Altered neural networks and cognition in a hereditary colon cancer.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

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's impact on weight loss maintenance that may be useful for designing future clinical trials and mechanistic studies.

Altered Resting State Brain Networks and Cognition in Familial Adenomatous Polyposis.

Familial Adenomatous Polyposis (FAP) is an autosomal dominant disorder caused by mutation of the APC gene presenting with numerous colorectal adenomatous polyps and a near 100% risk of colon cancer. Preliminary research findings from our group indicate that FAP patients experience significant deficits across many cognitive domains. In the current study, fMRI brain metrics in a FAP population and matched controls were used to further the mechanistic understanding of reported cognitive deficits. This research identified and characterized any possible differences in resting brain networks and associations between neural network changes and cognition from 34 participants (18 FAP patients, 16 healthy controls). Functional connectivity analysis was performed using FSL with independent component analysis (ICA) to identify functional networks. Significant differences between cases and controls were observed in 8 well-established resting state networks. With the addition of an aggregate cognitive measure as a covariate, these differences were virtually non-existent, indicating a strong correlation between cognition and brain activity at the network level. The data indicate robust and pervasive effects on functional neural network activity among FAP patients and these effects are likely involved in cognitive deficits associated with this disease.

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's disease.

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 Batería III Woodcock-Muñoz, FAP-cases performed significantly lower than controls, with all of the summary scores falling in the bottom quartile compared to controls (p < 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.

Resting-state functional connectivity, cortical GABA, and neuroactive steroids in peripartum and peripartum depressed women: a functional magnetic resonance imaging and spectroscopy study.

Postpartum depression (PPD) is associated with abnormalities in resting-state functional connectivity (RSFC) but the underlying neurochemistry is unclear. We hypothesized that peripartum GABAergic neuroactive steroids (NAS) are related to cortical GABA concentrations and RSFC in PPD as compared to healthy comparison women (HCW). To test this, we measured RSFC with fMRI and GABA+/Creatine (Cr) concentrations with proton magnetic resonance spectroscopy (1H MRS) in the pregenual anterior cingulate (pgACC) and occipital cortices (OCC) and quantified peripartum plasma NAS. We examined between-group differences in RSFC and the relationship between cortical GABA+/Cr concentrations with RSFC. We investigated the relationship between NAS, RSFC and cortical GABA+/Cr concentrations. Within the default mode network (DMN) an area of the dorsomedial prefrontal cortex (DMPFC) had greater connectivity with the rest of the DMN in PPD (peak voxel: MNI coordinates (2, 58, 32), p = 0.002) and was correlated to depression scores (peak HAM-D17 voxel: MNI coordinates (0, 60, 34), p = 0.008). pgACC GABA+/Cr correlated positively with DMPFC RSFC in a region spanning the right anterior/posterior insula and right temporal pole (r = +0.661, p = 0.000). OCC GABA+/Cr correlated positively with regions spanning both amygdalae (right amygdala: r = +0.522, p = 0.000; left amygdala: r = +0.651, p = 0.000) as well as superior parietal areas. Plasma allopregnanolone was higher in PPD (p = 0.03) and positively correlated with intra DMPFC connectivity (r = +0.548, p = 0.000) but not GABA+/Cr. These results provide initial evidence that PPD is associated with altered DMN connectivity; cortical GABA+/Cr concentrations are associated with postpartum RSFC and allopregnanolone is associated with postpartum intra-DMPFC connectivity.

Neurochemical differences between bipolar disorder type I and II in superior temporal cortices: A proton magnetic resonance spectroscopy study.

