verbal fluency correlated positively with objective daytime hot flashes. Hot flashes did not predict performance on any of the other secondary cognitive measures (ie, attention, working memory, visual memory), although poor sleep predicted worse performance on several outcome measures. Conclusions: Highly symptomatic women underreport the number of objective hot flashes that they experience by 43%. Verbal memory performance relates significantly to the objective number of hot flashes women experience but not to the number of hot flashes that they report. These findings suggest that physiological factors related to hot flashes, rather than psychological factors, predict poorer verbal memory function.

Sex-specific associations between peripheral oxytocin and emotion perception in schizophrenia

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 in 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.

Cognition in perimenopause: The effect of transition stage

ObjectiveThe aims of this cross-sectional study were to determine if cognitive function differs across stages of reproductive aging and to evaluate whether hormones or menopausal symptoms predict cognition in perimenopause. We hypothesized that women in late menopausal transition and early postmenopause would perform more poorly than those in the late reproductive stage on attention and verbal memory tasks, and that estradiol, depressive symptoms, anxiety symptoms, hot flashes, and sleep disturbance would predict cognitive performance on those tasks. MethodsOne hundred seventeen middle-aged women enrolled in the Rochester Investigation of Cognition Across Menopause were categorized into late reproductive stage (n = 34), early menopausal transition stage (n = 28), late menopausal transition stage (n = 41), or early postmenopause stage (n = 14) according to criteria from the Stages of Reproductive Aging Workshop +10. We administered a neuropsychological battery assessing six domains of cognition, assessed menopausal symptoms, and measured serum levels of estradiol and follicle-stimulating hormone. Multivariate regressions were conducted to determine the impact of menopausal stage and symptoms on cognition. ResultsWomen in the first year of postmenopause performed significantly worse than women in the late reproductive and late menopausal transition stages on measures of verbal learning, verbal memory, and motor function. They also performed significantly worse than women in the late menopausal transition stage on attention/working memory tasks. ConclusionsCognitive function does not change linearly across perimenopause. Decreases in attention/working memory, verbal learning, verbal memory, and fine motor speed may be most evident in the first year after the final menstrual period.

Reduced Levels of Vasopressin and Reduced Behavioral Modulation of Oxytocin in Psychotic Disorders

Oxytocin (OT) and arginine vasopressin (AVP) exert robust influence on social affiliation and specific cognitive processes in healthy individuals. Abnormalities in these neuroendocrine systems have been observed in psychotic disorders, but their relation to impairments in behavioral domains that these endocrines modulate is not well understood. We compared abnormalities of OT and AVP serum concentrations in probands with schizophrenia (n = 57), schizoaffective disorder (n = 34), and psychotic bipolar disorder (n = 75); their first-degree relatives without a history of psychosis (n = 61, 43, 91, respectively); and healthy controls (n = 66) and examined their association with emotion processing and cognition. AVP levels were lower in schizophrenia (P = .002) and bipolar probands (P = .03) and in relatives of schizophrenia probands (P = .002) compared with controls. OT levels did not differ between groups. Familiality estimates were robust for OT (h(2) = 0.79, P = 3.97e-15) and AVP (h(2) = 0.78, P = 3.93e-11). Higher levels of OT were associated with better emotion recognition (β = 0.40, P < .001) and general neuropsychological function (β = 0.26, P = .04) in healthy controls as expected but not in any proband or relative group. In schizophrenia, higher OT levels were related to greater positive symptom severity. The dissociation of OT levels and behavioral function in all proband and relative groups suggests that risk and illness factors associated with psychotic disorders are not related to reduced OT levels but to a disruption in the ability of physiological levels of OT to modulate social cognition and neuropsychological function. Decreased AVP levels may be a marker of biological vulnerability in schizophrenia because alterations were seen in probands and relatives, and familiality was high.

Cognitive function in women with HIV: findings from the Women's Interagency HIV Study.

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 to 2011, 1,521 (1,019 HIV-infected) participants from the Womens 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 well-matched groups of HIV-infected men and women are needed to evaluate possible sex differences in cognition.

Saccade Adaptation Abnormalities Implicate Dysfunction of Cerebellar-Dependent Learning Mechanisms in Autism Spectrum Disorders (ASD)

The cerebellar vermis (lobules VI-VII) has been implicated in both postmortem and neuroimaging studies of autism spectrum disorders (ASD). This region maintains the consistent accuracy of saccadic eye movements and plays an especially important role in correcting systematic errors in saccade amplitudes such as those induced by adaptation paradigms. Saccade adaptation paradigms have not yet been used to study ASD. Fifty-six individuals with ASD and 53 age-matched healthy controls performed an intrasaccadic target displacement task known to elicit saccadic adaptation reflected in an amplitude reduction. The rate of amplitude reduction and the variability of saccade amplitude across 180 adaptation trials were examined. Individuals with ASD adapted slower than healthy controls, and demonstrated more variability of their saccade amplitudes across trials prior to, during and after adaptation. Thirty percent of individuals with ASD did not significantly adapt, whereas only 6% of healthy controls failed to adapt. Adaptation rate and amplitude variability impairments were related to performance on a traditional neuropsychological test of manual motor control. The profile of impaired adaptation and reduced consistency of saccade accuracy indicates reduced neural plasticity within learning circuits of the oculomotor vermis that impedes the fine-tuning of motor behavior in ASD. These data provide functional evidence of abnormality in the cerebellar vermis that converges with previous reports of cellular and gross anatomic dysmorphology of this brain region in ASD.

Perinatal Depressive Symptoms in HIV-Infected Versus HIV-Uninfected Women: A Prospective Study from Preconception to Postpartum

OBJECTIVE Depression is common among HIV-infected women, predicts treatment nonadherence, and consequently may impact vertical transmission of HIV. We report findings from a study evaluating preconception, pregnancy, and postpartum depressive symptoms in HIV-infected vs. at-risk, HIV-uninfected women. METHODS We examined the prevalence and predictors of elevated perinatal (i.e., pregnancy and/or postpartum) depressive symptoms using a Center for Epidemiological Studies-Depression (CES-D) scale score of ≥16 in 139 HIV-infected and 105 HIV-uninfected women (62% African American) from the Womens Interagency HIV Study (WIHS). RESULTS The prevalence of elevated perinatal depressive symptoms did not differ by HIV serostatus (HIV-infected 44%, HIV-uninfected 50%, p=0.44). Among HIV-infected women, the strongest predictor of elevated symptoms was preconception depression (odds ratio [OR] 5.71, 95% confidence interval [CI] 2.67-12.19, p<0.001); crack, cocaine, and/or heroin use during preconception was marginally significant (OR 3.10, 95% CI 0.96-10.01, p=0.06). In the overall sample, additional significant predictors of perinatal depression included having multiple sex partners preconception (OR 2.20, 95% CI 1.12-4.32, p=0.02), use of preconception mental health services (OR 2.51, 95% CI 1.03-6.13, p=0.04), and not graduating from high school (OR 1.92, 95% CI 1.06-3.46, p=0.03). CONCLUSIONS Elevated perinatal depressive symptoms are common among HIV-infected and at-risk HIV-uninfected women. Depressive symptoms before pregnancy were the strongest predictor of perinatal symptoms. Findings underscore the importance of early and ongoing assessment and treatment to ensure low vertical transmission rates and improving postpregnancy outcomes for mothers and children.