Reciprocal relationships between stress and depressive symptoms: the essential role of the nucleus accumbens.

BACKGROUND: Stress and depression have a reciprocal relationship, but the neural underpinnings of this reciprocity are unclear. We investigated neuroimaging phenotypes that facilitate the reciprocity between stress and depressive symptoms. METHODS: In total, 22 195 participants (52.0% females) from the population-based UK Biobank study completed two visits (initial visit: 2006-2010, age = 55.0 ± 7.5 [40-70] years; second visit: 2014-2019; age = 62.7 ± 7.5 [44-80] years). Structural equation modeling was used to examine the longitudinal relationship between self-report stressful life events (SLEs) and depressive symptoms. Cross-sectional data were used to examine the overlap between neuroimaging correlates of SLEs and depressive symptoms on the second visit among 138 multimodal imaging phenotypes. RESULTS: Longitudinal data were consistent with significant bidirectional causal relationship between SLEs and depressive symptoms. In cross-sectional analyses, SLEs were significantly associated with lower bilateral nucleus accumbal volume and lower fractional anisotropy of the forceps major. Depressive symptoms were significantly associated with extensive white matter hyperintensities, thinner cortex, lower subcortical volume, and white matter microstructural deficits, mainly in corticostriatal-limbic structures. Lower bilateral nucleus accumbal volume were the only imaging phenotypes with overlapping effects of depressive symptoms and SLEs (B = -0.032 to -0.023, p = 0.006-0.034). Depressive symptoms and SLEs significantly partially mediated the effects of each other on left and right nucleus accumbens volume (proportion of effects mediated = 12.7-14.3%, p < 0.001-p = 0.008). For the left nucleus accumbens, post-hoc seed-based analysis showed lower resting-state functional connectivity with the left orbitofrontal cortex (cluster size = 83 voxels, p = 5.4 × 10-5) in participants with high v. no SLEs. CONCLUSIONS: The nucleus accumbens may play a key role in the reciprocity between stress and depressive symptoms.

Esketamine in depression: putative biomarkers from clinical research.

The discovery of racemic (R, S)-ketamine as a rapid-acting antidepressant and the subsequent FDA approval of its (S)-enantiomer, esketamine, for treatment-resistant depression (TRD) are significant advances in the development of novel neuropsychiatric therapeutics. Esketamine is now recognized as a powerful tool for addressing persistent symptoms of TRD compared to traditional oral antidepressants. However, research on biomarkers associated with antidepressant response to esketamine has remained sparse and, to date, has been largely extrapolated from racemic ketamine studies. Genetic, proteomic, and metabolomic profiles suggest that inflammation and mitochondrial function may play a role in esketamine's antidepressant effects, though these preliminary results require verification. In addition, neuroimaging research has consistently implicated the prefrontal cortex, striatum, and anterior cingulate cortex in esketamine's effects. Esketamine also shows promise in perioperative settings for reducing depression and anxiety, and these effects appear to correlate with increased peripheral biomarkers such as brain-derived neurotrophic factor and serotonin. Further indications are likely to be identified with the continued repurposing of racemic ketamine, providing further opportunity for biomarker study and mechanistic understanding of therapeutic effects. Novel methodologies and well-designed biomarker-focused clinical research trials are needed to more clearly elucidate esketamine's therapeutic actions as well as biologically identify those most likely to benefit from this agent, allowing for the improved personalization of antidepressant treatment.

Reward behaviour is regulated by the strength of hippocampus-nucleus accumbens synapses.

Reward drives motivated behaviours and is essential for survival, and therefore there is strong evolutionary pressure to retain contextual information about rewarding stimuli. This drive may be abnormally strong, such as in addiction, or weak, such as in depression, in which anhedonia (loss of pleasure in response to rewarding stimuli) is a prominent symptom. Hippocampal input to the shell of the nucleus accumbens (NAc) is important for driving NAc activity1,2 and activity-dependent modulation of the strength of this input may contribute to the proper regulation of goal-directed behaviours. However, there have been few robust descriptions of the mechanisms that underlie the induction or expression of long-term potentiation (LTP) at these synapses, and there is, to our knowledge, no evidence about whether such plasticity contributes to reward-related behaviour. Here we show that high-frequency activity induces LTP at hippocampus-NAc synapses in mice via canonical, but dopamine-independent, mechanisms. The induction of LTP at this synapse in vivo drives conditioned place preference, and activity at this synapse is required for conditioned place preference in response to a natural reward. Conversely, chronic stress, which induces anhedonia, decreases the strength of this synapse and impairs LTP, whereas antidepressant treatment is accompanied by a reversal of these stress-induced changes. We conclude that hippocampus-NAc synapses show activity-dependent plasticity and suggest that their strength may be critical for contextual reward behaviour.

