SUMMARY Peripheral processes that mediate beneficial effects of exercise on the brain remain sparsely explored. Here we show that a muscle secretory factor, Cathepsin B (CTSB) protein, is important for cognitive benefits of running. Proteomic analysis revealed elevated levels of CTSB in conditioned medium derived from skeletal muscle cell cultures treated with AMP-kinase agonist AICAR. Consistently, running increased CTSB levels in mouse gastrocnemius muscle and plasma. In addition, in male wildtype (WT), but not CTSB knockout (KO) mice running enhanced adult hippocampal neurogenesis and spatial memory. Furthermore, recombinant CTSB application enhanced expression of brain-derived neurotrophic factor (BDNF) and doublecortin (DCX) in adult hippocampal progenitor cells through a multifunctional protein, P11, dependent mechanism. Interestingly, in Rhesus monkeys and humans treadmill exercise elevated CTSB in plasma. In humans CTSB levels correlated with fitness and hippocampus-dependent memory function. Our findings suggest CTSB as a mediator of effects of exercise on cognition.

SEE MATTAR ET AL DOI101093/AWW151 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Functional brain networks demonstrate significant temporal variability and dynamic reconfiguration even in the resting state. Currently, most studies investigate temporal variability of brain networks at the scale of single (micro) or whole-brain (macro) connectivity. However, the mechanism underlying time-varying properties remains unclear, as the coupling between brain network variability and neural activity is not readily apparent when analysed at either micro or macroscales. We propose an intermediate (meso) scale analysis and characterize temporal variability of the functional architecture associated with a particular region. This yields a topography of variability that reflects the whole-brain and, most importantly, creates an analytical framework to establish the fundamental relationship between variability of regional functional architecture and its neural activity or structural connectivity. We find that temporal variability reflects the dynamical reconfiguration of a brain region into distinct functional modules at different times and may be indicative of brain flexibility and adaptability. Primary and unimodal sensory-motor cortices demonstrate low temporal variability, while transmodal areas, including heteromodal association areas and limbic system, demonstrate the high variability. In particular, regions with highest variability such as hippocampus/parahippocampus, inferior and middle temporal gyrus, olfactory gyrus and caudate are all related to learning, suggesting that the temporal variability may indicate the level of brain adaptability. With simultaneously recorded electroencephalography/functional magnetic resonance imaging and functional magnetic resonance imaging/diffusion tensor imaging data, we also find that variability of regional functional architecture is modulated by local blood oxygen level-dependent activity and α-band oscillation, and is governed by the ratio of intra- to inter-community structural connectivity. Application of the mesoscale variability measure to multicentre datasets of three mental disorders and matched controls involving 1180 subjects reveals that those regions demonstrating extreme, i.e. highest/lowest variability in controls are most liable to change in mental disorders. Specifically, we draw attention to the identification of diametrically opposing patterns of variability changes between schizophrenia and attention deficit hyperactivity disorder/autism. Regions of the default-mode network demonstrate lower variability in patients with schizophrenia, but high variability in patients with autism/attention deficit hyperactivity disorder, compared with respective controls. In contrast, subcortical regions, especially the thalamus, show higher variability in schizophrenia patients, but lower variability in patients with attention deficit hyperactivity disorder. The changes in variability of these regions are also closely related to symptom scores. Our work provides insights into the dyna...

Objectives: To investigate the prevalence and risk factors for poor mental health of Chinese university students during the Corona Virus Disease 2019 (COVID-19) pandemic. Method: Chinese nationwide on-line cross-sectional survey on university students, collected between February 12 th and 17 th , 2020. Primary outcome was prevalence of clinically-relevant posttraumatic stress disorder symptoms. Secondary outcomes on poor mental health included prevalence of clinically-relevant anxiety and depressive symptoms, while posttraumatic growth was considered as indicator of effective coping reaction. Results: Of 2,500 invited Chinese university students, 2,038 completed the survey. Prevalence of clinically-relevant PTSD, anxiety, and depressive symptoms, and post traumatic growth (PTG) was 30.8, 15.5, 23.3, and 66.9% respectively. Older age, knowing people who had been isolated, more ACEs, higher level of anxious attachment, and lower level of resilience all predicted primary outcome (all p < 0.01). Conclusions: A significant proportion of young adults exhibit clinically relevant posttraumatic stress disorder (PTSD), anxious or depressive symptoms, but a larger portion of individuals showed to effectively cope with COVID-19 pandemic. Interventions promoting resilience should be provided, even remotely, to those subjects with specific risk factors to develop poor mental health during COVID-19 or other pandemics with social isolation.

