Multi-Omics Profiling of Human Hippocampus Reveals Increased Inflammation and Transcription Instability in Major Depressive Disorder

Archives of suicide research

Psychiatric diagnosis rates in suicide decedents appear higher in European ancestry populations compared with East Asians. Shared genetic components exist between major depressive disorder (MDD)/schizophrenia (SCZ) and suicide, but no study has compared these shared polygenic architectures between Europeans and East Asians. We compared polygenic risk scores (PRSs) for MDD/SCZ determined from large data sets specific to each ancestry in European and East Asian suicide decedent samples. MDD/SCZ PRSs appeared more prominent in European suicides compared with Japanese suicides. A greater coexistence of psychiatric disorders in European suicide decedents than in East Asian suicide decedents may be partly explained by genetics. Our results are limited by the smaller sample size of our suicide decedents and sample size disparities between the European discovery data set and the …

Biological Psychiatry

BackgroundSuicidal ideation (SI) is associated with higher binding of the translocator protein 18k Da (TSPO), a putative marker of neuroinflammation. However, whether TSPO binding is related to acute emergence of SI and mood symptoms remains unclear. We compared brain TSPO binding in currently depressed subjects with and without history of suicide attempt; and assessed the relationship of TSPO binding to real-time reporting of stressors, suicidal ideation, and negative affect.MethodsFifty-three depressed subjects (n= 15 with prior suicidal behavior) underwent in vivo dynamic PET imaging with 11C-ER176 and concurrent arterial sampling. We quantified a weighted average of TSPO tracer distribution volume (VT) across 11 a priori regions. A subset of n= 21 subjects completed seven consecutive days of ecological momentary assessment (EMA) of their daily stressors, affective responses, and suicidal …

JAMA psychiatry

ImportanceSuicide rates in the US increased by 35.6% from 2001 to 2021. Given that most individuals die on their first attempt, earlier detection and intervention are crucial. Understanding modifiable risk factors is key to effective prevention strategies.ObjectiveTo identify distinct suicide profiles or classes, associated signs of suicidal intent, and patterns of modifiable risks for targeted prevention efforts.Design, Setting, and ParticipantsThis cross-sectional study used data from the 2003-2020 National Violent Death Reporting System Restricted Access Database for 306 800 suicide decedents. Statistical analysis was performed from July 2022 to June 2023.ExposuresSuicide decedent profiles were determined using latent class analyses of available data on suicide circumstances, toxicology, and methods.Main Outcomes and MeasuresDisclosure of recent intent, suicide note presence, and known psychotropic usage …

Cell Reports Medicine

Targeting oncogenes at the genomic DNA level can open new avenues for precision medicine. Significant efforts are ongoing to target oncogenes using RNA-targeted and protein-targeted platforms, but no progress has been made to target genomic DNA for cancer therapy. Here, we introduce a gamma peptide nucleic acid (γPNA)-based genomic DNA-targeted platform to silence oncogenes in vivo. γPNAs efficiently invade the mixed sequences of genomic DNA with high affinity and specificity. As a proof of concept, we establish that γPNA can inhibit c-Myc transcription in multiple cell lines. We evaluate the in vivo efficacy and safety of genomic DNA targeting in three pre-clinical models. We also establish that anti-transcription γPNA in combination with histone deacetylase inhibitors and chemotherapeutic drugs results in robust antitumor activity in cell-line- and patient-derived xenografts. Overall, this strategy offers …

Molecular Psychiatry

Human genetic studies indicate that suicidal ideation and behavior are both heritable. Most studies have examined associations between aberrant gene expression and suicide behavior, but behavior risk is linked to the severity of suicidal ideation. Through a gene network approach, this study investigates how gene co-expression patterns are associated with suicidal ideation and severity using RNA-seq data in peripheral blood from 46 live participants with elevated suicidal ideation and 46 with no ideation. Associations with the presence of suicidal ideation were found within 18 co-expressed modules (p < 0.05), as well as in 3 co-expressed modules associated with suicidal ideation severity (p < 0.05, not explained by severity of depression). Suicidal ideation presence and severity-related gene modules with enrichment of genes involved in defense against microbial infection, inflammation, and adaptive …

Nature Cell Biology

In the version of the article initially published, in Fig. 1b, the week 5 Polyclonal panel was a duplicate of week 6 in the same row. The original files were located, and the authors realised that in the Polyclonal row, the panels labelled weeks 3–5 should have been labelled weeks 4–6 and that the week 3 image was missing. This has now been corrected, and the amended Fig. 1b is shown below as Fig. 1.

