Two-year trajectories of anhedonia in adolescents at transdiagnostic risk for severe mental illness: Association with clinical symptoms and brain-symptom links.

Anhedonia emerges during adolescence and is characteristic of severe mental illness (SMI). To understand how anhedonia emerges, changes with time, and relates with other symptoms, there is a need to understand patterns of this symptom's course reflecting change or stability-and associations with clinical symptoms and neural reward circuitry in adolescents at risk of SMI. In total, 113 adolescents at low or high familial risk of developing SMI completed clinical measures at up to five time points across 2 years and functional magnetic resonance imaging scanning during a guessing reward task at baseline. Growth curve analysis was used to determine the trajectory of anhedonia across 2 years, including different phases (consummatory and anticipatory) and their association with clinical features (risk status, average suicidal ideation, and average depression across time) and neural activation in response to rewards (ventral striatum and dorsal medial prefrontal cortex). The findings revealed anhedonia decreased across 2 years. Furthermore, lower depression severity was associated with decreases in anhedonia across 2 years. There were no interactions between neural reward activation and anhedonia slopes in predicting clinical features. Exploratory analyses examining latent classes revealed three trajectory classes of anhedonia across phases. While preliminary, in the low and decreasing consummatory anhedonia trajectory class, there was a positive association between neural activation of the right ventral striatum in response to rewards and depression. Certain patterns of anhedonia development could confer risk or resilience for specific types of psychopathologies. The results are preliminary but do highlight the complexity and heterogeneity in anhedonia development. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Examining relationships among NODDI indices of white matter structure in prefrontal cortical-thalamic-striatal circuitry and OCD symptomatology.

Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.

Lifetime depression and mania/hypomania risk predicted by neural markers in three independent young adult samples during working memory and emotional regulation.

Objective markers of pathophysiological processes underlying lifetime depression and mania/hypomania risk can provide biologically informed targets for novel interventions to help prevent the onset of affective disorders in individuals with subsyndromal symptoms. Greater activity within and functional connectivity (FC) between the central executive network (CEN), supporting emotional regulation (ER) subcomponent processes such as working memory (WM), the default mode network (DMN), supporting self-related information processing, and the salience network (SN), is thought to interfere with cognitive functioning and predispose to depressive disorders. Using an emotional n-back paradigm designed to examine WM and ER capacity, we examined in young adults: (1) relationships among activity and FC in these networks and lifetime depression and mania/hypomania risk; (2) the extent to which these relationships were specific to lifetime depression risk versus lifetime mania/hypomania risk; (3) whether findings in a first, Discovery sample n = 101, 63 female, age = 23.85 (2.9) could be replicated in a two independent Test samples of young adults: Test sample 1: n = 90, 60 female, age = 21.7 (2.0); Test sample 2: n = 96, 65 female, age = 21.6 (2.1). The Mood Spectrum Self-Report (MOODS-SR-L) assessed lifetime mania/hypomania risk and depression risk. We showed significant clusters of activity to each contrast in similar locations in the anatomic mask in each Test sample as in the Discovery sample, and, using extracted mean BOLD signal from these clusters as IVs, we showed similar patterns of IV-DV relationships in each Test sample as in the Discovery sample. Specifically, in the Discovery sample, greater DMN activity during WM was associated with greater lifetime depression risk. This finding was specific to depression and replicated in both independent samples (all ps<0.05 qFDR). Greater CEN activity during ER was associated with increased lifetime depression risk and lifetime mania/hypomania risk in all three samples (all ps< 0.05 qFDR). These replicated findings provide promising objective, neural markers to better identify, and guide and monitor early interventions for, depression and mania/hypomania risk in young adults.

Linking Mitochondrial Dysfunction, Neurotransmitter, and Neural Network Abnormalities and Mania: Elucidating Neurobiological Mechanisms of the Therapeutic Effect of the Ketogenic Diet in Bipolar Disorder.

