Disrupted Resting-State Functional Connectivity in Medication-free Women with Postpartum Depression

Background: Women are at increased risk of developing depression in the postpartum, a time of gonadal steroid flux. Abnormalities of gonadal steroids have been identified in some depressed women at times of reproductive flux. Gonadal steroids modulate corticocortical and corticolimbic functional connectivity (FC) in healthy, non-puerperal subjects; however there are no published studies of FC in postpartum depression (PPD). Methods: Healthy comparison (HCS) (n=9) and medication-free subjects with unipolar PPD (n=8) were scanned at 3-9 weeks postpartum (using 3T Philips MRI) while ‘at rest’ with eyes open. Data analysis was carried out using SPM-8 and Data Processing Assistant for Resting-State fMRI (DPARSF) to perform seed based resting-state functional connectivity (rs-FC) analysis. Seeds were placed at bilateral anterior cingulate (ACC) and dorsolateral prefrontal cortices (DLPFC), hippocampi (HIPP) and amygdalae (AMYG). Correlation coefficients obtained from individual subject analysis were used in performing two-sample t-test to compare the two cohorts. Results: Functional connectivity maps revealed a more distributed pattern of connectivity with each seed (i.e. ACC, DLPFX, HIPP, and AMYG) for HCS than PPD. In PPD subjects as compared to HCS, there was attenuation of rs-FC between corticocortical and corticolimbic areas. Conclusions: In the early postpartum period, rs-FC patterns are disrupted in women with PPD in brain regions important for cognition, affect and the stress response. Larger studies are necessary to elucidate the role of disrupted neural connections in the pathophysiology of PPD and the potential modulatory role of gonadal steroids in women

Traumatic Brain Injury: Translation from Animal Models and Genetics to Improving Outcomes

This presentation offers background information on traumatic brain injury (TBI), a public health problem which affects approximately 1.7 million Americans each year. The presentation is part of a mini-symposium highlighting the interdisciplinary and translational nature of TBI research at the University of Massachusetts Medical School

Bioenergetic Measurements in Children with Bipolar Disorder: A Pilot 31^{31}P Magnetic Resonance Spectroscopy Study

Background: Research exploring Bipolar Disorder (BD) phenotypes and mitochondrial dysfunction, particularly in younger subjects, has been insufficient to date. Previous studies have found abnormal cerebral pH levels in adults with BD, which may be directly linked to abnormal mitochondrial activity. To date no such studies have been reported in children with BD. Methods: Phosphorus Magnetic Resonance Spectroscopy ($^{31}$P MRS) was used to determine pH, phopshocreatine (PCr) and inorganic phosphate (Pi) levels in 8 subjects with BD and 8 healthy comparison subjects (HCS) ages 11 to 20 years old. Results: There was no significant difference in pH between the patients and HCS. However, frontal pH values for patients with BD increased with age, contrary to studies of HCS and the pH values in the frontal lobe correlated negatively with the YMRS values. Global Pi was significantly lower in subjects with BD compared with HCS. There were no significant differences in PCr between the groups. Global PCr-to-Pi ratio (PCr/Pi) was significantly higher in subjects with BD compared with HCS. Conclusions: The change in Pi levels for the patients with BD coupled with the no difference in PCr levels, suggest an altered mitochondrial phosphorylation. However, our findings require further investigation of the underlying mechanisms with the notion that a mitochondrial dysfunction may manifest itself differently in children than that in adults. Limitations: Further investigations with larger patient populations are necessary to draw further conclusions

The Role of Glutamate and GABA in Autism Spectrum Disorders: Pilot Results from a Proton Magnetic Resonance Spectroscopy Study

Objectives: To measure the levels of glutamate, a major excitatory neurotransmitter; glutamine, a metabolite of glutamate; and γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter; in a pilot study of proton magnetic resonance spectroscopy (1H-MRS) findings in adolescents with Autism Spectrum Disorders (ASD). Methods: The subjects were assessed with the Autism Diagnostic Observation Schedule (ADOS), the Reading the Mind in the Eyes test (RMET) and the Social Responsiveness Scale (SRS). 1H-MRS measures of the anterior cingulate cortex were conducted using a Philips 3.0 T scanner. Results: To date, we have completed the data analysis on 18 subjects, 8 with ASD and 10 healthy control (HC) subjects. There was no significant difference between the combined glutamate + glutamine concentrations as measured by 1H-MRS (ASD = 12.0 ± 0.9 IU, HC = 11.6 ± 0.8 IU, p = 0.37). However, there was a higher than average glutamine level in the ASD group compared to healthy controls (ASD = 2.4 ± 0.2 IU, HC = 1.9 ± 0.3 IU, p = 0.01). This was accompanied by a trend toward lower GABA/Cr levels in the ASD group (ASD = 0.073 ± 0.010, HC = 0.082 ± 0.010, p = 0.06). Glutamine levels in the ACC were correlated positively with deficits of social cognition across groups (higher SRS, lower RMET scores). Those with higher glutamine levels made more errors when identifying emotions in the RMET task (r(10) = -0.77, p = 0.009), and also had more clinically significant scores on the SRS (r(10) = 0.87, p = 0.001). Conclusions: Our results present evidence that glutamine levels measured within the ACC region are higher for adolescent males with ASD than age-matched HC males, and signal that GABA levels may also be decreased in this region. These changes are correlated with deficits in social cognition