Computer Methods and Programs in Biomedicine

Background and objectiveCurrent methods for imaging reconstruction from high-ratio expansion microscopy (ExM) data are limited by anisotropic optical resolution and the requirement for extensive manual annotation, creating a significant bottleneck in the analysis of complex neuronal structures.MethodsWe devised an innovative approach called the IsoGAN model, which utilizes a contrastive unsupervised generative adversarial network to sidestep these constraints. This model leverages multi-scale and isotropic neuron/protein/blood vessel morphology data to generate high-fidelity 3D representations of these structures, eliminating the need for rigorous manual annotation and supervision. The IsoGAN model introduces simplified structures with idealized morphologies as shape priors to ensure high consistency in the generated neuronal profiles across all points in space and scalability for arbitrarily large …

Biological Psychiatry

BackgroundInflammation is associated with major depressive disorder (MDD) and suicidal behavior. Pro-inflammatory cytokines may function by altering hypothalamic-pituitary-adrenal (HPA) axis activity in MDD and suicidal behavior.MethodsMethods: We administered the Trier Social Stress Test (TSST), a well-established paradigm for inducing acute psychosocial stress, in patients with MDD (n= 57) and healthy volunteers (n= 41; HV). Patients in the MDD group were further characterized as suicide attempters (n= 26; SA) or non-attempters (n= 31; NA). Salivary cortisol and serum cytokines were collected at baseline and at additional timepoints during and after stressor in the TSST.ResultsBaseline interferon-gamma (IFN-γ) levels in the MDD SA group were lower (F= 4.036, df= 2, 98, p= 0.02) than in the MDD NA (p= 0.026) and HV (p= 0.049) groups. We did not detect group differences in baseline levels or in the …

International Journal of Neuropsychopharmacology

Objective Explore relationships of acute dissociative effects of intravenous ketamine with change in depression and suicidal ideation and with plasma metabolite levels in a randomized, midazolam-controlled trial. Method Data from a completed trial in suicidal, depressed participants (N=40) randomized to ketamine was used to examine relationships between ketamine treatment-emergent dissociative and psychotomimetic symptoms with pre/post-infusion changes in suicidal ideation and depression severity. Non-parametric correlational statistics were used. These methods were also used to explore associations between dissociative or psychotomimetic symptoms and blood levels of ketamine and metabolites in a subset (N=28) who provided blood samples immediately post-infusion. Results Neither acute dissociative nor psychotomimetic effects of …

In this work we report a -24dB LP11 mode suppression in a 7+1 to 1 Backward Pump-Signal Combiner. The mode content is measured using the S2 -Measurement technique. The high signal beam quality is attributed to a low overlap splice loss between the Tapered Fiber Bundle and the output fiber. The combiner output fiber is large mode area with a LP01 mode effective area of 584 um2.

JAMA Network Open

ImportanceQuestions have emerged as to whether standard intranasal naloxone dosing recommendations (ie, 1 dose with readministration every 2-3 minutes if needed) are adequate in the era of illicitly manufactured fentanyl and its derivatives (hereinafter, fentanyl).ObjectiveTo compare naloxone plasma concentrations between different intranasal naloxone repeat dosing strategies and to estimate their effect on fentanyl overdose.Design, Setting, and ParticipantsThis unblinded crossover randomized clinical trial was conducted with healthy participants in a clinical pharmacology unit (Spaulding Clinical Research, West Bend, Wisconsin) in March 2021. Inclusion criteria included age 18 to 55 years, nonsmoking status, and negative test results for the presence of alcohol or drugs of abuse. Data analysis was performed from October 2021 to May 2023.InterventionNaloxone administered as 1 dose (4 mg/0.1 mL) at 0 …