There is growing interest in the ketogenic diet as a treatment for bipolar disorder (BD), and there are promising anecdotal and small case study reports of efficacy. However, the neurobiological mechanisms by which diet-induced ketosis might ameliorate BD symptoms remain to be determined, particularly in manic and hypomanic states-defining features of BD. Identifying these mechanisms will provide new markers to guide personalized interventions and provide targets for novel treatment developments for individuals with BD. In this critical review, we describe recent findings highlighting 2 types of neurobiological abnormalities in BD: 1) mitochondrial dysfunction and 2) neurotransmitter and neural network functional abnormalities. We link these abnormalities to mania/hypomania and depression in BD and then describe the biological underpinnings by which the ketogenic diet may have a beneficial effect in individuals with BD. We end the review by describing approaches that can be employed in future studies to elucidate the neurobiology that underlies the therapeutic effect of the ketogenic diet in BD. Doing this may provide marker predictors to identify individuals who will respond well to the ketogenic diet, as well as offer neural targets for novel treatment developments for BD.

Sex differences in neural responses to emotional facial expressions are associated with lifetime depression and mania risk.

INTRODUCTION: No studies systematically examined sex differences in neural mechanisms underlying depression and mania/hypomania risk. METHOD: 80 females and 35 males, n = 115(age21.6±1.90) were scanned using 3TfMRI during an implicit emotional-faces task. We examined neural activation to all emotional faces versus baseline, using an anatomical region-of-interest mask comprising regions supporting emotion and salience processing. Sex was a covariate. Extracted parameter estimates(FWE < 0.05,k > 15), age, IQ and their sex interactions were independent variables(IV) in two penalized regression models: dependent variable either MOODS-SR-lifetime, depressive or manic domain score as measures of mania and depression risk. Subsequent Poisson regression models included the non-zero variables identified in the penalized regression models. We tested each model in 2 independent samples. Test sample-I,n = 108(21.6 ± 2.09 years,males/females = 33/75); Test sample-II,n = 93(23.7 ± 2.9 years,males/females = 31/62). RESULTS: Poisson regression models yielded significant relationships with depression and mania risk: Positive correlations were found between right fusiform activity and depression(beta = 0.610) and mania(beta = 0.690) risk. There was a significant interaction between sex and right fusiform activity(beta = -0.609) related to depression risk, where females had a positive relationship than; and a significant interaction(beta = 0.743) between sex and left precuneus activity related to mania risk, with a more negative relationship in females than males. All findings were replicated in the test samples(qs < 0.05,FDR). LIMITATIONS: No longitudinal follow-up. CONCLUSION: Greater visual attention to emotional faces might underlie greater depression and mania risk, and confer greater vulnerability to depression in females, because of heightened visual attention to emotional faces. Females have a more negative relationship between mania risk and left precuneus activity, suggesting heightened empathy might be associated with reduced mania/hypomania risk in females more than males.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in MECP2, which encodes methyl-CpG-binding protein 2, a transcriptional regulator of many genes, including brain-derived neurotrophic factor (BDNF). BDNF levels are lower in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of LM22A-4, a brain-penetrant, small-molecule ligand of the BDNF receptor TrkB (encoded by Ntrk2), on dendritic spine density and form in hippocampal pyramidal neurons and on behavioral phenotypes in female Mecp2 heterozygous (HET) mice. A 4-week systemic treatment of Mecp2 HET mice with LM22A-4 restored spine volume in MeCP2-expressing neurons to wild-type (WT) levels, whereas spine volume in MeCP2-lacking neurons remained comparable to that in neurons from female WT mice. Female Mecp2 HET mice engaged in aggressive behaviors more than WT mice, the levels of which were reduced to WT levels by the 4-week LM22A-4 treatment. These data provide additional support to the potential usefulness of novel therapies not only for RTT but also to other BDNF-related disorders.

Early Infant Prefrontal Cortical Microstructure Predicts Present and Future Emotionality.

