A machine-learning approach to model risk and protective factors of vulnerability to depression.

There are multiple risk and protective factors for depression. The association between these factors with vulnerability to depression is unclear. Such knowledge is an important insight into assessing risk for developing depression for precision interventions. Based on the behavioral data of 496 participants (all unmarried and not cohabiting, with a college education level or above), we applied machine-learning approaches to model risk and protective factors in estimating depression and its symptoms. Then, we employed Random Forest to identify important factors which were then used to differentiate participants who had high risk of depression from those who had low risk. Results revealed that risk and protective factors could significantly estimate depression and depressive symptoms. Feature selection revealed four key factors including three risk factors (brooding, perceived loneliness, and perceived stress) and one protective factor (resilience). The classification model built by the four factors achieved an ROC-AUC score of 75.50% to classify the high- and low-risk groups, which was comparable to the classification performance based on all risk and protective factors (ROC-AUC = 77.83%). Based on the selected four factors, we generated a mood vulnerability index useful for identifying people's risk for depression. Our findings provide potential clinical insights for developing quick screening tools for mood disorders and potential targets for intervention programs designed to improve depressive symptoms.

Retinal GABAergic Alterations in Adults with Autism Spectrum Disorder.

Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina, and in this study, we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: (1) the standard white flash, (2) the standard 30 Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30 mg of arbaclofen (STX209, GABAB agonist) in a randomized, double-blind, crossover order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with a decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by using an electroencephalogram in our prior study and with broader autistic traits measured with the autism quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in the central processing of sensory information, which may be upstream of more complex autistic phenotypes.

Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABAB activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

Effect of Tai Chi on Young Adults with Subthreshold Depression via a Stress-Reward Complex: A Randomized Controlled Trial.

BACKGROUND: Subthreshold depression is a highly prevalent mood disorder in young adults. Mind-body exercises, such as Tai Chi, have been adopted as interventions for clinical depressive symptoms. However, the possible effect and underlying mechanism of Tai Chi on subthreshold depression of young individuals remain unclear. This randomized controlled study aimed to evaluate the effects of Tai Chi training and tested the combined stress and reward circuitry model for subthreshold depression. RESULTS: A total of 103 participants completed this trial, with 49 in the 12-week 24-style Tai Chi group and 54 participants in control group. Our results showed significantly lower scores on depressive symptoms (P = 0.002) and anxiety symptoms (P = 0.009) and higher scores on quality of life (P = 0.002) after Tai Chi training. There were significant reductions in salivary cortisol levels (P = 0.007) and putamen gray matter volume (P < 0.001) in the Tai Chi group. The changes in cortisol levels and putamen gray matter volume had direct (bootstrapping confidence interval [- 0.91, - 0.11]) and indirect effects (bootstrapping confidence interval [- 0.65, - 0.19]) on the changes induced by Tai Chi training on depressive symptoms, respectively. CONCLUSION: The stress-reward complex results indicated an interaction between lowering stress levels and increasing reward circuitry activity associated with the alleviation of depressive symptoms among participants. The 12-week Tai Chi training was effective in improving the symptoms and quality of life of young adults with subthreshold depression. Trial Registration Chinese Registry of Clinical Trials (Registration Number: ChiCTR1900028289, Registered December 12, 2019).

Integrity of cerebellar tracts associated with the risk of bipolar disorder.

This study examined the structural brain differences across individuals of different BD stages and the risks of developing bipolar disorder (BD) associated with these brain differences. A total of 221 participants who were recruited from the Guangzhou Brain Hospital and the community were categorized into four groups: NC (healthy control) (N = 77), high risk (HR) (N = 42), ultra-high risk (UHR) (N = 38), and bipolar disorder (BD) (N = 64) based on a list of criteria. Their demographics, clinical characteristics, and diffusion magnetic resonance imaging (dMRI) data were collected. ANCOVA results showed that the HR group had significantly reduced mean diffusivity (MD) (p = 0.043) and radial diffusivity (RD) (p = 0.039) of the left portico-ponto-cerebellar tracts when compared with the BD group. Moreover, logistic regression results showed that the specific diffusivity measures of cerebellar tracts (e.g., cortico-ponto-cerebellar tract), particularly the RD and MD revealed differences between groups at different BD stages after controlling for the covariates. The findings suggested that specific diffusivity (RD and MD) of cerebellar tracts (e.g., cortico-ponto-cerebellar tract) revealed differences between groups at different BD stages which is helpful in detecting the trajectory changes in BD syndromes in the early stages of BD, particularly when the BD syndromes start from HR stage.

