κ-Opioid Receptor Plasma Levels Are Associated With Sex and Diagnosis of Major Depressive Disorder But Not Response to Ketamine.

BACKGROUND: Preclinical evidence indicates that the κ-opioid receptor (KOR)/dynorphin pathway is implicated in depressive-like behaviors. Ketamine is believed to partly exert its antidepressant effects by modulating the opioid system. This post hoc study examined the following research questions: (1) at baseline, were there differences in KOR or dynorphin plasma levels between individuals with major depressive disorder (MDD) and healthy volunteers (HVs) or between men and women? (2) in individuals with MDD, did KOR or dynorphin baseline plasma levels moderate ketamine's therapeutic effects or adverse effects? and (3) in individuals with MDD, were KOR or dynorphin plasma levels affected after treatment with ketamine compared with placebo? METHODS: Thirty-nine unmedicated individuals with MDD (23 women) and 25 HVs (16 women) received intravenous ketamine (0.5 mg/kg) and placebo in a randomized, crossover, double-blind trial. Blood was obtained from all participants at baseline and at 3 postinfusion time points (230 minutes, day 1, day 3). Linear mixed model regressions were used. RESULTS: At baseline, participants with MDD had lower KOR plasma levels than HVs ( F1,60 = 13.16, P < 0.001), and women (MDD and HVs) had higher KOR plasma levels than men ( F1,60 = 4.98, P = 0.03). Diagnosis and sex had no significant effects on baseline dynorphin levels. Baseline KOR and dynorphin levels did not moderate ketamine's therapeutic or adverse effects. Compared with placebo, ketamine was not associated with postinfusion changes in KOR or dynorphin levels. CONCLUSIONS: In humans, diagnosis of MDD and biological sex are involved with changes in components of the KOR/dynorphin pathway. Neither KOR nor dynorphin levels consistently moderated ketamine's therapeutic effects or adverse effects, nor were levels altered after ketamine infusion. TRIAL REGISTRATION: NCT00088699 ( ClinicalTrials.gov ).

Exploring static and dynamic relationships between burden of disease and research funding in the United States.

BACKGROUND: The relationship between burden of disease and research funding has been examined cross-sectionally, but temporal patterns have not been investigated. It is logical to assume that temporal improvements in disability-adjusted life-years (DALYs) reflect benefits from research funding; such assumptions are tempered by an unknown lag time for emergence of benefits from research. METHODS: We studied National Institutes of Health (NIH) research fund allocations and United States DALY estimates for overlapping disease categories (matched disease categories, MDC, N = 38). Using a general linear model, we separately analysed DALYs for MDCs in 2017 in relation to NIH research allocations in 2017 and 2007. We also examined how changes in DALYs were related to cumulative NIH research funding (2006-2017). After regressing DALY change on summed funding, we obtained model residuals as estimates of the discrepancy for each MDC between observed and expected change in burden, given funding. RESULTS: In 2017, there was a positive association between NIH research fund allocations and DALYs for the same year (F1,36 = 16.087, p = 0.0002921; slope = 0.35020; model R2 = 0.3088), suggesting proportionate allocation. There was a positive association between 2017 DALYs and 2007 NIH research allocation, implying a beneficial impact of research (F1,36 = 15.754, p = 0.0003; slope = 0.8845; model R2 = 0.3044). In contrast, there was a nonsignificant association between summed NIH funding and percent change in DALYs over 2006-2017 (F1,36 = 0.199; p = 0.65; beta coefficient = -1.144). When MDCs were ordered based on residuals, HIV/AIDS ranked first. Mental, neurologic or substance abuse (MNS) disorders comprised most residuals in the lower half. CONCLUSIONS: NIH fund allocation is proportional to DALYs for MDCs. Temporal changes in DALYs vary by MDCs, but they are not significantly related to cumulative research outlays. Further analysis of temporal changes in DALYs could help to inform research outlays for MDCs and to study the impact of research.

Disrupted sensorimotor and social-cognitive networks underlie symptoms in childhood-onset schizophrenia.