BACKGROUND: High levels of infant negative emotionality (NE) and low positive emotionality (PE) predict future emotional and behavioral problems. The prefrontal cortex (PFC) supports emotional regulation, with each PFC subregion specializing in specific emotional processes. Neurite orientation dispersion and density imaging estimates microstructural integrity and myelination via the neurite density index (NDI) and dispersion via the orientation dispersion index (ODI), with potential to more accurately evaluate microstructural alterations in the developing brain. Yet, no study has used these indices to examine associations between PFC microstructure and concurrent or developing infant emotionality. METHODS: We modeled PFC subregional NDI and ODI at 3 months with caregiver-reported infant NE and PE at 3 months (n = 61) and at 9 months (n = 50), using multivariable and subsequent bivariate regression models. RESULTS: The most robust statistically significant findings were positive associations among 3-month rostral anterior cingulate cortex (ACC) ODI and caudal ACC NDI and concurrent NE, a positive association between 3-month lateral orbitofrontal cortex ODI and prospective NE, and a negative association between 3-month dorsolateral PFC ODI and concurrent PE. Multivariate models also revealed that other PFC subregional microstructure measures, as well as infant and caregiver sociodemographic and clinical factors, predicted infant 3- and 9-month NE and PE. CONCLUSIONS: Greater NDI and ODI, reflecting greater microstructural complexity, in PFC regions supporting salience perception (rostral ACC), decision making (lateral orbitofrontal cortex), action selection (caudal ACC), and attentional processes (dorsolateral PFC) might result in greater integration of these subregions with other neural networks and greater attention to salient negative external cues, thus higher NE and/or lower PE. These findings provide potential infant cortical markers of future psychopathology risk.

Identifying tripartite relationship among cortical thickness, neuroticism, and mood and anxiety disorders.

The number of young adults seeking help for emotional distress, subsyndromal-syndromal mood/anxiety symptoms, including those associated with neuroticism, is rising and can be an early manifestation of mood/anxiety disorders. Identification of gray matter (GM) thickness alterations and their relationship with neuroticism and mood/anxiety symptoms can aid in earlier diagnosis and prevention of risk for future mood and anxiety disorders. In a transdiagnostic sample of young adults (n = 252;177 females; age 21.7 ± 2), Hypothesis (H) 1:regularized regression followed by multiple regression examined relationships among GM cortical thickness and clinician-rated depression, anxiety, and mania/hypomania; H2:the neuroticism factor and its subfactors as measured by NEO Personality Inventory (NEO-PI-R) were tested as mediators. Analyses revealed positive relationships between left parsopercularis thickness and depression (B = 4.87, p = 0.002), anxiety (B = 4.68, p = 0.002), mania/hypomania (B = 6.08, p ≤ 0.001); negative relationships between left inferior temporal gyrus (ITG) thickness and depression (B = - 5.64, p ≤ 0.001), anxiety (B = - 6.77, p ≤ 0.001), mania/hypomania (B = - 6.47, p ≤ 0.001); and positive relationships between left isthmus cingulate thickness (B = 2.84, p = 0.011), and anxiety. NEO anger/hostility mediated the relationship between left ITG thickness and mania/hypomania; NEO vulnerability mediated the relationship between left ITG thickness and depression. Examining the interrelationships among cortical thickness, neuroticism and mood and anxiety symptoms enriches the potential for identifying markers conferring risk for mood and anxiety disorders and can provide targets for personalized intervention strategies for these disorders.

The effect of slow wave sleep deprivation on mood in adolescents with depressive symptoms: A pilot study.