BACKGROUND: Despite the diagnostic challenges in categorizing bipolar disorder subtypes, bipolar I and II disorders (BD-I and BD-II respectively) are valid indices for researchers. Subtle neurobiological differences may underlie clinical differences between mood disorder subtypes. The aims of this study were to investigate neurochemical differences between bipolar disorder subtypes. METHODS: Euthymic BD-II patients (n = 21) are compared with BD-I (n = 28) and healthy comparison subjects (HCs, n = 30). Magnetic Resonance Imaging (MRI) and proton spectroscopy (1H MRS) were performed on a 3T Siemens Tim Trio system. MRS voxels were located in the left/right superior temporal cortices, and spectra acquired with the single voxel Point REsolved Spectroscopy Sequence (PRESS). The spectroscopic data were analyzed with LCModel (Version 6.3.0) software. RESULTS: There were significant differences between groups in terms of glutamate [F = 6.27, p = 0.003], glutamate + glutamine [F = 6.08, p = 0.004], inositol containing compounds (Ino) (F = 9.25, p < 0.001), NAA [F = 7.63, p = 0.001] and creatine + phosphocreatine [F = 11.06, p < 0.001] in the left hemisphere and Ino [F = 5.65, p = 0.005] in the right hemisphere. Post-hoc comparisons showed that the BD-I disorder group had significantly lower metabolite levels in comparison to the BD-II and the HC groups. LIMITATIONS: This was a cross-sectional study with a small sample size. In addition, patients were on various psychotropic medications, which may have impacted the results. CONCLUSIONS: Neurochemical levels, in the superior temporal cortices, measured with 1H-MRS discriminated between BD-II and BD-I. Although further studies are needed, one may speculate that the superior temporal cortices (particularly left hemispheric) play a critical role, whose pathology may be related to subtyping bipolar disorder.

White matter integrity in medication-free women with peripartum depression: a tract-based spatial statistics study.

Diffusion tensor imaging (DTI) studies in depression show decreased structural connectivity in the left anterior limb of the internal capsule and the genu of the corpus callosum but no such studies exist in peripartum depression (PPD), which affects 1 in 8 women. We analyzed fractional anisotropy (FA) as a measure of white matter integrity of these two tracts using tract-based spatial statistics (TBSS). We then conducted an exploratory whole-brain analysis to identify additional regions implicated in PPD. Seventy-five pregnant, medication-free women were evaluated with the Edinburgh Postnatal Depression Scale (EPDS) and Structured Clinical Interview (SCID) for DSM-IV-TR in pregnancy and in the postpartum. Structural MRI and DTI sequences were acquired in forty-four women within 2-8 weeks postpartum. TBSS data were analyzed between healthy comparison postpartum women (HCW) and women who developed PPD to determine differences in white matter integrity within the left anterior limb of the internal capsule and the genu of the corpus callosum, then analyzed across participants to explore correlation between FA and the EPDS score. An exploratory whole-brain analysis was also conducted to identify other potential regions showing differences in white matter integrity between groups, as well as correlation between EPDS and FA across groups. All results were corrected for multiple comparisons and analyses conducted using FSL, p < 0.05, K > 10. In comparison to HCW, women with PPD had significantly lower FA in left anterior limb of the internal capsule (p = 0.010). FA was negatively correlated with EPDS scores in the left anterior limb of the internal capsule (p = 0.019). In the whole-brain analysis, FA in the right retrolenticular internal capsule (p = 0.03) and two clusters within the body of the corpus callosum (p = 0.044, p = 0.050) were negatively correlated with EPDS; there were no between-group differences in FA. Reduced FA in the left anterior limb of the internal capsule suggests disruption of fronto-subcortical circuits in PPD. A negative correlation between FA within the body of the corpus callosum and EPDS total score could additionally reflect disrupted interhemispheric structural connectivity in women with depressive symptoms.

Glutamine/glutamate (Glx) concentration in prefrontal cortex predicts reversal learning performance in the marmoset.

This study used Magnetic Resonance Spectroscopy (MRS) to identify potential neurometabolitic markers of cognitive performance in male (n = 7) and female (n = 8) middle-aged (∼5 years old) common marmosets (Callithrix jacchus). Anesthetized marmosets were scanned with a 4.7 T/40 cm horizontal magnet equipped with 450 mT/m magnetic field gradients and a 20 G/cm magnetic field gradient insert, within 3 months of completing the CANTAB serial Reversal Learning task. Neurometabolite concentrations of N-Acetyl Asparate, Myo-Inositol, Choline, Phosphocreatine + creatine, Glutamate and Glutamine were acquired from a 3 mm3 voxel positioned in the Prefrontal Cortex (PFC). Males acquired the reversals (but not simple discriminations) faster than the females. Higher PFC Glx (glutamate + glutamine) concentration was associated with faster acquisition of the reversals. Interestingly, the correlation between cognitive performance and Glx was significant in males, but not in females. These results suggest that MRS is a useful tool to identify biochemical markers of cognitive performance in the healthy nonhuman primate brain and that biological sex modulates the relationship between neurochemical composition and cognition.

Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1.

