Ketamine induces multiple individually distinct whole-brain functional connectivity signatures.

Background: Ketamine has emerged as one of the most promising therapies for treatment-resistant depression. However, inter-individual variability in response to ketamine is still not well understood and it is unclear how ketamine's molecular mechanisms connect to its neural and behavioral effects. Methods: We conducted a single-blind placebo-controlled study, with participants blinded to their treatment condition. 40 healthy participants received acute ketamine (initial bolus 0.23 mg/kg, continuous infusion 0.58 mg/kg/hr). We quantified resting-state functional connectivity via data-driven global brain connectivity and related it to individual ketamine-induced symptom variation and cortical gene expression targets. Results: We found that: (i) both the neural and behavioral effects of acute ketamine are multi-dimensional, reflecting robust inter-individual variability; (ii) ketamine's data-driven principal neural gradient effect matched somatostatin (SST) and parvalbumin (PVALB) cortical gene expression patterns in humans, while the mean effect did not; and (iii) behavioral data-driven individual symptom variation mapped onto distinct neural gradients of ketamine, which were resolvable at the single-subject level. Conclusions: These results highlight the importance of considering individual behavioral and neural variation in response to ketamine. They also have implications for the development of individually precise pharmacological biomarkers for treatment selection in psychiatry. Funding: This study was supported by NIH grants DP5OD012109-01 (A.A.), 1U01MH121766 (A.A.), R01MH112746 (J.D.M.), 5R01MH112189 (A.A.), 5R01MH108590 (A.A.), NIAAA grant 2P50AA012870-11 (A.A.); NSF NeuroNex grant 2015276 (J.D.M.); Brain and Behavior Research Foundation Young Investigator Award (A.A.); SFARI Pilot Award (J.D.M., A.A.); Heffter Research Institute (Grant No. 1-190420) (FXV, KHP); Swiss Neuromatrix Foundation (Grant No. 2016-0111) (FXV, KHP); Swiss National Science Foundation under the framework of Neuron Cofund (Grant No. 01EW1908) (KHP); Usona Institute (2015 - 2056) (FXV). Clinical trial number: NCT03842800.

Ketamine is a widely used anesthetic as well as a popular illegal recreational drug. Recently, it has also gained attention as a potential treatment for depression, particularly in cases that don't respond to conventional therapies. However, individuals can vary in their response to ketamine. For example, the drug can alter some people's perception, such as seeing objects as larger or small than they are, while other individuals are unaffected. Although a single dose of ketamine was shown to improve depression symptoms in approximately 65% of patients, the treatment does not work for a significant portion of patients. Understanding why ketamine does not work for everyone could help to identify which patients would benefit most from the treatment. Previous studies investigating ketamine as a treatment for depression have typically included a group of individuals given ketamine and a group given a placebo drug. Assuming people respond similarly to ketamine, the responses in each group were averaged and compared to one another. However, this averaging of results may have masked any individual differences in response to ketamine. As a result, Moujaes et al. set out to investigate whether individuals show differences in brain activity and behavior in response to ketamine. Moujaes et al. monitored the brain activity and behavior of 40 healthy individuals that were first given a placebo drug and then ketamine. The results showed that brain activity and behavior varied significantly between individuals after ketamine administration. Genetic analysis revealed that different gene expression patterns paired with differences in ketamine response in individuals ­ an effect that was hidden when the results were averaged. Ketamine also caused greater differences in brain activity and behavior between individuals than other drugs, such as psychedelics, suggesting ketamine generates a particularly complex response in people. In the future, extending these findings in healthy individuals to those with depression will be crucial for determining whether differences in response to ketamine align with how effective ketamine treatment is for an individual.

The Safety and Comparative Effectiveness of Non-Psychoactive Cannabinoid Formulations for the Improvement of Sleep: A Double-Blinded, Randomized Controlled Trial.