BACKGROUND: There is an urgent need for safe, rapid-acting treatment strategies for adolescent depression. In depressed adults, slow wave sleep deprivation (SWSD) improved next-day mood without disrupting sleep duration, but SWSD has not been tested in adolescents. In a pilot study, the aim was to assess the effect of SWSD on sleep physiology and mood outcomes (depression, rumination, anhedonia) among adolescents with depressive symptoms. METHODS: Sixteen adolescents (17.44 ± 1.46 yr, 12 female) completed three nights of polysomnographic sleep recording: Baseline, SWSD, and Recovery nights. Acoustic stimulation (tones of random pitch, duration, and volume) suppressed slow wave sleep (SWS) in real-time during SWSD. After each night, depression, rumination, and anhedonia severity were assessed. RESULTS: SWSD successfully suppressed SWS, increased N2, and had minimal impact on Rapid Eye Movement (REM), nocturnal awakenings, and total sleep time. While SWSD did not improve depression or anhedonia severity overall, lower baseline non-REM alpha activity and greater SWS rebound during recovery sleep correlated with SWSD-related reduction in clinician-rated depression severity. Next-day rumination severity decreased after SWSD, with sustained improvements following recovery sleep. However, rumination improvement was not associated with SWS suppression, but rather reduction in total sleep time and REM in exploratory correlation models. LIMITATIONS: Small sample size and large proportion of females. CONCLUSION: SWSD did not improve depression in adolescents overall but a subset with low non-REM alpha activity and intact homeostatic sleep regulation may benefit from this approach. Findings from this pilot study also suggest that partial sleep deprivation may be a beneficial therapeutic strategy for rumination in adolescents.

Differential role of fusiform gyrus coupling in depressive and anxiety symptoms during emotion perception.

Anxiety and depression co-occur; the neural substrates of shared and unique components of these symptoms are not understood. Given emotional alterations in internalizing disorders, we hypothesized that function of regions associated with emotion processing/regulation, including the anterior cingulate cortex (ACC), amygdala and fusiform gyrus (FG), would differentiate these symptoms. Forty-three adults with depression completed an emotional functional magnetic resonance imaging task and the Hamilton Depression and Anxiety Scales. We transformed these scales to examine two orthogonal components, one representing internalizing symptom severity and the other the type of internalizing symptoms (anxiety vs depression). We extracted blood oxygen level dependent signal from FG subregions, ACC, and amygdala and performed generalized psychophysiological interaction analyses to assess relationships between symptoms and brain function. Type of internalizing symptoms was associated with FG3-FG1 coupling (F = 8.14, P = 0.007). More coupling was associated with a higher concentration of depression, demonstrating that intra-fusiform coupling is differentially associated with internalizing symptom type (anxiety vs depression). We found an interaction between task condition and internalizing symptoms and dorsal (F = 4.51, P = 0.014) and rostral ACC activity (F = 4.27, P = 0.012). Post hoc comparisons revealed that less activity was associated with greater symptom severity during emotional regulation. Functional coupling differences during emotional processing are associated with depressive relative to anxiety symptoms and internalizing symptom severity. These findings could inform future treatments for depression.

Continuous theta burst stimulation to dorsomedial prefrontal cortex in young adults with depression: Changes in resting frontostriatal functional connectivity relevant to positive mood.

Depression is associated with diminished positive affect (PA), postulated to reflect frontostriatal reward circuitry disruptions. Depression has consistently been associated with higher dorsomedial prefrontal cortex (dmPFC) activation, a region that regulates PA through ventral striatum (VS) connections. Low PA in depression may reflect dmPFC's aberrant functional connectivity (FC) with the VS. To test this, we applied theta burst stimulation (TBS) to dmPFC in 29 adults with depression (79% female, Mage = 21.4, SD = 2.04). Using a randomized, counterbalanced design, we administered 3 types of TBS at different sessions: intermittent (iTBS; potentiating), continuous (cTBS; depotentiating), and sham TBS (control). We used neuronavigation to target personalized dmPFC targets based on VS-dmPFC FC. PA and negative affect (NA), and resting-state fMRI were collected pre- and post-TBS. We found no changes in PA or NA with time (pre/post), condition (iTBS, cTBS, sham), or their interaction. Functional connectivity (FC) between the nucleus accumbens and dmPFC showed a significant condition (cTBS, iTBS, and sham) by time (pre-vs. post-TBS) interaction, and post-hoc testing showed decreased pre-to post-TBS for cTBS but not iTBS or sham. For cTBS only, reduced FC pre/post stimulation was associated with increased PA (but not NA). Our findings lend support to the proposed mechanistic model of aberrant FC between the dmPFC and VS in depression and suggest a way forward for treating depression in young adults. Future studies need to evaluate multi-session TBS to test clinical effects.