Amygdala-pons connectivity is hyperactive and associated with symptom severity in depression.

Knowledge of the neural underpinnings of processing sad information and how it differs in people with depression could elucidate the neural mechanisms perpetuating sad mood in depression. Here, we conduct a 7 T fMRI study to delineate the neural correlates involved only in processing sad information, including pons, amygdala, and corticolimbic regions. We then conduct a 3 T fMRI study to examine the resting-state connectivity in another sample of people with and without depression. Only clinically depressed people demonstrate hyperactive amygdala-pons connectivity. Furthermore, this connectivity is related to depression symptom severity and is a significant indicator of depression. We speculate that visual sad information reinforces depressed mood and stimulates the pons, strengthening the amygdala-pons connectivity. The relationship between this connectivity and depressive symptom severity suggests that guiding one's visual attention and processing of sad information may benefit mood regulation.

Meta-analytic evidence for the cognitive control model of loneliness in emotion processing.

Loneliness is strongly related to affective dysregulation. However, the neuropsychological mechanisms underpinning the loneliness-affective processing relationships remain unclear. Here, we first utilised the coordinate-based activation likelihood estimation method to confirm functional clusters related to loneliness, including the striatum, superior and medial frontal gyrus, insula, and cuneus. Meta-analytic connectivity modelling was then performed to characterise the functional connectivity of these clusters across studies using emotion tasks. Our results revealed that these clusters co-activated with the cognitive control networks. From the literature, we understand that loneliness and its neural correlates are highly related to regulating the attention biases to social rewards and social cues. Therefore, our findings provide a proof-of-concept that loneliness up-regulates the cognitive control networks to process socio-affective information. Prolonged up-regulation thus exhausts cognitive resources and hence, affective dysregulation. This study offers insight into the intricate role of cognitive and affective regulation in loneliness and social perception and provides meta-analytic evidence of the cognitive control model of loneliness and loneliness-related affective dysregulation, bringing significant clinical implications.

GABAB receptor modulation of visual sensory processing in adults with and without autism spectrum disorder.

Sensory atypicalities in autism spectrum disorder (ASD) are thought to arise at least partly from differences in γ-aminobutyric acid (GABA) receptor function. However, the evidence to date has been indirect, arising from correlational studies in patients and preclinical models. Here, we evaluated the role of GABA receptor directly, in 44 adults (n = 19 ASD). Baseline concentration of occipital lobe GABA+ (GABA plus coedited macromolecules) was measured using proton magnetic resonance spectroscopy (1H-MRS). Steady-state visual evoked potential (SSVEP) elicited by a passive visual surround suppression paradigm was compared after double-blind randomized oral administration of placebo or 15 to 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. In the placebo condition, the neurotypical SSVEP response was affected by both the foreground stimuli contrast and background interference (suppression). In ASD, however, all stimuli conditions had equal salience and background suppression of the foreground response was weaker. In the placebo condition, although there was no difference in GABA+ between groups, GABA+ concentration positively correlated with response to maximum foreground contrast during maximum background interference in neurotypicals, but not ASD. In neurotypicals, sensitivity to visual stimuli was disrupted by 30 mg of arbaclofen, whereas in ASD, it was made more "typical" and visual processing differences were abolished. Hence, differences in GABAergic function are fundamental to autistic (visual) sensory neurobiology and are modulated by GABAB activity.

Aberrant functional metastability and structural connectivity are associated with rumination in individuals with major depressive disorder.