bioRxiv

Spatial omics holds great potential to elucidate tissue architecture by dissecting underlying cell niches and cellular interactions. However, we lack an end-to-end computational framework that can effectively integrate different spatial omics tissue samples, quantitatively characterize cell niches based on biological knowledge of cell-cell communication and transcriptional regulation pathways, and discover spatial molecular programs of cells. We present NicheCompass, a graph deep learning method designed based on the principles of cellular communication. It utilizes existing knowledge of inter- and intracellular interaction pathways to learn an interpretable latent space of cells across multiple tissue samples, enabling the construction and querying of spatial reference atlases. NicheCompass learns the activity of an interaction pathway by modeling the process through the lens of cells receiving and processing signals from their tissue microenvironment, using a variety of mechanisms involving metabolic interactions, ligand-receptor interactions including downstream regulation, and regulons. In addition to leveraging existing knowledge, NicheCompass can learn novel spatially variable gene programs to model variation in the tissue. We showcase a comprehensive workflow encompassing data integration, niche identification, and functional interpretation, and demonstrate that NicheCompass outperforms existing approaches. NicheCompass is broadly applicable to spatial transcriptomics data, which we illustrate by mapping the architecture of diverse tissues during mouse embryonic development, and delineating basal (KRT14) and luminal …

Bacteria are emerging as living drugs to treat a broad range of disease indications. However, the inherent advantages of these replicating and immunostimulatory therapies also carry the potential for toxicity. Advances in synthetic biology and the integration of nanomedicine can address this challenge through the engineering of controllable systems that regulate spatial and temporal activation for improved safety and efficacy. Here, we review recent progress in nanobiotechnology-driven engineering of bacteria-based therapies, highlighting limitations and opportunities that will facilitate clinical translation.

Biological Psychiatry

BackgroundAntidepressant treatment response is limited in patients with Major Depression (MDD) and comorbid Borderline Personality Disorder (BPD). However, recent studies suggest that intravenous ketamine may be an effective antidepressant treatment in this population. It is unknown if this treatment would be effective in MDD and comorbid BPD if suicidal ideation was elevated.MethodsIntravenous, single infusion ketamine treated patients (. 5 mg/kg) in a recent clinical trial (Grunebaum et al., 2018) examining blinded ketamine’s effects on suicidal thinking in depression included 11 participants with comorbid BPD and a minimum Beck Scale for Suicidal Ideation (SSI) score of 9. Treatment response on the Hamilton Depression Scale (HDRS), Beck Depression Inventory (BDI), Profile of Mood States (POMS), and SSI were compared to 24 MDD non-BPD ketamine-treated participants with comparable SSI scores …

Clinical and Translational Science

Despite a rapid increase in pediatric mortality rate from prescription and illicit opioids, there is limited research on the dose‐dependent impact of opioids on respiratory depression in children, the leading cause of opioid‐associated death. In this article, we extend a previously developed translational model to cover pediatric populations by incorporating age‐dependent pharmacokinetic, pharmacodynamic, and physiological changes compared to adults. Our model reproduced previous perioperative clinical findings that adults and children have similar risk of respiratory depression at the same plasma fentanyl concentration when specific endpoints (minute ventilation, CO2 tension in the blood) were used. However, our model points to a potential caveat that, in a perioperative setting, routine use of mechanical ventilation and supplemental oxygen maintained the blood and tissue oxygen partial pressures in patients …

Identification to Biological Mechanisms Underlying Mood Disorders.’In the face of escalating global rates of mood disorders and their associated morbidity and mortality, improved treatment has never been more critical. Seeking treatment targets for medications identified by the molecular psychopathology of mood disorders is a huge advance over serendipity, which is how most antidepressant medications have been discovered to date. Encouragingly, progress in medical science is gradually illuminating the pathophysiology of mood disorders. For example, the microbiota-brain axis and its role in mediating immune imbalances present a promising frontier.This Research Topic journal issue focuses on neuro-immune regulatory dysfunction related to mood disorders, treatments targeting the gut microbiota, new clinical research on therapeutic mechanisms, and anti-inflammatory treatment studies. These avenues hold the promise of transforming our approach to mood disorder treatments. The Research Topic showcases four papers that delve into the relationship between treatment targets and the biological mechanisms underlying mood disorders. Li et al. dissect olfactory function in patients with bipolar disorder, offering a potential biomarker for early identification and providing nuanced insights into mood disorder subtypes and episodes. In another study, the interplay between inflammation, cytokines, and adolescent Major Depressive Disorder (MDD) was investigated; Maresin-1 was identified as a potential therapeutic target (Qiu et al.). Further, a review examines histamine’s role in