Specific Patterns of Endogenous Functional Connectivity Are Associated With Harm Avoidance in Obsessive-Compulsive Disorder.

BACKGROUND: Individuals with obsessive-compulsive disorder (OCD) show persistent avoidance behaviors, often in the absence of actual threat. Quality-of-life costs and heterogeneity support the need for novel brain-behavior intervention targets. Informed by mechanistic and anatomical studies of persistent avoidance in rodents and nonhuman primates, our goal was to test whether connections within a hypothesized persistent avoidance-related network predicted OCD-related harm avoidance (HA), a trait measure of persistent avoidance. We hypothesized that 1) HA, not an OCD diagnosis, would be associated with altered endogenous connectivity in at least one connection in the network; 2) HA-specific findings would be robust to comorbid symptoms; and 3) reliable findings would replicate in a holdout testing subsample. METHODS: Using resting-state functional connectivity magnetic resonance imaging, cross-validated elastic net for feature selection, and Poisson generalized linear models, we tested which connections significantly predicted HA in our training subsample (n = 73; 71.8% female; healthy control group n = 36, OCD group n = 37); robustness to comorbidities; and replicability in a testing subsample (n = 30; 56.7% female; healthy control group n = 15, OCD group n = 15). RESULTS: Stronger inverse connectivity between the right dorsal anterior cingulate cortex and right basolateral amygdala and stronger positive connectivity between the right ventral anterior insula and left ventral striatum were associated with greater HA across groups. Network connections did not discriminate OCD diagnostic status or predict HA-correlated traits, suggesting sensitivity to trait HA. The dorsal anterior cingulate cortex-basolateral amygdala relationship was robust to controlling for comorbidities and medication in individuals with OCD and was also predictive of HA in our testing subsample. CONCLUSIONS: Stronger inverse dorsal anterior cingulate cortex-basolateral amygdala connectivity was robustly and reliably associated with HA across groups and in OCD. Results support the relevance of a cross-species persistent avoidance-related network to OCD, with implications for precision-based approaches and treatment.

Perception of social inclusion/exclusion and response inhibition in adolescents with past suicide attempt: a multidomain task-based fMRI study.

The occurrence of suicidal behaviors increases during adolescence. Hypersensitivity to negative social signals and deficits in cognitive control are putative mechanisms of suicidal behaviors, which necessitate confirmation in youths. Multidomain functional neuroimaging could enhance the identification of patients at suicidal risk beyond standard clinical measures. Three groups of adolescents (N = 96; 78% females, age = 11.6-18.1) were included: patients with depressive disorders and previous suicide attempts (SA, n = 29); patient controls with depressive disorders but without any suicide attempt history (PC, n = 35); and healthy controls (HC, n = 32). We scanned participants with 3T-MRI during social inclusion/exclusion (Cyberball Game) and response inhibition (Go-NoGo) tasks. Neural activation was indexed by the blood-oxygenation-level dependent (BOLD) of the hemodynamic response during three conditions in the Cyberball Game ("Control condition", "Social Inclusion", and "Social Exclusion"), and two conditions in Go-NoGo task ("Go" and "NoGo" blocks). ANCOVA-style analysis identified group effects across three whole-brain contrasts: 1) NoGo vs. Go, 2) Social inclusion vs. control condition, 3) Social exclusion vs. control condition. We found that SA had lower activation in the left insula during social inclusion vs. control condition compared to PC and HC. Moreover, SA compared to PC had higher activity in the right middle prefrontal gyrus during social exclusion vs. control condition, and in bilateral precentral gyri during NoGo vs. Go conditions. Task-related behavioral and self-report measures (Self-reported emotional reactivity in the Cyberball Game, response times and number of errors in the Go-NoGo Task) did not discriminate groups. In conclusion, adolescent suicidal behaviors are likely associated with neural alterations related to the processing of social perception and response inhibition. Further research, involving prospective designs and diverse cohorts of patients, is necessary to explore the potential of neuroimaging as a tool in understanding the emergence and progression of suicidal behaviors.