Association between brain similarity to severe mental illnesses and comorbid cerebral, physical, and cognitive impairments.

Severe mental illnesses (SMIs) are often associated with compromised brain health, physical comorbidities, and cognitive deficits, but it is incompletely understood whether these comorbidities are intrinsic to SMI pathophysiology or secondary to having SMIs. We tested the hypothesis that cerebral, cardiometabolic, and cognitive impairments commonly observed in SMIs can be observed in non-psychiatric individuals with SMI-like brain patterns of deviation as seen on magnetic resonance imaging. 22,883 participants free of common neuropsychiatric conditions from the UK Biobank (age = 63.4 ± 7.5 years, range = 45-82 years, 50.9% female) were split into discovery and replication samples. The regional vulnerability index (RVI) was used to quantify each participant's respective brain similarity to meta-analytical patterns of schizophrenia spectrum disorder, bipolar disorder, and major depressive disorder in gray matter thickness, subcortical gray matter volume, and white matter integrity. Cluster analysis revealed five clusters with distinct RVI profiles. Compared with a cluster with no RVI elevation, a cluster with RVI elevation across all SMIs and brain structures showed significantly higher volume of white matter hyperintensities (Cohen's d = 0.59, pFDR < 10-16), poorer cardiovascular (Cohen's d = 0.30, pFDR < 10-16) and metabolic (Cohen's d = 0.12, pFDR = 1.3 × 10-4) health, and slower speed of information processing (|Cohen's d| = 0.11-0.17, pFDR = 1.6 × 10-3-4.6 × 10-8). This cluster also had significantly higher level of C-reactive protein and alcohol use (Cohen's d = 0.11 and 0.28, pFDR = 4.1 × 10-3 and 1.1 × 10-11). Three other clusters with respective RVI elevation in gray matter thickness, subcortical gray matter volume, and white matter integrity showed intermediate level of white matter hyperintensities, cardiometabolic health, and alcohol use. Our results suggest that cerebral, physical, and cognitive impairments in SMIs may be partly intrinsic via shared pathophysiological pathways with SMI-related brain anatomical changes.

Brain deficit patterns of metabolic illnesses overlap with those for major depressive disorder: A new metric of brain metabolic disease.

Metabolic illnesses (MET) are detrimental to brain integrity and are common comorbidities in patients with mental illnesses, including major depressive disorder (MDD). We quantified effects of MET on standard regional brain morphometric measures from 3D brain MRI as well as diffusion MRI in a large sample of UK BioBank participants. The pattern of regional effect sizes of MET in non-psychiatric UKBB subjects was significantly correlated with the spatial profile of regional effects reported by the largest meta-analyses in MDD but not in bipolar disorder, schizophrenia or Alzheimer's disease. We used a regional vulnerability index (RVI) for MET (RVI-MET) to measure individual's brain similarity to the expected patterns in MET in the UK Biobank sample. Subjects with MET showed a higher effect size for RVI-MET than for any of the individual brain measures. We replicated elevation of RVI-MET in a sample of MDD participants with MET versus non-MET. RVI-MET scores were significantly correlated with the volume of white matter hyperintensities, a neurological consequence of MET and age, in both groups. Higher RVI-MET in both samples was associated with obesity, tobacco smoking and frequent alcohol use but was unrelated to antidepressant use. In summary, MET effects on the brain were regionally specific and individual similarity to the pattern was more strongly associated with MET than any regional brain structural metric. Effects of MET overlapped with the reported brain differences in MDD, likely due to higher incidence of MET, smoking and alcohol use in subjects with MDD.

Frontal white matter association with sleep quality and the role of stress.