Rumination is a repetitive and compulsive thinking focusing on oneself, and the nature and consequences of distress. It is a core characteristic in psychiatric disorders characterized by affective dysregulation, and emerging evidence suggests that rumination is associated with aberrant dynamic functional connectivity and structural connectivity. However, the underlying neural mechanisms remain poorly understood. Here, we adopted a multimodal approach and tested the hypothesis that white matter connectivity forms the basis of the implications of temporal dynamics of functional connectivity in the rumination trait. Fifty-three depressed and ruminative individuals and a control group of 47 age- and gender-matched individuals with low levels of rumination underwent resting-state fMRI and diffusion tensor imaging. We found that lower global metastability and higher global synchrony of the dynamic functional connectivity were associated with higher levels of rumination. Specifically, the altered global synchrony and global metastability mediated the association between white matter integrity of the genu of the corpus callosum to rumination. Hence, our findings offered the first line of evidence for the intricate role of (sub)optimal transition of functional brain states in the connection of structural brain connectivity in ruminative thinking.

Qigong exercise enhances cognitive functions in the elderly via an interleukin-6-hippocampus pathway: A randomized active-controlled trial.

BACKGROUND: Evidence has suggested that exercise protects against cognitive decline in aging, but the recent lockdown measures associated with the COVID-19 pandemic have limited the opportunity for outdoor exercise. Herein we tested the effects of an indoor exercise, Qigong, on neurocognitive functioning as well as its potential neuro-immune pathway. METHODS: We conducted a 12-week randomized active-controlled trial with two study arms in cognitively healthy older people. We applied Wu Xing Ping Heng Gong (Qigong), which was designed by an experienced Daoist Qigong master, to the experimental group, whereas we applied the physical stretching exercise to the control group. The Qigong exercise consisted of a range of movements involving the stretching of arms and legs, the turning of the torso, and relaxing, which would follow the fundamental principles of Daoism and traditional Chinese medicine (e.g., Qi). We measured aging-sensitive neurocognitive abilities, serum interleukin-6 (IL-6) levels, and brain structural volumes in the experimental (Qigong, n = 22) and control groups (stretching, n = 26) before and after the 12-week training. RESULTS: We observed that Qigong caused significant improvement in processing speed (t (46) = 2.03, p = 0.048) and sustained attention (t (46) = -2.34, p = 0.023), increased hippocampal volume (t (41) = 3.94, p < 0.001), and reduced peripheral IL-6 levels (t (46) = -3.17, p = 0.003). Moreover, following Qigong training, greater reduction of peripheral IL-6 levels was associated with a greater increase of processing speed performance (bootstrapping CI: [0.16, 3.30]) and a more significant training-induced effect of hippocampal volume on the improvement in sustained attention (bootstrapping CI: [-0.35, -0.004]). CONCLUSION: Overall, these findings offer significant insight into the mechanistic role of peripheral IL-6-and its intricate interplay with neural processes-in the beneficial neurocognitive effects of Qigong. The findings have profound implications for early identification and intervention of older individuals vulnerable to cognitive decline, focusing on the neuro-immune pathway. The trial was registered at clinicaltrials.gov (identifier: NCT04641429).

Serotonin differentially modulates the temporal dynamics of the limbic response to facial emotions in male adults with and without autism spectrum disorder (ASD): a randomised placebo-controlled single-dose crossover trial.

Emotion processing-including signals from facial expressions-is often altered in individuals with autism spectrum disorder (ASD). The biological basis of this is poorly understood but may include neurochemically mediated differences in the responsivity of key 'limbic' regions (including amygdala, ventromedial prefrontal cortex (vmPFC) and nucleus accumbens (NAc)). Emerging evidence also suggests that ASD may be a disorder of brain temporal dynamics. Moreover, serotonin (5-HT) has been shown to be a key regulator of both facial-emotion processing and brain dynamics, and 5-HT abnormalities have been consistently implicated in ASD. To date, however, no one has examined how 5-HT influences the dynamics of facial-emotion processing in ASD. Therefore, we compared the influence of 5-HT on the responsivity of brain dynamics during facial-emotion processing in individuals with and without ASD. Participants completed a facial-emotion processing fMRI task at least 8 days apart using a randomised double-blind crossover design. At each visit they received either a single 20-mg oral dose of the selective serotonin reuptake inhibitor (SSRI) citalopram or placebo. We found that citalopram (which increases levels of 5-HT) caused sustained activation in key limbic regions during processing of negative facial emotions in adults with ASD-but not in neurotypical adults. The neurotypical adults' limbic response reverted more rapidly to baseline following a 5-HT-challenge. Our results suggest that serotonergic homoeostatic control of the temporal dynamics in limbic regions is altered in adults with ASD, and provide a fresh perspective on the biology of ASD.