bioRxiv

The serotonin 1A receptor has been linked to both the pathophysiology of major depressive disorder (MDD) and the antidepressant action of serotonin reuptake inhibitors. Most PET studies of the serotonin 1A receptor in MDD used the receptor antagonist radioligand, carbonyl-11CWAY100635 however the interpretation of the combined results has been contentious owing to reports of higher or lower binding in MDD with different outcome measures. The reasons for these divergent results originate from several sources, including properties of the radiotracer itself, which complicate its quantification and interpretation; as well as from previously reported differences between MDD and healthy volunteers in both reference tissue binding and plasma free fraction, which are typically assumed not to differ. Recently, we have developed two novel hierarchical multivariate methods which we validated for the quantification and analysis of 11CWAY100635, which show better accuracy and inferential efficiency compared to standard analysis approaches. Importantly, these new methods should theoretically be more resilient to many of the factors thought to have caused the discrepancies observed in previous studies. We sought to apply these methods in the largest 11CWAY100635 sample to date, consisting of 160 individuals, including 103 MDD patients, of whom 50 were not-recently-medicated and 53 were antidepressant-exposed, as well as 57 healthy volunteers. While the outcome measure discrepancies were substantial using conventional univariate analysis, our multivariate analysis techniques instead yielded highly consistent results across PET …

Cell Reports Medicine

Targeting oncogenes at the genomic DNA level can open new avenues for precision medicine. Significant efforts are ongoing to target oncogenes using RNA-targeted and protein-targeted platforms, but no progress has been made to target genomic DNA for cancer therapy. Here, we introduce a gamma peptide nucleic acid (γPNA)-based genomic DNA-targeted platform to silence oncogenes in vivo. γPNAs efficiently invade the mixed sequences of genomic DNA with high affinity and specificity. As a proof of concept, we establish that γPNA can inhibit c-Myc transcription in multiple cell lines. We evaluate the in vivo efficacy and safety of genomic DNA targeting in three pre-clinical models. We also establish that anti-transcription γPNA in combination with histone deacetylase inhibitors and chemotherapeutic drugs results in robust antitumor activity in cell-line- and patient-derived xenografts. Overall, this strategy offers …

bioRxiv

Vascular malformation, a key clinical phenotype of Proteus syndrome, lacks effective models for pathophysiological study and drug development due to limited patient sample access. To bridge this gap, we built a human vascular organoid model replicating Proteus syndrome's vasculature. Using CRISPR/Cas9 genome editing and gene overexpression, we created induced pluripotent stem cells (iPSCs) embodying the Proteus syndrome-specific AKTE17K point mutation for organoid generation. Our findings revealed that AKT overactivation in these organoids resulted in smaller sizes yet increased vascular connectivity, although with less stable connections. This could be due to the significant vasculogenesis induced by AKT overactivation. This phenomenon likely stems from boosted vasculogenesis triggered by AKT overactivation, leading to increased vascular sprouting. Additionally, a notable increase in dysfunctional PDGFRbeta+ mural cells, impaired in matrix secretion, was observed in these AKT-overactivated organoids. The application of AKT inhibitors (ARQ092, AZD5363, or GDC0068) reversed the vascular malformations; the inhibitors' effectiveness was directly linked to reduced connectivity in the organoids. In summary, our study introduces an innovative in vitro model combining organoid technology and gene editing to explore vascular pathophysiology in Proteus syndrome. This model not only simulates Proteus syndrome vasculature but also holds potential for mimicking vasculatures of other genetically driven diseases. It represents an advance in drug development for rare diseases, historically plagued by slow progress.