An important measure of brain health is the integrity of white matter connectivity structures that link brain regions. Studies have found an association between poorer sleep quality and decreased white matter integrity. Stress is among the strongest predictors of sleep quality. This study aimed to evaluate the association between sleep quality and white matter and to test if the relationship persisted after accounting for stress. White matter microstructures were measured by diffusion tensor imaging in a population of Old Order Amish/Mennonite (N = 240). Sleep quality was determined by the Pittsburgh Sleep Quality Index. Current stress levels were measured by the perceived stress scale. Exposure to lifetime stress was measured by the lifetime stressor inventory. Microstructures of four white matter tracts: left and right anterior limbs of internal capsule, left anterior corona radiata, and genu of corpus callosum were significantly correlated with sleep quality (all p ≤ 0.001). The current stress level was a significant predictor of sleep quality (p ≤ 0.001) while lifetime stress was not. PSQI remained significantly associated with white matter integrity in these frontal tracts (all p < 0.01) after accounting for current stress and lifetime stress, while current and lifetime stress were not significant predictors of white matter in any of the four models. Sleep quality did not have any substantial mediation role between stress and white matter integrity. Sleep quality was significantly associated with several frontal white matter tracts that connect brain structures important for sleep regulation regardless of current or past stress levels.

Cerebral blood flow and cardiovascular risk effects on resting brain regional homogeneity.

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10-3) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10-6) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10-6). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10-27). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors.

The additive impact of cardio-metabolic disorders and psychiatric illnesses on accelerated brain aging.

Severe mental illnesses (SMI) including major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia spectrum disorder (SSD) elevate accelerated brain aging risks. Cardio-metabolic disorders (CMD) are common comorbidities in SMI and negatively impact brain health. We validated a linear quantile regression index (QRI) approach against the machine learning "BrainAge" index in an independent SSD cohort (N = 206). We tested the direct and additive effects of SMI and CMD effects on accelerated brain aging in the N = 1,618 (604 M/1,014 F, average age = 63.53 ± 7.38) subjects with SMI and N = 11,849 (5,719 M/6,130 F; 64.42 ± 7.38) controls from the UK Biobank. Subjects were subdivided based on diagnostic status: SMI+/CMD+ (N = 665), SMI+/CMD- (N = 964), SMI-/CMD+ (N = 3,765), SMI-/CMD- (N = 8,083). SMI (F = 40.47, p = 2.06 × 10-10 ) and CMD (F = 24.69, p = 6.82 × 10-7 ) significantly, independently impacted whole-brain QRI in SMI+. SSD had the largest effect (Cohen's d = 1.42) then BD (d = 0.55), and MDD (d = 0.15). Hypertension had a significant effect on SMI+ (d = 0.19) and SMI- (d = 0.14). SMI effects were direct, independent of MD, and remained significant after correcting for effects of antipsychotic medications. Whole-brain QRI was significantly (p < 10-16 ) associated with the volume of white matter hyperintensities (WMH). However, WMH did not show significant association with SMI and was driven by CMD, chiefly hypertension (p < 10-16 ). We used a simple and robust index, QRI, the demonstrate additive effect of SMI and CMD on accelerated brain aging. We showed a greater effect of psychiatric illnesses on QRI compared to cardio-metabolic illness. Our findings suggest that subjects with SMI should be among the targets for interventions to protect against age-related cognitive decline.

Brain-wide versus genome-wide vulnerability biomarkers for severe mental illnesses.

Severe mental illnesses (SMI), including major depressive (MDD), bipolar (BD), and schizophrenia spectrum (SSD) disorders have multifactorial risk factors and capturing their complex etiopathophysiology in an individual remains challenging. Regional vulnerability index (RVI) was used to measure individual's brain-wide similarity to the expected SMI patterns derived from meta-analytical studies. It is analogous to polygenic risk scores (PRS) that measure individual's similarity to genome-wide patterns in SMI. We hypothesized that RVI is an intermediary phenotype between genome and symptoms and is sensitive to both genetic and environmental risks for SMI. UK Biobank sample of N = 17,053/19,265 M/F (age = 64.8 ± 7.4 years) and an independent sample of SSD patients and controls (N = 115/111 M/F, age = 35.2 ± 13.4) were used to test this hypothesis. UKBB participants with MDD had significantly higher RVI-MDD (Cohen's d = 0.20, p = 1 × 10-23 ) and PRS-MDD (d = 0.17, p = 1 × 10-15 ) than nonpsychiatric controls. UKBB participants with BD and SSD showed significant elevation in the respective RVIs (d = 0.65 and 0.60; p = 3 × 10-5 and .009, respectively) and PRS (d = 0.57 and 1.34; p = .002 and .002, respectively). Elevated RVI-SSD were replicated in an independent sample (d = 0.53, p = 5 × 10-5 ). RVI-MDD and RVI-SSD but not RVI-BD were associated with childhood adversity (p < .01). In nonpsychiatric controls, elevation in RVI and PRS were associated with lower cognitive performance (p < 10-5 ) in six out of seven domains and showed specificity with disorder-associated deficits. In summary, the RVI is a novel brain index for SMI and shows similar or better specificity for SMI than PRS, and together they may complement each other in the efforts to characterize the genomic to brain level risks for SMI.