Schizophrenia is increasingly recognized as a neurodevelopmental disorder with altered connectivity among brain networks. In the current study we examined large-scale network interactions in childhood-onset schizophrenia, a severe form of the disease with salient genetic and neurobiological abnormalities. Using a data-driven analysis of resting-state functional magnetic resonance imaging fluctuations, we characterized data from 19 patients with schizophrenia and 26 typically developing controls, group matched for age, sex, handedness, and magnitude of head motion during scanning. This approach identified 26 regions with decreased functional correlations in schizophrenia compared to controls. These regions were found to organize into two function-related networks, the first with regions associated with social and higher-level cognitive processing, and the second with regions involved in somatosensory and motor processing. Analyses of across- and within-network regional interactions revealed pronounced across-network decreases in functional connectivity in the schizophrenia group, as well as a set of across-network relationships with overall negative coupling indicating competitive or opponent network dynamics. Critically, across-network decreases in functional connectivity in schizophrenia predicted the severity of positive symptoms in the disorder, such as hallucinations and delusions. By contrast, decreases in functional connectivity within the social-cognitive network of regions predicted the severity of negative symptoms, such as impoverished speech and flattened affect. These results point toward the role that abnormal integration of sensorimotor and social-cognitive processing may play in the pathophysiology and symptomatology of schizophrenia.

Entactogen Effects of Ketamine: A Reverse-Translational Study.

OBJECTIVE: The authors sought to assess the prosocial, entactogen effects of ketamine. METHODS: Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg intravenously) or placebo. The primary endpoint was postinfusion self-reported pleasure on the four SHAPS items pertaining to social situations, including the item on helping others, between the ketamine and placebo groups. In a rodent experiment, the impact of ketamine on helping behavior in rats was assessed using the harm aversion task. The primary endpoint was a reduction in lever response rate relative to baseline, which indicated the willingness of rats to forgo obtaining sucrose to help protect their cage mate from electric shock. RESULTS: Relative to placebo, ketamine increased ratings of feeling pleasure from being with family or close friends, seeing other people's smiling faces, helping others, and receiving praise, for 1 week following treatment. In the rodent experiment, during the harm aversion task, ketamine-treated rats maintained lower response rates relative to baseline to a greater extent than what was observed in vehicle-treated rats for 6 days posttreatment and delivered fewer shocks overall. CONCLUSIONS: In patients with treatment-resistant depression, ketamine treatment was associated with increased pleasure from social situations, such as feeling pleasure from helping others. Ketamine-treated rats were more likely to protect their cage mate from harm, at the cost of obtaining sucrose. These findings suggest that ketamine has entactogen effects.

Longitudinally mapping the influence of sex and androgen signaling on the dynamics of human cortical maturation in adolescence.

Humans have systematic sex differences in brain-related behavior, cognition, and pattern of mental illness risk. Many of these differences emerge during adolescence, a developmental period of intense neurostructural and endocrine change. Here, by creating "movies" of sexually dimorphic brain development using longitudinal in vivo structural neuroimaging, we show regionally specific sex differences in development of the cerebral cortex during adolescence. Within cortical subsystems known to underpin domains of cognitive behavioral sex difference, structural change is faster in the sex that tends to perform less well within the domain in question. By stratifying participants through molecular analysis of the androgen receptor gene, we show that possession of an allele conferring more efficient functioning of this sex steroid receptor is associated with "masculinization" of adolescent cortical maturation. Our findings extend models first established in rodents, and suggest that in humans too, sex and sex steroids shape brain development in a spatiotemporally specific manner, within neural systems known to underpin sexually dimorphic behaviors.

An exploration of actigraphy in the context of ketamine and treatment-resistant depression.

OBJECTIVES: This study explored the potential of non-parametric and complexity analysis metrics to detect changes in activity post-ketamine and their association with depressive symptomatology. METHODS: Individuals with treatment-resistant depression (TRD: n = 27, 16F, 35.9 ± 10.8 years) and healthy volunteers (HVs: n = 9, 4F, 36.4 ± 9.59 years) had their activity monitored during an inpatient, double-blind, crossover study where they received an infusion of ketamine or saline placebo. All participants were 18-65 years old, medication-free, and had a MADRS score ≥20. Non-parametric metrics averaged over each study day, metrics derived from complexity analysis, and traditionally calculated non-parametric metrics averaged over two weeks were calculated from the actigraphy time series. A separate analysis was conducted for a subsample (n = 17) to assess the utility of these metrics in a hospital setting. RESULTS: In HVs, lower intradaily variability was observed within daily rest/activity patterns post-ketamine versus post-placebo (F = 5.16(1,15), p = 0.04). No other significant effects of drug or drug-by-time or correlations between depressive symptomatology and activity were detected. CONCLUSIONS: Weak associations between non-parametric variables and ketamine were found but were not consistent across actigraphy measures. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT00088699.

How does your cortex grow?

Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances toward this goal have come from two recent strands of in vivo structural magnetic resonance imaging research: (1) longitudinal study designs have revealed that factors such as sex, cognitive ability, and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time point; (2) largely cross-sectional applications of new surface-based morphometry (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV: cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time and applying SBM in >1250 longitudinally acquired brain scans from 647 healthy individuals aged 3-30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent interaction of changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical convex hull area, and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases, provides potent new research targets for basic and clinical neuroscience.

The association between variability, intensity, and persistence of suicidal ideation and prospective suicidal behavior in the systematic treatment enhancement program for bipolar disorder (STEP-BD) study.

BACKGROUND: This study sought to examine the association between prospective suicidal behavior and variability, intensity, and persistence of suicidal ideation (SI) in bipolar disorder (BD). METHODS: Data were drawn from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), a naturalistic study of 4360 outpatients 15 years or older with BD. In separate models, logistic regressions with suicidal behavior (first attempt or death by suicide) as the outcome variable and SI variability (fluctuating levels of SI over time, measured as ordinal dispersion of SI score), intensity (median SI score over time in study), or persistence (number of visits with reported SI) as the explanatory variables were used to examine the relationship between SI characteristics and odds of future suicidal behavior events. RESULTS: After adjusting for possible confounders, the odds of prospective suicidal behavior were 1.2 times greater per 10% increase in SI variability. SI persistence was not associated with suicidal behavior. For SI intensity, a median SI score of 'rare/fleeting' or 'several days' of SI was not associated with suicidal behavior, but the odds of prospective suicidal behavior were nearly five times greater for participants with the highest observed median SI intensity score of 'nearly every day'. CONCLUSIONS: The findings suggest that, in BD participants, monitoring SI variability may be clinically useful for assessing suicide risk.

Predictors of suicidal ideation trajectories in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.

A better understanding of suicidal ideation (SI), including patterns of SI, may help elucidate links between depression, SI, and suicidal behavior. This study sought to identify trajectories of SI in a large, community-based clinical trial of participants with major depressive disorder (MDD) and to investigate the relationships between these trajectories and predictors of interest, including anxiety and anhedonia. A longitudinal latent class analysis was conducted in 3923 participants enrolled in Level 1 of the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study of citalopram for the treatment of MDD. An unconditional latent class analysis was conducted using SI at study weeks 0, 2, 4, 6, and 9 as the indicators. A multinomial regression was then conducted with SI trajectory as the outcome and anhedonia, severity of depressive symptoms, atypical depression, anxiety, history of suicide attempt, history of substance abuse, history of trauma, and other covariates as the predictors. Four SI trajectories were identified: 1) variable SI; 2) little-to-no SI; 3) persistent SI; and 4) improving SI. Compared to the little-to-no SI trajectory, those with more severe anhedonia were more likely to experience persistent SI, while those with more severe anxiety were more likely to experience improving SI. Factors that distinguish SI trajectories, such as anxiety and anhedonia, may be critical targets for intervention or profiles for prognosis.

The mental health impact of contact with COVID-19 patients on healthcare workers in the United States.

This study assessed the relationship between contact with COVID-19 patients and the mental health of healthcare workers (HCWs) in the United States (US). In a convenience sample of 957 HCWs who completed an anonymous online survey between April-May 2020, HCWs who provided direct care to confirmed or suspected COVID-19 patients reported increased depressive and posttraumatic symptoms compared to HCWs with no COVID-19 patient contact. Additionally, more frequent contact was associated with higher distress. More data drawn from diverse samples that better represent US HCWs are needed to fully assess the scope of this association.

Increased neuroinflammatory and arachidonic acid cascade markers, and reduced synaptic proteins, in brain of HIV-1 transgenic rats.