Axonal degeneration is a critical, early event in many acute and chronic neurological disorders. It has been consistently observed after traumatic brain injury, but whether axon degeneration is a driver of traumatic brain injury remains unclear. Molecular pathways underlying the pathology of traumatic brain injury have not been defined, and there is no efficacious treatment for traumatic brain injury. Here we show that mice lacking the mouse Toll receptor adaptor Sarm1 (sterile α/Armadillo/Toll-Interleukin receptor homology domain protein) gene, a key mediator of Wallerian degeneration, demonstrate multiple improved traumatic brain injury-associated phenotypes after injury in a closed-head mild traumatic brain injury model. Sarm1(-/-) mice developed fewer ß-amyloid precursor protein aggregates in axons of the corpus callosum after traumatic brain injury as compared to Sarm1(+/+) mice. Furthermore, mice lacking Sarm1 had reduced plasma concentrations of the phophorylated axonal neurofilament subunit H, indicating that axonal integrity is maintained after traumatic brain injury. Strikingly, whereas wild-type mice exibited a number of behavioural deficits after traumatic brain injury, we observed a strong, early preservation of neurological function in Sarm1(-/-) animals. Finally, using in vivo proton magnetic resonance spectroscopy we found tissue signatures consistent with substantially preserved neuronal energy metabolism in Sarm1(-/-) mice compared to controls immediately following traumatic brain injury. Our results indicate that the SARM1-mediated prodegenerative pathway promotes pathogenesis in traumatic brain injury and suggest that anti-SARM1 therapeutics are a viable approach for preserving neurological function after traumatic brain injury.

Effects of Recent Concussion on Brain Bioenergetics: A Phosphorus-31 Magnetic Resonance Spectroscopy Study.

BACKGROUND: Although clinical evaluations and neurocognitive assessments are commonly used to evaluate the extent of and recovery from concussion, brain bioenergetics could provide a more quantitative marker. The neurometabolic response to a concussion is thought to increase neuronal energy consumption and thus the demand for nucleoside triphosphate (NTP). OBJECTIVE: We investigated the possible disruption in high-energy metabolism within the prefrontal cortex of college athletes who had either had a concussion within the past 6 months (n=14) or had never had a concussion (n=13). We hypothesized that concussed athletes would have imbalanced brain bioenergetics resulting from increased NTP consumption, and these biochemical changes would correspond to impaired cognitive abilities. METHODS: We used phosphorus-31 magnetic resonance spectroscopy to quantify high-energy phosphates. We performed the neuroimaging in conjunction with neurocognitive assessments targeting prefrontal cortex-mediated tasks. RESULTS: Our results revealed significantly lower γ-NTP levels in the athletes after concussion. Although the concussed and non-concussed participants performed similarly in neurocognitive assessments, lower levels of γ-NTP were associated with worse scores on neurocognitive tasks. CONCLUSIONS: Our results support the concept of increased energy demand in the prefrontal cortex of a concussed brain, and we found that while neurocognitive assessments appear normal, brain energetics may be abnormal. A longitudinal study could help establish brain NTP levels as a biomarker to aid in diagnosis and to assess recovery in concussed patients.

Vitamin D3 Supplemental Treatment for Mania in Youth with Bipolar Spectrum Disorders.

OBJECTIVE: We aimed to determine the effect of an open-label 8 week Vitamin D3 supplementation on manic symptoms, anterior cingulate cortex (ACC) glutamate, and γ-aminobutyric acid (GABA) in youth exhibiting symptoms of mania; that is, patients with bipolar spectrum disorders (BSD). We hypothesized that an 8 week Vitamin D3 supplementation would improve symptoms of mania, decrease ACC glutamate, and increase ACC GABA in BSD patients. Single time point metabolite levels were also evaluated in typically developing children (TD). METHODS: The BSD group included patients not only diagnosed with BD but also those exhibiting bipolar symptomology, including BD not otherwise specified (BD-NOS) and subthreshold mood ratings (Young Mania Rating Scale [YMRS] ≥8 and Clinical Global Impressions - Severity [CGI-S] ≥3). Inclusion criteria were: male or female participants, 6-17 years old. Sixteen youth with BSD exhibiting manic symptoms and 19 TD were included. BSD patients were asked to a take daily dose (2000 IU) of Vitamin D3 (for 8 weeks) as a supplement. Neuroimaging data were acquired in both groups at baseline, and also for the BSD group at the end of 8 week Vitamin D3 supplementation. RESULTS: Baseline ACC GABA/creatine (Cr) was lower in BSD than in TD (F[1,31]=8.91, p=0.007). Following an 8 week Vitamin D3 supplementation, in BSD patients, there was a significant decrease in YMRS scores (t=-3.66, p=0.002, df=15) and Children's Depression Rating Scale (CDRS) scores (t=-2.93, p=0.01, df=15); and a significant increase in ACC GABA (t=3.18, p=0.007, df=14). CONCLUSIONS: Following an 8 week open label trial with Vitamin D3, BSD patients exhibited improvement in their mood symptoms in conjunction with their brain neurochemistry.