Comparing empirical kinship derived heritability for imaging genetics traits in the UK biobank and human connectome project.

Imaging genetics analyses use neuroimaging traits as intermediate phenotypes to infer the degree of genetic contribution to brain structure and function in health and/or illness. Coefficients of relatedness (CR) summarize the degree of genetic similarity among subjects and are used to estimate the heritability - the proportion of phenotypic variance explained by genetic factors. The CR can be inferred directly from genome-wide genotype data to explain the degree of shared variation in common genetic polymorphisms (SNP-heritability) among related or unrelated subjects. We developed a central processing and graphics processing unit (CPU and GPU) accelerated Fast and Powerful Heritability Inference (FPHI) approach that linearizes likelihood calculations to overcome the ∼N2-3 computational effort dependency on sample size of classical likelihood approaches. We calculated for 60 regional and 1.3 × 105 voxel-wise traits in N = 1,206 twin and sibling participants from the Human Connectome Project (HCP) (550 M/656 F, age = 28.8 ± 3.7 years) and N = 37,432 (17,531 M/19,901 F; age = 63.7 ± 7.5 years) participants from the UK Biobank (UKBB). The FPHI estimates were in excellent agreement with heritability values calculated using Genome-wide Complex Trait Analysis software (r = 0.96 and 0.98 in HCP and UKBB sample) while significantly reducing computational (102-4 times). The regional and voxel-wise traits heritability estimates for the HCP and UKBB were likewise in excellent agreement (r = 0.63-0.76, p < 10-10). In summary, the hardware-accelerated FPHI made it practical to calculate heritability values for voxel-wise neuroimaging traits, even in very large samples such as the UKBB. The patterns of additive genetic variance in neuroimaging traits measured in a large sample of related and unrelated individuals showed excellent agreement regardless of the estimation method. The code and instruction to execute these analyses are available at www.solar-eclipse-genetics.org.

Motor neuron disease, TDP-43 pathology, and memory deficits in mice expressing ALS-FTD-linked UBQLN2 mutations.

Missense mutations in ubiquilin 2 (UBQLN2) cause ALS with frontotemporal dementia (ALS-FTD). Animal models of ALS are useful for understanding the mechanisms of pathogenesis and for preclinical investigations. However, previous rodent models carrying UBQLN2 mutations failed to manifest any sign of motor neuron disease. Here, we show that lines of mice expressing either the ALS-FTD-linked P497S or P506T UBQLN2 mutations have cognitive deficits, shortened lifespans, and develop motor neuron disease, mimicking the human disease. Neuropathologic analysis of the mice with end-stage disease revealed the accumulation of ubiquitinated inclusions in the brain and spinal cord, astrocytosis, a reduction in the number of hippocampal neurons, and reduced staining of TAR-DNA binding protein 43 in the nucleus, with concomitant formation of ubiquitin+ inclusions in the cytoplasm of spinal motor neurons. Moreover, both lines displayed denervation muscle atrophy and age-dependent loss of motor neurons that correlated with a reduction in the number of large-caliber axons. By contrast, two mouse lines expressing WT UBQLN2 were mostly devoid of clinical and pathological signs of disease. These UBQLN2 mouse models provide valuable tools for identifying the mechanisms underlying ALS-FTD pathogenesis and for investigating therapeutic strategies to halt disease.

