Effects of sex, menstrual cycle phase, and endogenous hormones on cognition in schizophrenia

In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform better on “female-dominant” tasks (verbal memory/fluency) and worse on “male-dominant” tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone

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

Autonomic Nervous System Activity and Menopausal Symptoms

Hot Flashes (HFs) occur in up to 75% of women transitioning through menopause. Previous research suggests objective HFs may shift the balance between the calming branch (parasympathetic) and the ‘fight or flight’ branch (sympathetic) of the autonomic nervous system (ANS) through withdrawal of calming activity. There is limited evidence about the effect of HFs on the ‘fight or flight’ branch of the ANS. Independent of ANS changes, HFs are associated with decreased cardiovascular health (CVH). The link between CVH and the physiology of HFs is not understood. Here we investigate differences in ANS function between women with frequent or infrequent self-reported and objectively detected HFs. Participants included 40 midlife women (Mean age = 52.1) from a parent study investigating associations between menopausal symptoms and cognition: half reported frequent HFs (>30 per week) and half reported infrequent HFs (0.40). At thirty minutes after wake, women with objective HFs had an attenuated awakening response of salivary alpha-amylase compared to women without objective HFs (β=0.71, SE= 0.32, p=0.03, d=0.73). The total number of objective HFs was the best predictor of area under the curve and awakening response of sAA. Our findings support a state shift in autonomic balance towards increased ‘fight or flight’ activation with objective, but not self-reported, HFs. In addition, we found evidence that objective HFs have a dose-dependent relationship with sympathetic activity. Finally, our findings suggest that withdrawal of parasympathetic activity occurs transiently during objective HFs, but not during a validated posture challenge. Overall, our data provide evidence that objective hot flashes are associated with a shift in the balance between the sympathetic and parasympathetic branches of the autonomic nervous system; specifically, towards increased sympathetic tone with increased frequency of objective HFs

Cognitive Effects of Repeated Acute Exposure to Very High Altitude Among Altitude-Experienced Workers at 5050 m

Background: We investigated altitude effects on different cognitive domains among perennial shift-workers at the Atacama Large Millimeter/submillimeter Array Observatory (5050 m), Chile. Materials and Methods: Twenty healthy male workers were recruited and assigned to either a moderate-altitude first (MAF group, Test 1: 2900 m and Test 2: 5050 m) or to a high-altitude first (HAF group, Test 1: 5050 m and Test 2: 2900 m). Test 1 was conducted at the beginning and Test 2 at the end of the shift-work week. Processing speed (RTI, reaction time), attention (AST, attention-switching task, and RVP, rapid visual processing), and executive function (OTS, One Touch Stockings of Cambridge) were assessed. Results: Of the three cognitive domains assessed, only processing speed showed altitude-at-test group interaction (RTI median five choice reaction time: F1, 17 = 6.980,  = 0.291, p = 0.017). With acclimatization, there was a decrease in AST reaction latency mean (t17 = −2.155, dz = 1.086, p = 0.046), an increase in RVP accuracy (t17 = 2.733, dz = 1.398, p = 0.014), and a decrease in OTS mean latency first choice (t17 = −2.375, dz = 1.211, p = 0.03). Decreased variability in cognitive function was observed in AST reaction latency standard deviation (t17 = −2.524, dz = 1.282, p = 0.022) and in RVP response latency standard deviation (t17 = −2.35, dz = 1.177, p = 0.03) with acclimatization. At 5050 m of elevation, SpO2 was positively correlated with executive function in the MAF group (OTS problems solved on first choice: r(5) = 0.839, p = 0.018) and negatively correlated with executive function latency standard deviations in the HAF group (OTS latency to first choice standard deviation: r(10) = −0.618, p = 0.032). Conclusions: Our findings highlight the importance of acclimatization and improvement of blood oxygen level, even among high altitude-experienced workers, to optimize performance of cognitively demanding work and reduce high altitude-associated health risks

Effects on Cognitive Functioning of Acute, Subacute and Repeated Exposures to High Altitude