BACKGROUND: Cognitive impairment has been reported in human immune deficiency virus-1- (HIV-1-) infected patients as well as in HIV-1 transgenic (Tg) rats. This impairment has been linked to neuroinflammation, disturbed brain arachidonic acid (AA) metabolism, and synapto-dendritic injury. We recently reported upregulated brain AA metabolism in 7- to 9-month-old HIV-1 Tg rats. We hypothesized that these HIV-1 Tg rats also would show upregulated brain inflammatory and AA cascade markers and a deficit of synaptic proteins. METHODS: We measured protein and mRNA levels of markers of neuroinflammation and the AA cascade, as well as pro-apoptotic factors and synaptic proteins, in brains from 7- to 9-month-old HIV-1 Tg and control rats. RESULTS: Compared with control brain, HIV-1 Tg rat brain showed immunoreactivity to glycoprotein 120 and tat HIV-1 viral proteins, and significantly higher protein and mRNA levels of (1) the inflammatory cytokines interleukin-1ß and tumor necrosis factor α, (2) the activated microglial/macrophage marker CD11b, (3) AA cascade enzymes: AA-selective Ca2+-dependent cytosolic phospholipase A2 (cPLA2)-IVA, secretory sPLA2-IIA, cyclooxygenase (COX)-2, membrane prostaglandin E2 synthase, 5-lipoxygenase (LOX) and 15-LOX, cytochrome p450 epoxygenase, and (4) transcription factor NF-κBp50 DNA binding activity. HIV-1 Tg rat brain also exhibited signs of cell injury, including significantly decreased levels of brain-derived neurotrophic factor (BDNF) and drebrin, a marker of post-synaptic excitatory dendritic spines. Expression of Ca2+-independent iPLA2-VIA and COX-1 was unchanged. CONCLUSIONS: HIV-1 Tg rats show elevated brain markers of neuroinflammation and AA metabolism, with a deficit in several synaptic proteins. These changes are associated with viral proteins and may contribute to cognitive impairment. The HIV-1 Tg rat may be a useful model for understanding progression and treatment of cognitive impairment in HIV-1 patients.

A twin study of intracerebral volumetric relationships.

Using high resolution magnetic resonance imaging data, we examined the interrelationships between eight cerebral lobar volumetric measures via both exploratory and confirmatory factor analyses in a large sample (N = 484) of pediatric twins and singletons. These analyses suggest the presence of strong genetic correlations between cerebral structures, particularly between regions of like tissue type or in spatial proximity. Structural modeling estimated that most of the variance in all structures is associated with highly correlated lobar latent factors, with differences in genetic covariance and heritability driven by a common genetic factor that influenced gray and white matter differently. Reanalysis including total brain volume as a covariate dramatically reduced the total residual variance and disproportionately influenced the additive genetic variance in all regions of interest.

Can 'floating' predict treatment response to ketamine? Data from three randomized trials of individuals with treatment-resistant depression.

Ketamine has rapid-acting antidepressant properties but also potentially concerning transient dissociative side effects (SEs). Recent studies noted a positive correlation between treatment response to ketamine and general dissociative SEs, as well as "floating", a depersonalization SE (a subtype of the dissociative SEs). This analysis sought to determine whether floating mediates treatment response to ketamine. Data were pooled from three double-blind, crossover, placebo-controlled ketamine clinical trials across which 82 participants with treatment-resistant depression (TRD) (44 with bipolar depression and 38 with major depressive disorder) received placebo and ketamine (0.5 mg/kg) infusions. SEs were actively solicited in a standardized fashion before and after ketamine infusion. The hypothesis that a post-infusion experience of floating would mediate antidepressant response to ketamine was assessed at 230 min post-infusion and at Day 1. Montgomery-Asberg Depression Rating Scale (MADRS) total score was the dependent variable in a linear mixed effects model. Ketamine significantly decreased MADRS scores (p < 0.0001), but no relationship was detected between floating and MADRS score at either 230 min or Day 1 post-infusion. The hypothesized mediation effect of floating was also not detected at either 230 min or Day 1 post-infusion. Taken together, the findings do not support the hypothesis that ketamine's antidepressant effects are mediated by the dissociative depersonalization subtype SE of floating.

Comprehensive assessment of side effects associated with a single dose of ketamine in treatment-resistant depression.

BACKGROUND: Concerns about ketamine for treating depression include abuse potential and the occurrence of psychotomimetic effects. This study sought to comprehensively assess side effects (SEs) associated with a single subanesthetic-dose intravenous ketamine infusion. A secondary aim was to examine the relationship between Clinician-Administered Dissociative States Scale (CADSS) scores and dissociative symptoms reported on a comprehensive, clinician-administered SE questionnaire. METHODS: Data from 188 participants were pooled from four placebo-controlled, crossover ketamine trials and one open-label study (n = 163 with either treatment-resistant major depressive disorder or bipolar disorder and 25 healthy controls). SEs were actively solicited in a standardized fashion and monitored over the time-course of each study. Statistical analyses assessed the effect of drug (ketamine, placebo) on SEs and measured the relationship between CADSS total score and SEs contemporaneously endorsed during structured interviews. RESULTS: Forty-four of 120 SEs occurred in at least 5% of participants over all trials. Thirty-three of these 44 SEs were significantly associated with active drug administration (versus placebo). The most common SE was feeling strange/weird/loopy. Most SEs peaked within an hour of ketamine administration and resolved completely by two hours post-infusion. No serious drug-related adverse events or increased ketamine craving/abuse post-administration were observed. A positive correlation was found between dissociative SEs and total CADSS score. LIMITATIONS: The post-hoc nature of the analysis; the limited generalizability of a single subanesthetic-dose ketamine infusion; and the lack of formal measures to assess ketamine's cognitive, urological, or addictive potential. CONCLUSIONS: No long-lasting significant SEs occurred over the approximately three-month follow-up period.