Demyelination as a harbinger of lymphoma: a case report and review of primary central nervous system lymphoma preceded by multifocal sentinel demyelination.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) may rarely be preceded by "sentinel demyelination," a pathologic entity characterized by histologically confirmed demyelinating inflammatory brain lesions that mimic multiple sclerosis (MS) or acute disseminated encephalomyelitis (ADEM). Interpreting the overlapping radiologic and clinical characteristics associated with each of these conditions-contrast-enhancing demyelination of white matter and relapsing and remitting steroid-responsive symptoms respectively-can be a significant diagnostic challenge. CASE PRESENTATION: We describe a 57-year-old woman with an unusual clinical course who presented with multi-focal enhancing white matter lesions demonstrated to be inflammatory demyelination by brain biopsy. Despite a good initial response to steroids and rituximab for treatment of presumed tumefactive multiple sclerosis, the patient's condition rapidly deteriorated, and a repeat brain biopsy six months later was consistent with a diagnosis of diffuse large B-cell lymphoma. CONCLUSIONS: Early clinical suspicion for PCNSL and awareness that biopsied lesions may initially show sentinel demyelination suggestive of alternate diagnoses may be essential for early initiation of appropriate therapies and mitigation of disease progression. Clinical, pathophysiological, and diagnostic aspects of sentinel demyelination and PCNSL are discussed.

Corticosterone mediates the synaptic and behavioral effects of chronic stress at rat hippocampal temporoammonic synapses.

Chronic stress is thought to impart risk for depression via alterations in brain structure and function, but contributions of specific mediators in generating these changes remain unclear. We test the hypothesis that stress-induced increases in corticosterone (CORT), the primary rodent glucocorticoid, are the key mediator of stress-induced depressive-like behavioral changes and synaptic dysfunction in the rat hippocampus. In rats, we correlated changes in cognitive and affective behavioral tasks (spatial memory consolidation, anhedonia, and neohypophagia) with impaired excitatory strength at temporoammonic-CA1 (TA-CA1) synapses, an archetypical stress-sensitive excitatory synapse. We tested whether elevated CORT was sufficient and necessary to generate a depressive-like behavioral phenotype and decreased excitatory signaling observed at TA-CA1 after chronic unpredictable stress (CUS). Chronic CORT administration induced an anhedonia-like behavioral state and neohypophagic behavior. Like CUS, chronic, but not acute, CORT generated an impaired synaptic phenotype characterized by reduced α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-preferring glutamate receptor-mediated excitation at TA-CA1 synapses, decreased AMPA-type glutamate receptor subunit 1 protein expression, and altered serotonin-1B receptor-mediated potentiation. Repeatedly blunting stress-induced increases of CORT during CUS with the CORT synthesis inhibitor metyrapone (MET) prevented these stress-induced neurobehavioral changes. MET also prevented the CUS-induced impairment of spatial memory consolidation. We conclude that corticosterone is sufficient and necessary to mediate glutamatergic dysfunction underlying stress-induced synaptic and behavioral phenotypes. Our results indicate that chronic excessive glucocorticoids cause specific synaptic deficits in the hippocampus, a major center for cognitive and emotional processing, that accompany stress-induced behavioral dysfunction. Maintaining excitatory strength at stress-sensitive synapses at key loci throughout corticomesolimbic reward circuitry appears critical for maintaining normal cognitive and emotional behavior.

Chronic stress induces a selective decrease in AMPA receptor-mediated synaptic excitation at hippocampal temporoammonic-CA1 synapses.

Chronic stress promotes depression, but how it disrupts cognition and mood remains unknown. Chronic stress causes atrophy of pyramidal cell dendrites in the hippocampus and cortex in human and animal models, and a depressive-like behavioral state. We now test the hypothesis that excitatory temporoammonic (TA) synapses in the distal dendrites of CA1 pyramidal cells in rats are altered by chronic unpredictable stress (CUS) and restored by chronic antidepressant treatment, in conjunction with the behavioral consequences of CUS. We observed a decrease in AMPAR-mediated excitation at TA-CA1 synapses, but not Schaffer collateral-CA1 synapses, after CUS, with a corresponding layer-specific decrease in GluA1 expression. Both changes were reversed by chronic fluoxetine. CUS also disrupted long-term memory consolidation in the Morris water maze, a function of TA-CA1 synapses. The decreases in TA-CA1 AMPAR-mediated excitation and performance in the consolidation test were correlated positively with decreases in sucrose preference, a measure of anhedonia. We conclude that chronic stress selectively decreases AMPAR number and function at specific synapses and suggest that this underlies various depressive endophenotypes. Our findings provide evidence that glutamatergic dysfunction is an underlying cause of depression and that current first-line antidepressant drugs act by restoring excitatory synaptic strength. Our findings suggest novel therapeutic targets for this debilitating disease.

Impact of lifetime stressor exposure on neuroenergetics in schizophrenia spectrum disorders.