Biological Psychiatry

BackgroundDeep brain stimulation (DBS) for obsessive-compulsive disorder (OCD) achieves clinical benefit in 66% of treatment-resistant patients. However, there is still a lack of a fundamental understanding of the neurophysiological basis of the relationship between OCD behavior and neural activity. Recent advances in surgical neuromodulation have enabled continuous monitoring of neural activity during everyday activities. Here, our goal was to use these passive, continuous recordings to better understand the neurophysiological basis of clinical response after DBS for OCD.MethodsIn five individuals with treatment-resistant OCD receiving DBS targeted to the ventral striatum (VS), we recorded local field potential power in the alpha-theta (9 Hz) band in continuous 10-minute intervals for several months (before DBS: 25±20 days, after DBS: 184±86 days).ResultsOur results reveal neurophysiological features …

Biological Psychiatry

BackgroundComparative research suggests that the hypothalamus is critical in switching between survival behaviors such as avoidance and hunting and it has been recently known as an “anxiety center”. However, the role of hypothalamus in humans is unclear due to the lack of naturalistic experimental paradigms and the difficulty of investigating human hypothalamic signals given its small size and low tissue contrast.MethodsWe introduce a gamified experimental paradigm where participants switch between hunting virtual prey and escaping from virtual predators. Deep learning-based segmentation enabled identifying individual-specific hypothalamus and the imaging sequence was optimized for hypothalamic signal acquisition. We investigated how hypothalamus and its connected regions encode switching using Multi-voxel pattern analysis (MVPA) and multi-voxel connectivity analysis. Computational …

Biological Psychiatry

BackgroundDespite knowledge of distal risk factors for suicide (ie, childhood maltreatment), there is a dearth of developmentally informed psychobiological theories of suicide that test potentially modifiable proximal risk factors. Utilizing a short-term longitudinal design, this study investigates two potentially modifiable cognitive risk factors for suicidal ideation following childhood maltreatment: elevated threat and lower reward sensitivity.MethodsUndergraduates (n= 839) completed a screener assessing trait reward and threat sensitivities, history of suicidal thoughts and behaviors (STBs), and childhood maltreatment. Utilizing ecological momentary assessment (EMA), a high-risk subset of participants (n= 45; observations= 1,343; history of suicidal ideation= 100%, clinically relevant depression= 60%, anxiety= 57.8%) completed daily measures (three per day) of STBs and state reward and threat sensitivities for two …

Biological Psychiatry

BackgroundSensory symptoms are a core feature of autism spectrum disorder (ASD). Sensory information is known to be gated by subcortical structures and modulated by cortical signals such as alpha-band oscillations. Here we investigated the potential relationship between volumetric measures of subcortical nuclei and alpha power, and their association with sensory measures.MethodsParticipants included 29 autistic adults (Mage= 24±3 years; 17 female, 12 male) and 23 typically-developing controls (Mage= 23±3 years; 11 female, 12 male). Participants underwent a T1-weighted MRI scan to provide neuroanatomical metrics, EEG recordings to measure alpha oscillations, and completed the Adult Sensory Profile-2 self-report questionnaire of sensory symptoms. The EEG paradigm consisted of 50 thirty-second trials with flickering bilateral checkerboards visually presented for 10 seconds separated by 20 …

Biological Psychiatry

BackgroundThe ability to learn and adapt to changing social norms is integral to healthy social functioning. Norms are learned through experience, whereby norm prediction errors, or the differences between predicted and experienced norms, drive internal norm adaptation. Previous work has mostly relied on noninvasive methods such as imaging, which identify macro-scale cortical circuits involved in norm adaptation but typically leave micro-structures in subcortical regions unexamined. Here, we leverage behavioral modeling and single-unit recording to determine the computational roles of single neurons in the substantia nigra, a midbrain region whose activity is difficult to measure with imaging, in norm adaptation.MethodsWe collected substantia nigra single-unit recordings in neurosurgery patients as they played an iterative ultimatum game with “human” and “computer” partners. Using computational modeling …