BACKGROUND: Clinical evidence on the use of cannabidiol (CBD) for sleep remains limited. Even fewer studies have tested the comparative effectiveness of cannabinoid formulations found within CBD products used for sleep or how they compare to other complementary therapies such as melatonin. METHODS: Participants (N = 1,793 adults experiencing symptoms of sleep disturbance) were randomly assigned to receive a 4-week supply of 1 of 6 products (all capsules) containing either 15 mg CBD or 5 mg melatonin, alone or in combination with minor cannabinoids. Sleep disturbance was assessed over a period of 5 weeks (baseline week and 4 weeks of product use) using Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A, administered via weekly online surveys. A linear mixed-effects regression model was used to assess the differences in the change in sleep disturbance through time between each active product arm and CBD isolate. RESULTS: All formulations exhibited a favorable safety profile (12% of participants reported a side effect and none were severe) and led to significant improvements in sleep disturbance (p < 0.001 in within-group comparisons). Most participants (56% to 75%) across all formulations experienced a clinically important improvement in their sleep quality. There were no significant differences in effect, however, between 15 mg CBD isolate and formulations containing 15 mg CBD and 15 mg cannabinol (CBN), alone or in combination with 5 mg cannabichromene (CBC). There were also no significant differences in effect between 15 mg CBD isolate and formulations containing 5 mg melatonin, alone or in combination with 15 mg CBD and 15 mg CBN. CONCLUSIONS: Our findings suggest that chronic use of a low dose of CBD is safe and could improve sleep quality, though these effects do not exceed that of 5 mg melatonin. Moreover, the addition of low doses of CBN and CBC may not improve the effect of formulations containing CBD or melatonin isolate.

White Noise-Is Anxiety in Late-Life Associated With White Matter Hyperintensity Burden?

OBJECTIVE: We investigated the relationship between anxiety phenotypes (global anxiety, worry, and rumination) and white matter hyperintensities (WMH), with special consideration for the roles of age and executive function (EF). Our hypotheses were 1) anxiety phenotypes would be associated with WMH and 2) EF would moderate this relationship. DESIGN: Cross-sectional. SETTING: Participants were recruited from the local community (Pittsburgh, PA). PARTICIPANTS: We recruited 110 older adults (age ≥ 50) with varying worry severity and clinical comorbidity. INTERVENTIONS: Not applicable. MEASUREMENTS: Demographics (age, sex, race, education), clinical measures (cumulative illness burden, global anxiety, worry, and rumination), EF, and WMH quantified with magnetic resonance imaging. RESULTS: Lower global anxiety and worry severity were significantly correlated with higher WMH volume, though the global anxiety relationship was not significant after controlling for age. Rumination as not associated with WMH burden. EF was not correlated with either global anxiety, worry, rumination, or WMH. However, in those with advanced age and/or greater WMH burden, there was an association between worry and EF as well as EF and WMH. CONCLUSION: Longitudinal studies are needed in order to clarify the complex interactions between anxiety phenotypes, WMH, and EF.

Intestinal microbial circadian rhythms drive sex differences in host immunity and metabolism.

Circadian rhythms dynamically regulate sex differences in metabolism and immunity, and circadian disruption increases the risk of metabolic disorders. We investigated the role of sex-specific intestinal microbial circadian rhythms in host metabolism using germ-free and conventionalized mice and manipulation of dietary-derived fat, fiber, and microbiota-accessible carbohydrates. Our findings demonstrate that sex differences in circadian rhythms of genes involved in immunity and metabolism depend on oscillations in microbiota, microbial metabolic functions, and microbial metabolites. Further, we show that consuming an obesogenic, high-fat, low-fiber diet produced sex-specific changes in circadian rhythms in microbiota, metabolites, and host gene expression, which were linked to sex differences in the severity of metabolic dysfunction. Our results reveal that microbial circadian rhythms contribute to sex differences in immunity and metabolism and that dietary factors can entrain new circadian rhythms and modify the magnitude of sex differences in host-microbe circadian dynamics.

A Randomized, Double-Blind, Placebo-Controlled Decentralized Trial to Assess Sleep, Health Outcomes, and Overall Well-Being in Healthy Adults Reporting Disturbed Sleep, Taking a Melatonin-Free Supplement.

Inadequate sleep is a global health concern. Sleep is multidimensional and complex; new multi-ingredient agents are needed. This study assessed the comparative effects of two multi-ingredient supplements on sleep relative to placebo. Adults (N = 620) seeking better sleep were randomly assigned to receive one of three study products. Sleep A (contained lower (0.35 mg THC and higher levels of botanicals (75 mg each hops oil and valerian oil), Sleep B (contained higher THC (0.85 mg) and lower botanicals (20 mg each hops oil and valerian oil) or placebo) for 4 weeks. Sleep disturbance was assessed at baseline and weekly using NIH's Patient-Reported Outcomes Measurement Information System (PROMIS™) Sleep Disturbance SF 8A survey. Anxiety, stress, pain, and well-being were assessed using validated measures at baseline and weekly. A linear mixed-effects regression model was used to assess the change in health outcome score between active product groups and the placebo. There was a significant difference in sleep disturbance, anxiety, stress, and well-being between Sleep A and placebo. There was no significant difference in any health parameter between Sleep B and placebo. Side effects were mild or moderate. There were no significant differences in the frequency of side effects between the study groups. A botanical blend containing a low concentration of THC improved sleep disturbance, anxiety, stress, and well-being in healthy individuals that reported better sleep as a primary health concern.