Relationship among Glutamine, γ-Aminobutyric Acid, and Social Cognition in Autism Spectrum Disorders.

OBJECTIVE: An imbalance of excitatory and inhibitory neurotransmission in autism spectrum disorder (ASD) has been proposed. We compared glutamate (Glu), glutamine (Gln), and γ-aminobutyric acid (GABA) levels in the anterior cingulate cortex (ACC) of 13 males with ASD and 14 typically developing (TD) males (ages 13-17), and correlated these levels with intelligence quotient (IQ) and measures of social cognition. METHODS: Social cognition was evaluated by administration of the Social Responsiveness Scale (SRS) and the Reading the Mind in the Eyes Test (RMET). We acquired proton magnetic resonance spectroscopy ((1)H-MRS) data from the bilateral ACC using the single voxel point resolved spectroscopy sequence (PRESS) to quantify Glu and Gln, and Mescher-Garwood point-resolved spectroscopy sequence (MEGA-PRESS) to quantify GABA levels referenced to creatine (Cr). RESULTS: There were higher Gln levels (p=0.04), and lower GABA/Cre levels (p=0.09) in the ASD group than in the TD group. There was no difference in Glu levels between groups. Gln was negatively correlated with RMET score (rho=-0.62, p=0.001) and IQ (rho=-0.56, p=0.003), and positively correlated with SRS scores (rho=0.53, p=0.007). GABA/Cre levels were positively correlated with RMET score (rho=0.34, p=0.09) and IQ (rho=0.36, p=0.07), and negatively correlated with SRS score (rho=-0.34, p=0.09). CONCLUSIONS: These data suggest an imbalance between glutamatergic neurotransmission and GABA-ergic neurotransmission in ASD. Higher Gln levels and lower GABA/Cre levels were associated with lower IQ and greater impairments in social cognition across groups.

A resting state functional magnetic resonance imaging study of concussion in collegiate athletes.

Sports-related concussions are currently diagnosed through multi-domain assessment by a medical professional and may utilize neurocognitive testing as an aid. However, these tests have only been able to detect differences in the days to week post-concussion. Here, we investigate a measure of brain function, namely resting state functional connectivity, which may detect residual brain differences in the weeks to months after concussion. Twenty-one student athletes (9 concussed within 6 months of enrollment; 12 non-concussed; between ages 18 and 22 years) were recruited for this study. All participants completed the Wisconsin Card Sorting Task and the Color-Word Interference Test. Neuroimaging data, specifically resting state functional Magnetic Resonance Imaging data, were acquired to examine resting state functional connectivity. Two sample t-tests were used to compare the neurocognitive scores and resting state functional connectivity patterns among concussed and non-concussed participants. Correlations between neurocognitive scores and resting state functional connectivity measures were also determined across all subjects. There were no significant differences in neurocognitive performance between concussed and non-concussed groups. Concussed subjects had significantly increased connections between areas of the brain that underlie executive function. Across all subjects, better neurocognitive performance corresponded to stronger brain connectivity. Even at rest, brains of concussed athletes may have to 'work harder' than their healthy peers to achieve similar neurocognitive results. Resting state brain connectivity may be able to detect prolonged brain differences in concussed athletes in a more quantitative manner than neurocognitive test scores.

Effect of diet on brain metabolites and behavior in spontaneously hypertensive rats.