Robustness of sex-differences in functional connectivity over time in middle-aged marmosets

Nonhuman primates (NHPs) are an essential research model for gaining a comprehensive understanding of the neural mechanisms of neurocognitive aging in our own species. In the present study, we used resting state functional connectivity (rsFC) to investigate the relationship between prefrontal cortical and striatal neural interactions, and cognitive flexibility, in unanaesthetized common marmosets (Callithrix jacchus) at two time points during late middle age (8 months apart, similar to a span of 5-6 years in humans). Based on our previous findings, we also determine the reproducibility of connectivity measures over the course of 8 months, particularly previously observed sex differences in rsFC. Male marmosets exhibited remarkably similar patterns of stronger functional connectivity relative to females and greater cognitive flexibility between the two imaging time points. Network analysis revealed that the consistent sex differences in connectivity and related cognitive associations were characterized by greater node strength and/or degree values in several prefrontal, premotor and temporal regions, as well as stronger intra PFC connectivity, in males compared to females. The current study supports the existence of robust sex differences in prefrontal and striatal resting state networks that may contribute to differences in cognitive function and offers insight on the neural systems that may be compromised in cognitive aging and age-related conditions such as mild cognitive impairment and Alzheimer\u27s disease

Sex Differences in Cognitive Flexibility and Resting Brain Networks in Middle-Aged Marmosets

Sex differences in human cognitive performance are well characterized. However, the neural correlates of these differences remain elusive. This issue may be clarified using nonhuman primates, for which sociocultural influences are minimized. We used the marmoset (Callithrix jacchus) to investigate sex differences in two aspects of executive function: reversal learning and intradimensional/extradimensional (ID/ED) set shifting. Stress reactivity and motor function were also assessed. In agreement with human literature, females needed more trials than males to acquire the reversals. No sex differences in ED set shifting or motivational measures were observed. The findings suggest enhanced habit formation in females, perhaps due to striatal estrogenic effects. Both sexes showed increased urinary cortisol during social separation stressor, but females showed an earlier increase in cortisol and a greater increase in agitated locomotion, possibly indicating enhanced stress reactivity. Independent of sex, basal cortisol predicted cognitive performance. No sex differences were found in motor performance. Associations between brain networks and reversal learning performance were investigated using resting state fMRI. Resting state functional connectivity (rsFC) analyses revealed sex differences in cognitive networks, with differences in overall neural network metrics and specific regions, including the prefrontal cortex, caudate, putamen, and nucleus accumbens. Correlations between cognitive flexibility and neural connectivity indicate that sex differences in cognitive flexibility are related to sex-dependent patterns of resting brain networks. Overall, our findings reveal sex differences in reversal learning, brain networks, and their relationship in the marmoset, positioning this species as an excellent model to investigate the biological basis of cognitive sex differences

Measuring Changes in Brain Metabolite Levels Using Live-animal Magnetic Resonance Spectroscopy and Offline LC-MS Metabolomics in a Binge-ethanol Murine Model

Alcoholism and acute alcohol binge are significant public health concerns. Liquid chromatography-mass spectrometry (LC-MS) based metabolomics is a robust and sensitive technique for determining and quantifying transient or permanent biochemical changes within the central nervous system (CNS). However, access to human tissue and CNS biofluid for such analyses is limited in a clinical context. In-vivo magnetic resonance spectroscopy (MRS) is an attractive alternative for clinical measurement but currently the technique is limited to a small to a number of well-characterized, highly abundant analytes. We therefore seek to correlate LC-MS and MRS measurements to better understand and leverage the strengths of each. Following live animal MRS measurement, metabolites in hippocampal brain punch homogenates were quantified by LC-MS, and a Spearman’s correlation coefficient was calculated. We found that the measurements for glutamine and glutamate,, were significantly correlated. Other established neurochemicals, including NAA and aspartate, showed non-significant correlations. NAAG showed little correlation between the two measurements. Additional experiments are ongoing to resolve these discrepancies, and determine how to achieve better agreement between the two methods. In addition,, we used Elements (Proteome Software) to determine differentially expressed metabolites between ethanol exposed and control mice.. An initial pass shows more than 1000 peak-picked features identified in the two conditions, with approximately 200 analytes identified in the metabolite database (human) based on accurate mass. Differentially expressed candidates can be validated further using tandem mass spectrometry and, where possible, the use of authentic standards. Metabolites that change after binge ethanol exposure are reported along with an overview of comparing MRS with LC-MS datasets