N-acetylasparate and lactate are two prominent brain metabolites closely related to mitochondrial functioning. Prior research revealing lower levels of NAA and higher levels of lactate in the cerebral cortex of patients with schizophrenia suggest possible abnormalities in the energy supply pathway necessary for brain function. Given that stress and adversity are a strong risk factor for a variety of mental health problems, including psychotic disorders, we investigated the hypothesis that stress contributes to abnormal neuroenergetics in patients with schizophrenia. To test this hypothesis, we used the Stress and Adversity Inventory (STRAIN) to comprehensively assess the lifetime stressor exposure profiles of 35 patients with schizophrenia spectrum disorders and 33 healthy controls who were also assessed with proton magnetic resonance spectroscopy at the anterior cingulate cortex using 3 Tesla scanner. Consistent with the hypothesis, greater lifetime stressor exposure was significantly associated with lower levels of N-acetylasparate (ß = -0.36, p = .005) and higher levels of lactate (ß = 0.43, p = .001). Moreover, these results were driven by patients, as these associations were significant for the patient but not control group. Though preliminary, these findings suggest a possible role for stress processes in the pathophysiology of abnormal neuroenergetics in schizophrenia.

Revisiting delusion subtypes in schizophrenia based on their underlying structures.

A clear understanding of the pathophysiology of schizophrenia and related spectrum disorders has been limited by clinical heterogeneity. We investigated whether relative severity and predominance of one or more delusion subtypes might yield clinically differentiable patient profiles. Patients (N = 286) with schizophrenia spectrum disorders (SSD) completed the 21-item Peters et al. Delusions Inventory (PDI-21). We performed factor analysis followed by k-means clustering to identify delusion factors and patient subtypes. Patients were further assessed via the Brief Psychiatric Rating Scale, Brief Negative Symptom Scale, Digit Symbol and Digit Substitution tasks, use of cannabis and tobacco, and stressful life events. The overall patient sample clustered into subtypes corresponding to Low-Delusion, Grandiose-Predominant, Paranoid-Predominant, and Pan-Delusion patients. Paranoid-Predominant and Pan-Delusion patients showed significantly higher burden of positive symptoms, while Low-Delusion patients showed the highest burden of negative symptoms. The Paranoia delusion factor score showed a positive association with Digit Symbol and Digit Substitution tasks in the overall sample, and the Paranoid-Predominant subtype exhibited the best performance on both tasks. Grandiose-Predominant patients showed significantly higher tobacco smoking severity than other subtypes, while Paranoid-Predominant patients were significantly more likely to have a lifetime diagnosis of Cannabis Use Disorder. We suggest that delusion self-report inventories such as the PDI-21 may be of utility in identifying sub-syndromes in SSD. From the current study, a Paranoid-Predominant form may be most distinctive, with features including less cognitive impairment and a stronger association with cannabis use.

Depression, stress and regional cerebral blood flow.

Decreased cerebral blood flow (CBF) may be an important mechanism associated with depression. In this study we aimed to determine if the association of CBF and depression is dependent on current level of depression or the tendency to experience depression over time (trait depression), and if CBF is influenced by depression-related factors such as stressful life experiences and antidepressant medication use. CBF was measured in 254 participants from the Amish Connectome Project (age 18-76, 99 men and 154 women) using arterial spin labeling. All participants underwent assessment of symptoms of depression measured with the Beck Depression Inventory and Maryland Trait and State Depression scales. Individuals diagnosed with a unipolar depressive disorder had significantly lower average gray matter CBF compared to individuals with no history of depression or to individuals with a history of depression that was in remission at time of study. Trait depression was significantly associated with lower CBF, with the associations strongest in cingulate gyrus and frontal white matter. Use of antidepressant medication and more stressful life experiences were also associated with significantly lower CBF. Resting CBF in specific brain regions is associated with trait depression, experience of stressful life events, and current antidepressant use, and may provide a valuable biomarker for further studies.

Ancestral, Pregnancy, and Negative Early-Life Risks Shape Children's Brain (Dis)similarity to Schizophrenia.