Biological psychiatry

BackgroundThe psychopathological syndrome of formal thought disorder (FTD) is not only present in schizophrenia (SZ), but also highly prevalent in major depressive disorder and bipolar disorder. It remains unknown how alterations in the structural white matter connectome of the brain correlate with psychopathological FTD dimensions across affective and psychotic disorders.MethodsUsing FTD items of the Scale for the Assessment of Positive Symptoms and Scale for the Assessment of Negative Symptoms, we performed exploratory and confirmatory factor analyses in 864 patients with major depressive disorder (n = 689), bipolar disorder (n = 108), or SZ (n = 67) to identify psychopathological FTD dimensions. We used T1- and diffusion-weighted magnetic resonance imaging to reconstruct the structural connectome of the brain. To investigate the association of FTD subdimensions and global structural …

Biological psychiatry

BackgroundCarriers of the 1q21.1 distal and 15q11.2 BP1-BP2 copy number variants exhibit regional and global brain differences compared with noncarriers. However, interpreting regional differences is challenging if a global difference drives the regional brain differences. Intraindividual variability measures can be used to test for regional differences beyond global differences in brain structure.MethodsMagnetic resonance imaging data were used to obtain regional brain values for 1q21.1 distal deletion (n = 30) and duplication (n = 27) and 15q11.2 BP1-BP2 deletion (n = 170) and duplication (n = 243) carriers and matched noncarriers (n = 2350). Regional intra-deviation scores, i.e., the standardized difference between an individual’s regional difference and global difference, were used to test for regional differences that diverge from the global difference.ResultsFor the 1q21.1 distal deletion carriers, cortical …

Biological Psychiatry

Functional magnetic resonance imaging connectivity measures have been used to identify and optimize brain circuit targets for neuromodulation treatments such as transcranial magnetic stimulation (TMS) and deep brain stimulation (1, 2). This approach leverages interconnected brain networks to assess convergence across treatment modalities and datasets (3). For example, brain lesions causing depression and neuromodulation sites relieving depression functionally connect to a similar brain network across 14 independent datasets (4). This convergent causal depression circuit was derived with a normative functional connectome database from 1000 healthy adults (5).Age is one of many factors that have been explored as connectomic variables (6, 7). Adult connectome databases are frequently used to retrospectively evaluate or prospectively identify targets for TMS clinical trials in adults based on resting-state …

Biological Psychiatry

BackgroundAntidepressant response to ketamine is greatest in patients with a family history of alcohol use disorder (AUD), however it remains unclear if this is true for a personal history of alcohol use. The purpose of this study is to confirm if an individual history of alcohol use can predict antidepressant response to ketamine.MethodsThis was a retrospective cohort study of patients with Major Depressive Disorder (MDD) that received intravenous ketamine. As a comparator, we also studied patients receiving electroconvulsive therapy (ECT) at the same center. Depression was quantified using the Quick Inventory of Depressive Symptomatology (QIDS), and alcohol use was quantified using the Alcohol Use Disorder Identification Test question 3 (AUDIT-3).Results178 patients completed the initial course of three ketamine treatments, and 1851 patients received at least 10 ECT treatments. With ketamine, history of …

Biological Psychiatry

BackgroundTranscranial magnetic stimulation (TMS) and deep brain stimulation (DBS) can treat some neuropsychiatric disorders, but anatomical targets for anxiety remain unclear. Lesion network mapping can be used to optimize existing targets but has not been shown to identify novel effective targets.MethodsAcross seven datasets (n= 936), we used a normative connectome database (n= 1000) to estimate connectivity of lesions and stimulation sites that modify anxiety independent of depression. Datasets included incidental brain lesions, routine clinical TMS sites which show incidental variability in location, TMS sites in a clinical trial that targeted a specific brain coordinate but measured incidental variability in brain connectivity, and subthalamic DBS sites in Parkinson's disease.ResultsLesions (n= 451) and TMS sites (n= 111) that modify anxiety were connected to a common normative brain circuit (p= 0.01). In …