Attention-deficit hyperactivity disorder (ADHD) is a heterogeneous psychiatric disorder affecting 5-10% of children. One of the suggested mechanisms underlying the pathophysiology of ADHD is insufficient energy supply to neurons. Here, we investigated the role of omega 3 fatty acids in altering neural energy metabolism and behavior of spontaneously hypertensive rats (SHR), which is an animal model of ADHD. To this end, we employed Proton Magnetic Resonance Spectroscopy ((1)H MRS) to evaluate changes in brain neurochemistry in the SHR following consumption of one of three experimental diets (starting PND 21): fish oil enriched (FOE), regular (RD) and animal fat enriched (AFE) diet. Behavioral tests were performed to evaluate differences in locomotor activity and risk-taking behavior (starting PND 44). Comparison of frontal lobe metabolites showed that increased amounts of omega 3 fatty acids decreased total Creatine levels (tCr), but did not change Glutamate (Glu), total N-Acetylaspartate (tNAA), Lactate (Lac), Choline (Cho) or Inositol (Ino) levels. Although behavior was not significantly affected by different diets, significant correlations were observed between brain metabolites and behavior in the open field and elevated plus maze. SHR with higher levels of brain tCr and Glu exhibited greater hyperactivity in a familiar environment. On the other hand, risk-taking exploration of the elevated plus maze's open arms correlated negatively with forebrain tNAA and Lac levels. These findings support the possible alteration in energy metabolites in ADHD, correlating with hyperactivity in the animal model. The data also suggest that omega 3 fatty acids alter brain energy and phospholipid metabolism.

Areas of the brain modulated by single-dose methylphenidate treatment in youth with ADHD during task-based fMRI: a systematic review.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a psychiatric disorder affecting 5% of children. Methylphenidate (MPH) is a common medication for ADHD. Studies examining MPH's effect on pediatric ADHD patients' brain function using functional magnetic resonance imaging (fMRI) have not been compiled. The goals of this systematic review were to determine (1) which areas of the brain in pediatric ADHD patients are modulated by a single dose of MPH, (2) whether areas modulated by MPH differ by task type performed during fMRI data acquisition, and (3) whether changes in brain activation due to MPH relate to clinical improvements in ADHD-related symptoms. METHODS: We searched the electronic databases PubMed and PsycINFO (1967-2011) using the following terms: ADHD AND (methylphenidate OR MPH OR ritalin) AND (neuroimaging OR MRI OR fMRI OR BOLD OR event related), and identified 200 abstracts, 9 of which were reviewed based on predefined criteria. RESULTS: In ADHD patients the middle and inferior frontal gyri, basal ganglia, and cerebellum were most often affected by MPH. The middle and inferior frontal gyri were frequently affected by MPH during inhibitory control tasks. Correlation between brain regions and clinical improvement was not possible due to the lack of symptom improvement measures within the included studies. CONCLUSIONS: Throughout nine task-based fMRI studies investigating MPH's effect on the brains of pediatric patients with ADHD, MPH resulted in increased activation within frontal lobes, basal ganglia, and cerebellum. In most cases, this increase "normalized" activation of at least some brain areas to that seen in typically developing children.

GABAergic neuroactive steroids and resting-state functional connectivity in postpartum depression: a preliminary study.

Postpartum depression (PPD) affects up to 1 in 8 women. The early postpartum period is characterized by a downward physiological shift from relatively elevated levels of sex steroids during pregnancy to diminished levels after parturition. Sex steroids influence functional brain connectivity in healthy non-puerperal subjects. This study tests the hypothesis that PPD is associated with attenuation of resting-state functional connectivity (rs-fc) within corticolimbic regions implicated in depression and alterations in neuroactive steroid concentrations as compared to healthy postpartum women. Subjects (n = 32) were prospectively evaluated during pregnancy and in the postpartum with repeated plasma neuroactive steroid measurements and mood and psychosocial assessments. Healthy comparison subjects (HCS) and medication-free subjects with unipolar PPD (PPD) were examined using functional magnetic resonance imaging (fMRI) within 9 weeks of delivery. We performed rs-fc analysis with seeds placed in the anterior cingulate cortex (ACC), and bilateral amygdala (AMYG), hippocampi (HIPP) and dorsolateral prefrontal cortices (DLPFCs). Postpartum rs-fc and perinatal neuroactive steroid plasma concentrations, quantified by liquid chromatography/mass spectrometry, were compared between groups. PPD subjects showed attenuation of connectivity for each of the tested regions (i.e. ACC, AMYG, HIPP and DLPFC) and between corticocortical and corticolimbic regions vs. HCS. Perinatal concentrations of pregnanolone, allopregnanolone and pregnenolone were not different between groups. This is the first report of a disruption in the rs-fc patterns in medication-free subjects with PPD. This disruption may contribute to the development of PPD, at a time of falling neuroactive steroid concentrations.

Bioenergetic measurements in children with bipolar disorder: a pilot 31P 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.