Neurocognitive functions are affected by high altitude, however the altitude effects of acclimatization and repeated exposures are unclear. We investigated the effects of acute, subacute and repeated exposure to 5,050 m on cognition among altitude-naïve participants compared to control subjects tested at low altitude. Twenty-one altitude-naïve individuals (25.3 ± 3.8 years, 13 females) were exposed to 5,050 m for 1 week ( and re-exposed after a week of rest at sea-level (). Baseline (BL, 520 m), acute (Day 1, HA1) and acclimatization (Day 6, HA6, 5,050 m) measurements were taken in both cycles. Seventeen control subjects (24.9 ± 2.6 years, 12 females) were tested over a similar period in Calgary, Canada (1,103 m). The Reaction Time (RTI), Attention Switching Task (AST), Rapid Visual Processing (RVP) and One Touch Stockings of Cambridge (OTS) tasks were administered and outcomes were expressed in milliseconds/frequencies. Lake Louise Score (LLS) and blood oxygen saturation (SpO) were recorded. In both cycles, no significant changes were found with acute exposure on the AST total score, mean latency and SD. Significant changes were found upon acclimatization solely in the altitude group, with improved AST Mean Latency [HA1 (588 ± 92) vs. HA6 (526 ± 91), < 0.001] and Latency SD [HA1 (189 ± 86) vs. HA6 (135 ± 65), < 0.001] compared to acute exposure, in . No significant differences were present in the control group. When entering Acute SpO (HA1-BL), Acclimatization SpO (HA6-BL) and LLS score as covariates for both cycles, the effects of acclimatization on AST outcomes disappeared indicating that the changes were partially explained by SpO and LLS. The changes in AST Mean Latency [ΔBL (-61.2 ± 70.2) vs. ΔHA6 (-28.0 ± 58), = 0.005] and the changes in Latency SD [ΔBL (-28.4 ± 41.2) vs. ΔHA6 (-0.2235 ± 34.8), = 0.007] across the two cycles were smaller with acclimatization. However, the percent changes did not differ between cycles. These results indicate independent effects of altitude across repeated exposures. Selective and sustained attention are impaired at altitude and improves with acclimatization.The observed changes are associated, in part, with AMS score and SpO. The gains in cognition with acclimatization during a first exposure are not carried over to repeated exposures

Sex and Diagnosis-Specific Associations Between DNA Methylation of the Oxytocin Receptor Gene With Emotion Processing and Temporal-Limbic and Prefrontal Brain Volumes in Psychotic Disorders

BackgroundThe oxytocin (OT) system, including receptor epigenetic mechanisms, has been shown to influence emotion processing, especially in females. Whether OT receptor (OXTR) epigenetic alterations occur across psychotic disorders in relation to illness-related disturbances in social cognition and brain anatomy is unknown.MethodsParticipants with affective and nonaffective psychotic disorders (92 women, 75 men) and healthy controls (38 women, 37 men) from the Chicago site of the BSNIP study completed the Penn Emotion Recognition Test (ER-40), a facial emotion recognition task. We measured cytosine methylation at site -934 upstream of the OXTR start codon in DNA from whole blood, and for the first time their relationship with plasma OT levels assessed by enzyme-immunoassay. Volumes of brain regions supporting social cognition were measured from MRI scans using FreeSurfer.ResultsPatients with prototypic schizophrenia features showed higher levels of DNA methylation than those with prototypic bipolar features. Methylation was higher in women than men, and was associated with poorer emotion recognition only in female patients and controls. Greater methylation was associated with smaller volumes in temporal-limbic and prefrontal regions associated previously with social cognition, but only in healthy women and females with schizophrenia.ConclusionDNA methylation of the OXTR site -934 was higher in schizophrenia spectrum than bipolar patients. Among patients, it was linked to behavioral deficits in social cognition and neuroanatomic structures known to support emotion processing only in schizophrenia spectrum individuals

Effects of sex, menstrual cycle phase, and endogenous hormones on cognition in schizophrenia

BACKGROUND: In women with schizophrenia, cognition has been shown to be enhanced following administration of hormone therapy or oxytocin. We examined how natural hormonal changes across the menstrual cycle influence cognition in women with schizophrenia. We hypothesized that female patients would perform better on “female-dominant” tasks (verbal memory/fluency) and worse on “male-dominant” tasks (visuospatial) during the early follicular phase (low estradiol and progesterone) compared to midluteal phase (high estradiol and progesterone) in relation to estradiol but not progesterone. METHODS: Fifty-four women (23 with schizophrenia) completed cognitive assessments and provided blood for sex steroid assays and oxytocin at early follicular (Days 2–4) and midluteal (Days 20–22) phases. Men were included to verify the expected pattern of sex differences on cognitive tests. RESULTS: Expected sex differences were observed on “female-dominant” and “male-dominant” tasks (p<0.001), but the magnitude of those differences did not differ between patients and controls (p=0.44). Cognitive performance did not change across the menstrual cycle on “female-dominant” or “male-dominant” tasks in either group. Estradiol and progesterone levels were unrelated to cognitive performance. Oxytocin levels did not change across the menstrual cycle but were positively related to performance on “female-dominant” tasks in female patients only (p<0.05). CONCLUSIONS: Sex differences in cognitive function are preserved in schizophrenia. Oxytocin levels do not change across the cycle, but relate to enhanced performance on female dominant tests in women. Physiological levels of oxytocin may thus have a more powerful benefit in some cognitive domains than estrogens in schizophrenia