Impact of symptomatic menopausal transition on the occurrence of depression, anxiety, and sleep disorders: A real-world multi-site study.

BACKGROUND: The menopause transition is a vulnerable period that can be associated with changes in mood and cognition. The present study aimed to investigate whether a symptomatic menopausal transition increases the risks of depression, anxiety, and sleep disorders. METHODS: This population-based, retrospective cohort study analysed data from five electronic health record databases in South Korea. Women aged 45-64 years with and without symptomatic menopausal transition were matched 1:1 using propensity-score matching. Subgroup analyses were conducted according to age and use of hormone replacement therapy (HRT). A primary analysis of 5-year follow-up data was conducted, and an intention-to-treat analysis was performed to identify different risk windows over 5 or 10 years. The primary outcome was first-time diagnosis of depression, anxiety, and sleep disorder. We used Cox proportional hazard models and a meta-analysis to calculate the summary hazard ratio (HR) estimates across the databases. RESULTS: Propensity-score matching resulted in a sample of 17,098 women. Summary HRs for depression (2.10; 95% confidence interval [CI] 1.63-2.71), anxiety (1.64; 95% CI 1.01-2.66), and sleep disorders (1.47; 95% CI 1.16-1.88) were higher in the symptomatic menopausal transition group. In the subgroup analysis, the use of HRT was associated with an increased risk of depression (2.21; 95% CI 1.07-4.55) and sleep disorders (2.51; 95% CI 1.25-5.04) when compared with non-use of HRT. CONCLUSIONS: Our findings suggest that women with symptomatic menopausal transition exhibit an increased risk of developing depression, anxiety, and sleep disorders. Therefore, women experiencing a symptomatic menopausal transition should be monitored closely so that interventions can be applied early.

Identifying sex-specific risk architectures for predicting amyloid deposition using neural networks.

In older adults without dementia, White Matter Hyperintensities (WMH) in MRI have been shown to be highly associated with cerebral amyloid deposition, measured by the Pittsburgh compound B (PiB) PET. However, the relation to age, sex, and education in explaining this association is not well understood. We use the voxel counts of regional WMH, age, one-hot encoded sex, and education to predict the regional PiB using a multilayer perceptron with only rectilinear activations using mean squared error. We then develop a novel, robust metric to understand the relevance of each input variable for prediction. Our observations indicate that sex is the most relevant predictor of PiB and that WMH is not relevant for prediction. These results indicate that there is a sex-specific risk architecture for Aß deposition.

History of major depressive disorder is associated with differences in implicit learning of emotional faces.

Major depressive disorder is often associated with worsened reward learning, with blunted reward response persisting after remission. In this study, we developed a probabilistic learning task with social rewards as a learning signal. We examined the impacts of depression on social rewards (facial affect displays) as an implicit learning signal. Fifty-seven participants without a history of depression and sixty-two participants with a history of depression (current or remitted) completed a structured clinical interview and an implicit learning task with social reward. Participants underwent an open-ended interview to evaluate whether they knew the rule consciously. Linear mixed effects models revealed that participants without a history of depression learned faster and showed a stronger preference towards the positive than the negative stimulus when compared to the participants with a history of depression. In contrast, those with a history depression learned slower on average and displayed greater variability in stimulus preference. We did not detect any differences in learning between those with current and remitted depression. The results indicate that on a probabilistic social reward task, people with a history of depression exhibit slower reward learning and greater variability in their learning behavior. Improving our understanding of alterations in social reward learning and their associations with depression and anhedonia may help to develop translatable psychotherapeutic approaches for modification of maladaptive emotion regulation.

Reward and loss incentives improve spatial working memory by shaping trial-by-trial posterior frontoparietal signals.