Imaging neuroinflammation in Alzheimer's disease with radiolabeled arachidonic acid and PET.

UNLABELLED: Incorporation coefficients (K*) of arachidonic acid (AA) in the brain are increased in a rat model of neuroinflammation, as are other markers of AA metabolism. Data also indicate that neuroinflammation contributes to Alzheimer's disease (AD). On the basis of these observations, K* for AA was hypothesized to be elevated in patients with AD. METHODS: A total of 8 patients with AD with an average (+/-SD) Mini-Mental State Examination score of 14.7+/-8.4 (mean age, 71.7+/-11.2 y) and 9 controls with a normal Mini-Mental State Examination score (mean age, 68.7+/-5.6 y) were studied. Each subject received a (15)O-water PET scan of regional cerebral blood flow, followed after 15 min by a 1-(11)C-AA scan of regional K* for AA. RESULTS: In the patients with AD, compared with control subjects, global gray matter K* for AA (corrected or uncorrected for the partial-volume error [PVE]) was significantly elevated, whereas only PVE-uncorrected global cerebral blood flow was reduced significantly (P<0.05). A false-discovery-rate procedure indicated that PVE-corrected K* for AA was increased in 78 of 90 identified hemispheric gray matter regions. PVE-corrected regional cerebral blood flow, although decreased in 12 regions at P<0.01 by an unpaired t test, did not survive the false-discovery-rate procedure. The surviving K* increments were widespread in the neocortex but were absent in caudate, pallidum, and thalamic regions. CONCLUSION: These preliminary results show that K* for AA is widely elevated in the AD brain, particularly in regions reported to have high densities of senile (neuritic) plaques with activated microglia. To the extent that the elevations represent upregulated AA metabolism associated with neuroinflammation, PET with 1-(11)C-AA could be used to examine neuroinflammation in patients with AD and other brain diseases.

Attenuated resting-state functional connectivity in patients with childhood- and adult-onset schizophrenia.

BACKGROUND: Childhood-onset schizophrenia (COS) is a rare, severe form of the adult-onset disorder (AOS). Our previous resting-state fMRI study identified attenuated functional connectivity in COS compared with controls. Here, we ask whether COS and AOS patients and their siblings exhibit similar abnormalities of functional connectivity. METHODS: A whole-brain, data-driven approach was used to assess resting-state functional connectivity differences in COS (patients/siblings/controls, n: 26/28/33) and AOS (n: 19/28/30). There were no significant differences in age, sex, or head motion across groups in each dataset and as designed, the COS dataset has a significantly lower age than the AOS. RESULTS: Both COS and AOS patients showed decreased functional connectivity relative to controls among a wide set of brain regions (P<0.05, corrected), but their siblings did not. Decreased connectivity in COS and AOS patients showed no amplitude differences and was not modulated by age-at-onset or medication doses. Cluster analysis revealed that these regions fell into two large-scale networks: one sensorimotor network and one centered on default-mode network regions, but including higher-order cognitive areas only in COS. Decreased connectivity between these two networks was notable (P<0.05, corrected) for both patient groups. CONCLUSIONS: A shared pattern of attenuated functional connectivity was found in COS and AOS, supporting the continuity of childhood-onset and adult-onset schizophrenia. Connections were altered between sensorimotor areas and default-mode areas in both COS and AOS, suggesting potential abnormalities in processes of self-monitoring and sensory prediction. The absence of substantial dysconnectivity in siblings indicates that attenuation is state-related.

Puberty-related influences on brain development.

Puberty is a time of striking changes in cognition and behavior. To indirectly assess the effects of puberty-related influences on the underlying neuroanatomy of these behavioral changes we will review and synthesize neuroimaging data from typically developing children and adolescents and from those with anomalous hormone or sex chromosome profiles. The trajectories (size by age) of brain morphometry differ between boys and girls, with girls generally reaching peak gray matter thickness 1-2 years earlier than boys. Both boys and girls with congenital adrenal hyperplasia (characterized by high levels of intrauterine testosterone), have smaller amygdala volume but the brain morphometry of girls with CAH did not otherwise significantly differ from controls. Subjects with XXY have gray matter reductions in the insula, temporal gyri, amygdala, hippocampus, and cingulate-areas consistent with the language-based learning difficulties common in this group.