Biological Psychiatry

BackgroundRetrospective analyses of causal neuroimaging data suggest that “dysphoric” versus “anxiosomatic” depressive symptoms preferentially respond to different TMS targets within the prefrontal cortex (PFC). However, symptom-specific modulation has never been tested prospectively.MethodsIn this double-blind randomized controlled trial, 31 individuals with comorbid depression and anxiety received 6 weeks (30 treatments) of repetitive transcranial magnetic stimulation (rTMS) using traditional parameters (eg, 10Hz frequency, 3000 pulses per treatment). Participants were randomly assigned to receive MRI-based neuronavigated rTMS at the “dysphoric” target in dorsolateral PFC or the “anxiosomatic” target in dorsomedial PFC. Participants and raters were blinded to group assignment. Our primary outcome measure was the rank-transformed ratio of Beck Depression Inventory (BDI) to Beck Anxiety …

Biological Psychiatry

BackgroundNormalization of aberrant functional connectivity may underlie the antidepressant effects of repetitive transcranial magnetic stimulation (rTMS). The underlying molecular basis of such changes remains unknown, limiting discovery and evaluation of therapeutic targets. Using proton magnetic resonance spectroscopy, we evaluated how neurometabolites related to seed-based whole-brain connectivity and corresponding depression symptoms prior to and following rTMS.MethodsRight dorsal anterior cingulate (dACC) glutamate (Glu) and Glx metabolite concentrations, resting state functional connectivity (11 min runs x 2), and depression symptom domains from the Inventory of Depression Symptomatology-Self Report scale were measured before (n= 25) and after (n= 17) a standard course of 10Hz rTMS to the left dorsolateral prefrontal cortex. Seeds were constructed from average dACC voxel placement …

Biological Psychiatry

BackgroundEpidemiological studies suggest that maternal diet quality during pregnancy may influence the risk of neurodevelopmental disorders in offspring. Here, we investigated associations between maternal intake of dietary fiber and attention-deficit/hyperactivity disorder (ADHD) symptoms in early childhood.MethodsWe used longitudinal data of up to 21,852 mother-father-child trios (49.2% female offspring) from MoBa (the Norwegian Mother, Father, and Child Cohort Study). The relationships between maternal fiber intake during pregnancy and offspring ADHD symptoms at ages 3, 5, and 8 years were examined using 1) multivariate regression (overall levels of ADHD symptoms), 2) latent class analysis (subclasses of ADHD symptoms by sex at each age), and 3) latent growth curves (longitudinal change in offspring ADHD symptoms). Covariates were ADHD polygenic scores in child and parents, total energy …

Biological Psychiatry

BackgroundNo treatments exist for pathologically elevated risky decision-making (RDM), likely due to insufficient mechanistic knowledge. The Iowa Gambling Task (IGT) quantifies RDM in clinical populations and animal models. The anterior cingulate cortex (ACC) is implicated in IGT performance in healthy humans. We investigated ACC regulation of specific RDM-related behaviors by chemogenetically inhibiting it in mice performing the IGT.MethodsWe virally expressed the inhibitory DREADD (designer receptor exclusively activated by designer drugs) hM4Di (AAV8-hSyn-hM4Di-mCherry; n= 13) or control protein mCherry (AAV8-hSyn-mCherry; n= 10) in ACC of female and male C57BL/6J mice. Deschloroclozapine (DCZ; 0 or 0.1 mg/kg; within-subjects) was administered to temporarily inhibit ACC before a single 60-min IGT session. Consistent with human testing, the IGT presented four options (illuminated …

Biological Psychiatry

BackgroundPsychosocial experiences affect children's development and health. Urban environments in particular expose children to chronic stress, which impacts the HPA axis and leads to an altered glucocorticoid response. Because glucocorticoids have a major anti-inflammatory action, negative psychosocial experiences may be associated with immunological disorders, including asthma. However, the molecular mechanisms underlying the effect of negative psychosocial experiences on asthma and their interaction with genetic risk remain unknown.MethodsWe have established a longitudinal cohort in Metropolitan Detroit, composed of> 250 children with asthma, most of whom identify as African American. We have collected clinical, psychosocial, and genetic data, bulk and single-cell gene expression, and chromatin accessibility in peripheral blood mononuclear cells. We used a generalized linear model with …