Integrating motivational signals with cognition is critical for goal-directed activities. The mechanisms that link neural changes with motivated working memory continue to be understood. Here, we tested how externally cued and non-cued (internally represented) reward and loss impact spatial working memory precision and neural circuits in human subjects using fMRI. We translated the classic delayed-response spatial working memory paradigm from non-human primate studies to take advantage of a continuous numeric measure of working memory precision, and the wealth of translational neuroscience yielded by these studies. Our results demonstrated that both cued and non-cued reward and loss improved spatial working memory precision. Visual association regions of the posterior prefrontal and parietal cortices, specifically the precentral sulcus (PCS) and intraparietal sulcus (IPS), had increased BOLD signal during incentivized spatial working memory. A subset of these regions had trial-by-trial increases in BOLD signal that were associated with better working memory precision, suggesting that these regions may be critical for linking neural signals with motivated working memory. In contrast, regions straddling executive networks, including areas in the dorsolateral prefrontal cortex, anterior parietal cortex and cerebellum displayed decreased BOLD signal during incentivized working memory. While reward and loss similarly impacted working memory processes, they dissociated during feedback when money won or avoided in loss was given based on working memory performance. During feedback, the trial-by-trial amount and valence of reward/loss received was dissociated amongst regions such as the ventral striatum, habenula and periaqueductal gray. Overall, this work suggests motivated spatial working memory is supported by complex sensory processes, and that the IPS and PCS in the posterior frontoparietal cortices may be key regions for integrating motivational signals with spatial working memory precision.

Are All Anxieties Created Equal? Stress-related Networks and Anxiety Phenotypes in Old Age.

OBJECTIVE: The dysregulation of stress-related networks due to chronic symptoms such as severe worry and/or rumination is one of the putative pathways linking anxiety in late-life with cognitive decline and increased cardiovascular burden. Symptoms such as severe worry or rumination respond poorly to standard treatment and drive the morbidity associated with anxiety in older adults. We assessed if any of the neural networks anchored in the stress-related regions of interest (ROIs) are associated with distinct anxiety phenotypes (worry, rumination and global anxiety). METHODS: We recruited older participants (over 50 years of age) with varying levels of worry (N = 91) to undergo resting state fMRI. We computed seed-based connectivity for each ROI: the bed nucleus of the stria terminalis, the paraventricular nucleus of the hypothalamus, habenula, and amygdala. We limited our connectivity analyses to extracted regions for each seeded ROI-based network based on their canonical networks in 1,000 participants (Neurosynth). Using connectivity and clinical factors, we fit cross-validated elastic net models to predict scores on Penn State Worry Questionnaire, Rumination Subscale Questionnaire, Hamilton Anxiety Rating Scale, and Perceived Stress Scale. RESULTS: We identified several distinct connectivity patterns that predict anxiety phenotypes' severity. Greater worry was associated with greater paraventricular nucleus of the hypothalamus -subgenual anterior cingulate cortex, parahippocampal, and olfactory and amygdala-PHC connectivity. Greater global anxiety was associated with lower amygdala-superior temporal gyrus connectivity. Greater perceived stress was associated with lower amygdala-inferior temporal gyrus and amygdala-fusiform gyrus connectivity. CONCLUSION: Our study suggests that various late-life anxiety phenotypes (worry, global anxiety, rumination) may be associated with varying functional connectivity related to stress and emotion regulation. This may aid in the development of future targeted interventions.

Coping long term with active suicide in adolescents: Results from a pilot randomized controlled trial.

BACKGROUND: To adapt the Coping Long Term with Active Suicide Program (CLASP) for use with adolescents (CLASP-A) and to assess its feasibility and acceptability on an inpatient psychiatric unit. CLASP-A entailed three individual sessions and one family session, followed by a series of outpatient phone calls to adolescent and a designated parent/guardian over 6 months of follow-up. METHODS: The open trial phase involved 17 adolescent/parent pairs, followed by a pilot randomized controlled trial (RCT) in which adolescent/parent pairs were randomized to CLASP-A (n = 25) or enhanced treatment as usual (ETAU; n = 25). Assessments were completed at baseline, 3- and 6-month follow-ups. RESULTS: In the open trial, average in-person session attendance was 67%, and study treatment satisfaction was high. To enhance feasibility, we adapted CLASP-A to be completed in three individual sessions for the RCT; 77% of the sessions were completed and study satisfaction remained high in adolescents (3.32/4.0) and parents (3.62/4.0). There were no significant differences between groups in number of suicide attempts or readmissions during follow-up. CONCLUSION: Data indicate feasibility and acceptability of CLASP-A. However, the absence of treatment effects between groups raises questions regarding CLASP's potential efficacy with adolescents or the need for more extensive adaptations for adolescents.