Neural markers of mania that distinguish inpatient adolescents with bipolar disorder from those with other psychopathology.

Pediatric bipolar disorder (BD) is difficult to distinguish from other psychiatric disorders, a challenge which can result in delayed or incorrect interventions. Using neuroimaging we aimed to identify neural measures differentiating a rarified sample of inpatient adolescents with BD from other inpatient psychopathology (OP) and healthy adolescents (HC) during a reward task. We hypothesized reduced subcortical and elevated cortical activation in BD relative to other groups, and that these markers will be related to self-reported mania scores. We examined inpatient adolescents with diagnosis of BD-I/II (n = 29), OP (n = 43), and HC (n = 20) from the Inpatient Child and Adolescent Bipolar Spectrum Imaging study. Inpatient adolescents with BD showed reduced activity in right thalamus, left thalamus, and left amygdala, relative to inpatient adolescents with OP and HC. This reduced neural function explained 21% of the variance in past month and 23% of the variance in lifetime mania scores. Lower activity in regions associated with the reward network, during reward processing, differentiates BD from OP in inpatient adolescents and explains >20% of the variance in mania scores. These findings highlight potential targets to aid earlier identification of, and guide new treatment developments for, pediatric BD.

Patterns of Neural Network Functional Connectivity Associated With Mania/Hypomania and Depression Risk in 3 Independent Young Adult Samples.

Importance: Mania/hypomania is the pathognomonic feature of bipolar disorder (BD). Established, reliable neural markers denoting mania/hypomania risk to help with early risk detection and diagnosis and guide the targeting of pathophysiologically informed interventions are lacking. Objective: To identify patterns of neural responses associated with lifetime mania/hypomania risk, the specificity of such neural responses to mania/hypomania risk vs depression risk, and the extent of replication of findings in 2 independent test samples. Design, Setting, and Participants: This cross-sectional study included 3 independent samples of young adults aged 18 to 30 years without BD or active substance use disorder within the past 3 months who were recruited from the community through advertising. Of 603 approached, 299 were ultimately included and underwent functional magnetic resonance imaging at the University of Pittsburgh, Pittsburgh, Pennsylvania, from July 2014 to May 2023. Main Outcomes and Measures: Activity and functional connectivity to approach-related emotions were examined using a region-of-interest mask supporting emotion processing and emotional regulation. The Mood Spectrum Self-Report assessed lifetime mania/hypomania risk and depression risk. In the discovery sample, elastic net regression models identified neural variables associated with mania/hypomania and depression risk; multivariable regression models identified the extent to which selected variables were significantly associated with each risk measure. Multivariable regression models then determined whether associations in the discovery sample replicated in both test samples. Results: A total of 299 participants were included. The discovery sample included 114 individuals (mean [SD] age, 21.60 [1.91] years; 80 female and 34 male); test sample 1, 103 individuals (mean [SD] age, 21.57 [2.09] years; 30 male and 73 female); and test sample 2, 82 individuals (mean [SD] age, 23.43 [2.86] years; 48 female, 29 male, and 5 nonbinary). Associations between neuroimaging variables and Mood Spectrum Self-Report measures were consistent across all 3 samples. Bilateral amygdala-left amygdala functional connectivity and bilateral ventrolateral prefrontal cortex-right dorsolateral prefrontal cortex functional connectivity were positively associated with mania/hypomania risk: discovery omnibus χ2 = 1671.7 (P < .001); test sample 1 omnibus χ2 = 1790.6 (P < .001); test sample 2 omnibus χ2 = 632.7 (P < .001). Bilateral amygdala-left amygdala functional connectivity and right caudate activity were positively associated and negatively associated with depression risk, respectively: discovery omnibus χ2 = 2566.2 (P < .001); test sample 1 omnibus χ2 = 2935.9 (P < .001); test sample 2 omnibus χ2 = 1004.5 (P < .001). Conclusions and Relevance: In this study of young adults, greater interamygdala functional connectivity was associated with greater risk of both mania/hypomania and depression. By contrast, greater functional connectivity between ventral attention or salience and central executive networks and greater caudate deactivation were reliably associated with greater risk of mania/hypomania and depression, respectively. These replicated findings indicate promising neural markers distinguishing mania/hypomania-specific risk from depression-specific risk and may provide neural targets to guide and monitor interventions for mania/hypomania and depression in at-risk individuals.