Ubiquitous neurocognitive dysfunction in familial adenomatous polyposis: proof-of-concept of the role of APC protein in neurocognitive function

Background: Familial adenomatous polyposis (FAP) is an autosomal dominant disorder caused by germline mutations in the APC gene. Patients with FAP have multiple extraintestinal manifestations that follow a genotype-phenotype pattern; however, few data exist characterizing their cognitive abilities. Given the role of the APC protein in development of the central nervous system, we hypothesized that patients with FAP would show differences in cognitive functioning compared to controls. Methods: Matched case-control study designed to evaluate cognitive function using the Test of Nonverbal Intelligence-4, the Bateria III Woodcock-Munoz, and the Behavior Rating Inventory of Executive Functions-Adult. Twenty-six individuals with FAP (mean age = 34.2 +/- 15.0 years) and 25 age-gender and educational level matched controls (mean age = 32.7 +/- 13.8 years) were evaluated. Results: FAP-cases had significantly lower IQ (p = 0.005). Across all tasks of the Bateria III Woodcock-Munoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls (p \u3c 0.0001). Patients with FAP scored within the deficient range for Long-Term Retrieval and Cognitive Fluency. Conclusion: APC protein has an important role in neurocognitive function. The pervasive nature of the observed cognitive dysfunction suggests that loss or dysfunction of the APC protein impacts processes in cortical and subcortical brain regions. Additional studies examining larger ethnically diverse cohorts with FAP are warranted

Trends and determinants of stillbirth in developing countries: results from the Global Network\u27s Population-Based Birth Registry.

BACKGROUND: Stillbirth rates remain high, especially in low and middle-income countries, where rates are 25 per 1000, ten-fold higher than in high-income countries. The United Nations\u27 Every Newborn Action Plan has set a goal of 12 stillbirths per 1000 births by 2030 for all countries. METHODS: From a population-based pregnancy outcome registry, including data from 2010 to 2016 from two sites each in Africa (Zambia and Kenya) and India (Nagpur and Belagavi), as well as sites in Pakistan and Guatemala, we evaluated the stillbirth rates and rates of annual decline as well as risk factors for 427,111 births of which 12,181 were stillbirths. RESULTS: The mean stillbirth rates for the sites were 21.3 per 1000 births for Africa, 25.3 per 1000 births for India, 56.9 per 1000 births for Pakistan and 19.9 per 1000 births for Guatemala. From 2010 to 2016, across all sites, the mean stillbirth rate declined from 31.7 per 1000 births to 26.4 per 1000 births for an average annual decline of 3.0%. Risk factors for stillbirth were similar across the sites and included maternal age \u3c 20 years and age \u3e 35 years. Compared to parity 1-2, zero parity and parity \u3e 3 were both associated with increased stillbirth risk and compared to women with any prenatal care, women with no prenatal care had significantly increased risk of stillbirth in all sites. CONCLUSIONS: At the current rates of decline, stillbirth rates in these sites will not reach the Every Newborn Action Plan goal of 12 per 1000 births by 2030. More attention to the risk factors and treating the causes of stillbirths will be required to reach the Every Newborn Action Plan goal of stillbirth reduction. TRIAL REGISTRATION: NCT01073475

Keeping weight off: Mindfulness-Based Stress Reduction alters amygdala functional connectivity during weight loss maintenance in a randomized control trial

Obesity is associated with significant comorbidities and financial costs. While behavioral interventions produce clinically meaningful weight loss, weight loss maintenance is challenging. The objective was to improve understanding of the neural and psychological mechanisms modified by mindfulness that may predict clinical outcomes. Individuals who intentionally recently lost weight were randomized to Mindfulness-Based Stress Reduction (MBSR) or a control healthy living course. Anthropometric and psychological factors were measured at baseline, 8 weeks and 6 months. Functional connectivity (FC) analysis was performed at baseline and 8 weeks to examine FC changes between regions of interest selected a priori, and independent components identified by independent component analysis. The association of pre-post FC changes with 6-month weight and psychometric outcomes was then analyzed. Significant group x time interaction was found for FC between the amygdala and ventromedial prefrontal cortex, such that FC increased in the MBSR group and decreased in controls. Non-significant changes in weight were observed at 6 months, where the mindfulness group maintained their weight while the controls showed a weight increase of 3.4% in BMI. Change in FC at 8-weeks between ventromedial prefrontal cortex and several ROIs was associated with change in depression symptoms but not weight at 6 months. This pilot study provides preliminary evidence of neural mechanisms that may be involved in MBSR\u27s impact on weight loss maintenance that may be useful for designing future clinical trials and mechanistic studies