Negative Affect Shared with Siblings is Associated with Structural Brain Network Efficiency and Loneliness in Adolescents.

Loneliness has a strong neurobiological basis reflected by its specific relationships with structural brain connectivity. Critically, affect traits are highly related to loneliness, which shows close association with the onset and severity of major depressive disorder. This diffusion imaging study was conducted on a sample of adolescent siblings to examine whether positive and negative affect traits were related to loneliness, with brain network efficiency playing a mediating role. The findings of this study confirmed that both global and average local efficiency negatively mediated the association between low positive affect and high negative affect and loneliness, and the mediation was more sensitive to sibling-shared affect traits. The findings have important implications for interventions targeted at reducing the detrimental impact of familiar negative emotional experiences and loneliness.

Cerebellar neural markers of susceptibility to social isolation and positive affective processing.

Chronic loneliness predicts mood disturbances and onset of major depressive disorder. However, little research has examined the neural correlates of individual difference in susceptibility to perceiving loneliness. In addition, the role of cerebellum, which is heavily implicated in social, cognitive and affective processes, in loneliness is unclear. We studied 99 healthy individuals divided into susceptible, concordant and robust groups depending on whether the participant's loneliness level was greater, comparable or less than her/his objective social isolation level. The cerebellar gray matter structure, functional activity and connectivity patterns during performing an emotion stroop task were examined. We found greater posterior and medial cerebellar volume in the susceptible group than the other groups. In addition, the posterior and medial cerebellar activities when processing positive versus neutral words exhibited significant interactive effects of both loneliness and social network, and susceptibility to isolation. Loneliness and social network also had positive effects on the right posterior cerebellar functional connectivity with the visual and premotor cortices. Our findings provide novel evidence on the intricate role of the cerebellum in loneliness and susceptibility to isolation, suggesting that socio-cognitive processes of the cerebellum in the hedonic domain may be a key mechanism underlying loneliness proneness.

Neurodevelopmental changes in the relationship between stress perception and prefrontal-amygdala functional circuitry.

Our brain during distinct developmental phases may show differential responses to perceived psychological stress, yet existing research specifically examining neurodevelopmental changes in stress processing is scarce. To fill in this research gap, this functional magnetic resonance imaging (fMRI) study examined the relationship between perceived stress and resting-state neural connectivity patterns among 67 healthy volunteers belonging to three age groups (adolescents, young adults and adults), who were supposed to be at separate neurodevelopmental phases and exhibit different affect regulatory processes in the brain. While the groups showed no significant difference in self-reported general perceived stress levels, the functional connectivity between amygdala and ventromedial prefrontal cortex (vmPFC) was positively and negatively correlated with perceived stress in adolescents and young adults respectively, while no significant correlations were observed in adults. Furthermore, among adolescents, the causal functional interaction between amygdala and vmPFC exhibited bottom-up connectivity, and that between amygdala and subgenual anterior cingulate cortex exhibited top-down connectivity, both of which changed to bilateral directions, i.e. both bottom-up and top-down connections, in both young adults and adults, supporting the notion that the amygdala and prefrontal cortical circuitries undergo functional reorganizations during brain development. These novel findings have important clinical implications in treating stress-related affective disorders in young individuals.

A developmental social neuroscience model for understanding loneliness in adolescence.

Loneliness is prevalent in adolescents. Although it can be a normative experience, children and adolescents who experience loneliness are often at risk for anxiety, depression, and suicide. Research efforts have been made to identify the neurobiological basis of such distressful feelings in our social brain. In adolescents, the social brain is still undergoing significant development, which may contribute to their increased and differential sensitivity to the social environment. Many behavioral studies have shown the significance of attachment security and social skills in adolescents' interactions with the social world. In this review, we propose a developmental social neuroscience model that extends from the social neuroscience model of loneliness. In particular, we argue that the social brain and social skills are both important for the development of adolescents' perceived loneliness and that adolescents' familial attachment sets the baseline for neurobiological development. By reviewing the related behavioral and neuroimaging literature, we propose a developmental social neuroscience model to explain the heightened perception of loneliness in adolescents using social skills and attachment style as neurobiological moderators. We encourage future researchers to investigate adolescents' perceived social connectedness from the developmental neuroscience perspective.