White matter integrity in bipolar disorder investigated with diffusion tensor magnetic resonance imaging and fractal geometry.

BACKGROUND: Growing evidence suggests the presence of white matter (WM) alterations in bipolar disorder (BD). In this study we aimed to investigate the state of WM structures, in terms of tissue integrity and morphological complexity, in BD patients compared to healthy controls (HC), in an attempt to better elucidate the microstructural changes associated with BD. METHODS: We collected a dataset of 399 Diffusion Tensor Magnetic Resonance Imaging (167 BD and 232 healthy controls) images, acquired at five different sites, which was processed with Tract-Based Spatial Statistics (TBSS) and fractal analysis. RESULTS: The TBSS analysis demonstrated significantly lower FA values in the BD group. Diffusion abnormalities were primarily located in the temporo-parietal network. The Fractal Dimension (FD) analysis did not reveal consistent significant differences in the morphological complexity of WM structures between the groups. When the FD values of patients were considered individually, it is possible to notice some localized significant deviations from the healthy population. LIMITATIONS: DTI sequences have not been harmonized before acquisition, samples' sizes are heterogeneous. CONCLUSIONS: This study, by applying both TBSS and FD analyses, allows to evaluate diffusion and structural alterations of WM at the same time. The evaluation of WM integrity from these two different perspectives could be useful to better understand the pathophysiological and morphological changes underpinning bipolar disorder.

A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in methyl-CpG-binding protein-2 (MECP2), encoding a transcriptional regulator of many genes, including brain-derived neurotrophic factor (Bdnf). BDNF mRNA and protein levels are lower in RTT autopsy brains and in multiple brain regions of Mecp2-deficient mice, and experimentally increasing BDNF levels improve atypical phenotypes in Mecp2 mutant mice. Due to the low blood-brain barrier permeability of BDNF itself, we tested the effects of a brain penetrant, small molecule ligand of its TrkB receptors. Applied in vitro, LM22A-4 increased dendritic spine density in pyramidal neurons in cultured hippocampal slices from postnatal day (P) 7 male Mecp2 knockout (KO) mice as much as recombinant BDNF, and both effects were prevented by the TrkB receptor inhibitors K-252a and ANA-12. Consistent with its partial agonist activity, LM22A-4 did not affect spine density in CA1 pyramidal neurons in slice cultures from male wildtype (WT) mice, where typical BDNF levels outcompete its binding to TrkB. To identify neurons of known genotypes in the "mosaic" brain of female Mecp2 heterozygous (HET) mice, we treated 4-6-month-old female MeCP2-GFP WT and HET mice with peripheral injections of LM22A-4 for 4 weeks. Surprisingly, mutant neurons lacking MeCP2-GFP showed dendritic spine volumes comparable to that in WT controls, while MeCP2-GFP-expressing neurons showed larger spines, similar to the phenotype we described in symptomatic male Mecp2 KO mice where all neurons lack MeCP2. Consistent with this non-cell-autonomous mechanism, a 4-week systemic treatment with LM22A-4 had an effect only in MeCP2-GFP-expressing neurons in female Mecp2 HET mice, bringing dendritic spine volumes down to WT control levels, and without affecting spines of MeCP2-GFP-lacking neurons. At the behavioral level, we found that female Mecp2 HET mice engaged in aggressive behaviors significantly more than WT controls, which were reduced to WT levels by a 4-week systemic treatment with LM22A-4. Altogether, these data revealed differences in dendritic spine size and altered behaviors in Mecp2 HET mice, while providing support to the potential usefulness of BDNF-related therapeutic approaches such as the partial TrkB agonist LM22A-4.