Biological Psychiatry

BackgroundSerotonergic psychedelics, such as psilocybin, alter perceptual and cognitive systems that are functionally integrated with the amygdala. These changes can alter cognition and emotions that are hypothesised to contribute to their therapeutic utility. However, the neural mechanisms of cognitive and subcortical systems altered by psychedelics are not well understood.MethodsWe used functional MRI resting state images collected during a randomised, double-blinded, placebo-controlled clinical trial of 24 healthy adults under 0.2mg/kg psilocybin to estimate the directed (i.e., effective) changes between the amygdala and three large-scale resting-state networks involved in cognition. These networks are the default mode network (DMN), the salience network (SN), and the central executive network (CEN).ResultsWe found a pattern of decreased top-down effective connectivity from these resting-state …

Biological Psychiatry

BackgroundAdvances in precision imaging suggest that strong neuro-behavior associations can be found using dense sampling of individuals exhibiting severe symptoms, while large sample sizes are critical for replicating neuro-behavior associations. It remains unclear whether the sample characteristics, such as symptom severity, and sample size have a unique or additive impact on the reproducibility of neuro-symptom relationship.MethodsWe analyzed resting-state functional magnetic resonance imaging (rs-fMRI) and 32 symptom variables from the Philadelphia Neurodevelopmental Cohort dataset (n= 1,216, 8-21 y/o). 350 subjects were identified as the psychosis group. Principal component analysis (PCA) of symptom variables identified data-driven PCs and individual PC scores. Individual global brain connectivity (GBC) was estimated by averaging Pearson's correlation values between the rs-fMRI time …

Biological Psychiatry

BackgroundIndividuals with post-traumatic stress disorder (PTSD) often exhibit dysregulation of the autonomic nervous system (ANS), characterized by heightened sympathetic nervous system (SNS) activity or reduced parasympathetic nervous system activity (PNS), which may contribute to the hyperarousal and hypervigilance symptoms commonly observed in PTSD. Additionally, altered ANS functioning has been associated with the severity and persistence of PTSD symptoms. However, most studies have included only one measure of the ANS (ie, SNS or PNS) without attention to the role of ANS coordination.MethodsThis study examines the impact of ANS coordination (ie, reciprocal activation of the SNS and PNS) on the association between childhood maltreatment (CM) and self-reported PTSD symptoms in a sample of 97 adolescents, ages 10-15. Sympathetic and parasympathetic nervous system activity were …

Biological Psychiatry

BackgroundSocial cognition encompasses the psychological processes that allow people to interact with others and harness social support. While there is evidence of brain volume reduction in pregnancy in areas involving social cognition, there is limited research examining social cognition in pregnancy and its link with social support. We aimed to assess social cognition in pregnancy and postpartum and a potential correlation with perceived social support.MethodsParticipants completed the Movie for the Assessment of Social Cognition (MASC) and the Interpersonal Support Evaluation List (ISEL) which assesses 4 domains of perceived social support (appraisal, tangible, self-esteem, and belonging) during the third trimester of pregnancy and at three months postpartum. Paired Sample T-test compared MASC accuracy scores for those who completed the MASC at both across time points (n= 53). The Pearson …

Biological Psychiatry

BackgroundRacial discrimination (RD) is a chronic stressor that can influence biological adaptations, including functional changes in threat-related neural networks and epigenetic alterations that reflect advanced cellular aging. We examined associations between RD, resting-state functional connectivity, and DNA methylation age (Horvath's clock) in a sample of trauma-exposed Black American women.MethodsNinety adult Black American women (age 18-62 years) recruited as part of a long-standing study of trauma, the Grady Trauma Project, completed assessments of RD, trauma and posttraumatic stress disorder (PTSD) and underwent resting-state fMRI. Blood samples were collected for DNA methylation/Horvath's clock calculation in a subset (n= 49). Seed-to-voxel connectivity analyses were performed (using the CONN toolbox) with a brainstem seed region critically involved with threat response, the locus …