The Integrity of the Corpus Callosum Mitigates the Impact of Blood Pressure on the Ventral Attention Network and Information Processing Speed in Healthy Adults.

Hypertension is a risk factor for cognitive impairment in older age. However, evidence of the neural basis of the relationship between the deterioration of cognitive function and elevated blood pressure is sparse. Based on previous research, we speculate that variations in brain connectivity are closely related to elevated blood pressure even before the onset of clinical conditions and apparent cognitive decline in individuals over 60 years of age. Forty cognitively healthy adults were recruited. Each received a blood pressure test before and after the cognitive assessment in various domains. Diffusion tensor imaging (DTI) and resting-state functional magnetic resonance imaging (rsfMRI) data were collected. Our findings confirm that elevated blood pressure is associated with brain connectivity variations in cognitively healthy individuals. The integrity of the splenium of the corpus callosum is closely related to individual differences in systolic blood pressure. In particular, elevated systolic blood pressure is related to resting-state ventral attention network (VAN) and information processing speed. Serial mediation analyses have further revealed that lower integrity of the splenium statistically predicts elevated systolic blood pressure, which in turn predicts weakened functional connectivity (FC) within the VAN and eventually poorer processing speed. The current study sheds light on how neural correlates are involved in the impact of elevated blood pressure on cognitive functioning.

A Multi-Dimensional and Integrative Approach to Examining the High-Risk and Ultra-High-Risk Stages of Bipolar Disorder.

BACKGROUND: Validating the high-risk (HR) and ultra-high-risk (UHR) stages of bipolar disorder (BP) may help enable early intervention strategies. METHODS: We followed up with 44 offspring of parents with BP, subdividing into the HR and UHR categories. The offspring were aged 8-28 years and were free of any current DSM-IV diagnoses. Our multilevel, integrative approach encompassed gray matter (GM) volumes, brain network connectivity, neuropsychological performance, and clinical outcomes. FINDINGS: Compared with the healthy controls (HCs) (n = 33), the HR offspring (n = 26) showed GM volume reductions in the right orbitofrontal cortex. Compared with the HR offspring, the UHR offspring (n = 18) exhibited increased GM volumes in four regions. Both the HR and UHR offspring displayed abnormalities in the inferior occipital cortex regarding the measures of degree and centrality, reflecting the connections and roles of the region, respectively. In the UHR versus the HR offspring, the UHR offspring exhibited upwards-shifted small world topologies that reflect high clustering and efficiency in the brain networks. Compared with the HCs, the UHR offspring had significantly lower assortativity, which was suggestive of vulnerability. Finally, processing speed, visual-spatial, and general function were impaired in the UHR offspring but not in the HR offspring. INTERPRETATION: The abnormalities observed in the HR offspring appear to be inherited, whereas those associated with the UHR offspring represent stage-specific changes predisposing them to developing the disorder.

A Pontine Region is a Neural Correlate of the Human Affective Processing Network.

The in vivo neural activity of the pons during the perception of affective stimuli has not been studied despite the strong implications of its role in affective processing. To examine the activity of the pons during the viewing of affective stimuli, and to verify its functional and structural connectivity with other affective neural correlates, a multimodal magnetic resonance imaging methodology was employed in this study. We observed the in vivo activity of the pons when viewing affective stimuli. Furthermore, small-world connectivity indicated that the functional connectivity (FC) between the pons and the cortico-limbic affective regions was meaningful, with the coefficient λ being positively associated with self-reported emotional reactivity. The FC between the pons and the cortico-limbic-striatal areas was related to self-reported negative affect. Corroborating this finding was the observation that the tract passing through the pons and the left hippocampus was negatively related to self-reported positive affect and positively correlated with emotional reactivity. Our findings support the framework that the pons works conjunctively with the distributed cortico-limbic-striatal systems in shaping individuals' affective states and reactivity. Our work paves the path for future research on the contribution of the pons to the precipitation and maintenance of affective disorders.