BACKGROUND: Familial, obstetric, and early-life environmental risks for schizophrenia spectrum disorder (SSD) alter normal cerebral development, leading to the formation of characteristic brain deficit patterns prior to onset of symptoms. We hypothesized that the insidious effects of these risks may increase brain similarity to adult SSD deficit patterns in prepubescent children. METHODS: We used data collected by the Adolescent Brain Cognitive Development (ABCD) Study (N = 8940, age = 9.9 ± 0.1 years, 4307/4633 female/male), including 727 (age = 9.9 ± 0.1 years, 351/376 female/male) children with family history of SSD, to evaluate unfavorable cerebral effects of ancestral SSD history, pre/perinatal environment, and negative early-life environment. We used a regional vulnerability index to measure the alignment of a child's cerebral patterns with the adult SSD pattern derived from a large meta-analysis of case-control differences. RESULTS: In children with a family history of SSD, the regional vulnerability index captured significantly more variance in ancestral history than traditional whole-brain and regional brain measurements. In children with and without family history of SSD, the regional vulnerability index also captured more variance associated with negative pre/perinatal environment and early-life experiences than traditional brain measurements. CONCLUSIONS: In summary, in a cohort in which most children will not develop SSD, familial, pre/perinatal, and early developmental risks can alter brain patterns in the direction observed in adult patients with SSD. Individual similarity to adult SSD patterns may provide an early biomarker of the effects of genetic and developmental risks on the brain prior to psychotic or prodromal symptom onset.

Effects of independent versus dependent stressful life events on major symptom domains of schizophrenia.

We evaluated two models to link stressful life events (SLEs) with the psychopathology of schizophrenia spectrum disorders (SSD). We separated SLEs into independent (iSLEs, unlikely influenced by one's behavior) and dependent (dSLEs, likely influenced by one's behavior). Stress-diathesis and stress generation models were evaluated for the relationship between total, i- and d- SLEs and the severity of positive, negative, and depressive symptoms in participants with SSD. Participants with SSD (n = 286; 196 males; age = 37.5 ± 13.5 years) and community controls (n = 121; 83 males; 35.4 ± 13.9 years) completed self-report of lifetime negative total, i- and d- SLEs. Participants with SSD reported a significantly higher number of total SLEs compared to controls (B = 1.11, p = 6.4 × 10-6). Positive symptom severity was positively associated with the total number of SLEs (ß = 0.20, p = 0.001). iSLEs (ß = 0.11, p = 0.09) and dSLEs (ß = 0.21, p = 0.0006) showed similar association with positive symptoms (p = 0.16) suggesting stress-diathesis effects. Negative symptom severity was negatively associated with the number of SLEs (ß = -0.19, p = 0.003) and dSLEs (ß = -0.20, p = 0.001) but not iSLEs (ß = -0.04, p = 0.52), suggesting stress generation effects. Depressive symptom severity was positively associated with SLEs (ß = 0.34, p = 1.0 × 10-8), and the association was not statistically stronger for dSLEs (ß = 0.33, p = 2.7 × 10-8) than iSLEs (ß = 0.21, p = 0.0006), p = 0.085, suggesting stress-diathesis effects. The SLE - symptom relationships in SSD may be attributed to stress generation or stress-diathesis, depending on symptom domain. Findings call for a domain-specific approach to clinical intervention for SLEs in SSD.

Neuromodulator-evoked synaptic metaplasticity within a central pattern generator network.

Synapses show short-term activity-dependent dynamics that alter the strength of neuronal interactions. This synaptic plasticity can be tuned by neuromodulation as a form of metaplasticity. We examined neuromodulator-induced metaplasticity at a graded chemical synapse in a model central pattern generator (CPG), the pyloric network of the spiny lobster stomatogastric ganglion. Dopamine, serotonin, and octopamine each produce a unique motor pattern from the pyloric network, partially through their modulation of synaptic strength in the network. We characterized synaptic depression and its amine modulation at the graded synapse from the pyloric dilator neuron to the lateral pyloric neuron (PD→LP synapse), driving the PD neuron with both long square pulses and trains of realistic waveforms over a range of presynaptic voltages. We found that the three amines can differentially affect the amplitude of graded synaptic transmission independently of the synaptic dynamics. Low concentrations of dopamine had weak and variable effects on the strength of the graded inhibitory postsynaptic potentials (gIPSPs) but reliably accelerated the onset of synaptic depression and recovery from depression independently of gIPSP amplitude. Octopamine enhanced gIPSP amplitude but decreased the amount of synaptic depression; it slowed the onset of depression and accelerated its recovery during square pulse stimulation. Serotonin reduced gIPSP amplitude but increased the amount of synaptic depression and accelerated the onset of depression. These results suggest that amine-induced metaplasticity at graded chemical synapses can alter the parameters of synaptic dynamics in multiple and independent ways.