The biological mechanisms underlying long-term partner bonds in humans are unclear. The evolutionarily conserved neuropeptide oxytocin (OXT) is associated with the formation of partner bonds in some species via interactions with brain dopamine reward systems. However, whether it plays a similar role in humans has as yet not been established. Here, we report the results of a discovery and a replication study, each involving a double-blind, placebocontrolled, within-subject, pharmaco-functional MRI experiment with 20 heterosexual pair-bonded male volunteers. In both experiments, intranasal OXT treatment (24 IU) made subjects perceive their female partner's face as more attractive compared with unfamiliar women but had no effect on the attractiveness of other familiar women. This enhanced positive partner bias was paralleled by an increased response to partner stimuli compared with unfamiliar women in brain reward regions including the ventral tegmental area and the nucleus accumbens (NAcc). In the left NAcc, OXT even augmented the neural response to the partner compared with a familiar woman, indicating that this finding is partner-bond specific rather than due to familiarity. Taken together, our results suggest that OXT could contribute to romantic bonds in men by enhancing their partner's attractiveness and reward value compared with other women.emotion | functional imaging | love | monogamy L ove and enduring romantic bonds can bring the elation of profound joy and pleasure but also, when broken, the deepest sorrow and despair. Although love is the source of a large variety of emotions and feelings and celebrated in all human cultures by countless works of art, as yet surprisingly little is known about the neurobiological underpinnings of long-term pair bonds (i.e., enduring attachments between sexual partners) in humans.Indeed, very few other mammalian species [∼3-5% (1)] exhibit pair bonds, with the most investigated species being the prairie vole (Microtus ochrogaster) (2). In prairie voles, partner bonds are formed after the neuropeptides oxytocin (OXT) or arginine vasopressin (AVP) are released in the brain during mating. Their effects on bonding are mediated via interactions with dopamine (DA) release, particularly in the ventral tegmental area (VTA) and nucleus accumbens (NAcc). Furthermore, in different species of voles, a monogamous, as opposed to polygamous, pattern of behavior is associated with a higher density of dopamine D2 receptors (D2R) in the medial prefrontal cortex (mPFC) (3) and of OXT receptors (OXTR) in mPFC, NAcc, and caudate putamen (4, 5). In prairie voles, D2R activation in the NAcc facilitates a partner preference and bond formation in the absence of mating in both sexes (6), whereas the direct injection of OXT into the NAcc (7) does so in females and of AVP into the lateral septum of males (8). Conversely, the infusion of an AVP antagonist into the ventral pallidum of male prairie voles prevents partner preference formation (9). However, nonspecific intracerebroventricular administr...

The neuropeptide oxytocin (OXT) can enhance the impact of positive social cues but may reduce that of negative ones by inhibiting amygdala activation, although it is unclear whether the latter causes blunted emotional and mnemonic responses. In two independent double-blind placebo-controlled experiments, each involving over 70 healthy male subjects, we investigated whether OXT affects modulation of startle reactivity by aversive social stimuli as well as subsequent memory for them. Intranasal OXT potentiated acoustic startle responses to negative stimuli, without affecting behavioral valence or arousal judgments, and biased subsequent memory toward negative rather than neutral items. A functional MRI analysis of this mnemonic effect revealed that, whereas OXT inhibited amygdala responses to negative stimuli, it facilitated left insula responses for subsequently remembered items and increased functional coupling between the left amygdala, left anterior insula, and left inferior frontal gyrus. Our results therefore show that OXT can potentiate the protective and mnemonic impact of aversive social information despite reducing amygdala activity, and suggest that the insula may play a role in emotional modulation of memory. (5), social recognition (6-8) and related memory (9-11), social reinforcement learning and emotional empathy (12), and social judgments (13)(14)(15).This prosocial perspective on OXT is challenged, however, by evidence that OXT also enhances envy and schadenfreude (gloating) (16), ethno-centrism (including prejudice, xenophobia, and racial bias) (4), and outgroup derogation (17). Moreover, OXT hinders trust and cooperation when social information about interaction partners is lacking (18). Furthermore, OXT appears to negatively bias recollections of maternal care and closeness and to diminish trust and cooperation in insecurely or anxiously attached individuals (19,20).In an attempt to reconcile this controversial evidence, it has been proposed that the social effects of OXT could be mediated by reduced anxiety or by an increased perceptual salience of social cues (21). The anxiolytic action of OXT has been confirmed by showing reduced amygdala responses to aversive social stimuli in healthy people (22-25; but see also refs. 26 and 27), and subjects with social phobia (28). It is compatible with decreased endocrine and subjective responses to social stress (29), as well as reduced negative cognitive self-appraisal in individuals scoring high in traitanxiety (30). In contrast, the social salience hypothesis has gained substantial support from studies demonstrating increased eye contact (31) and improved mind-reading from facial expressions (32) as a result of OXT treatment. Whether these mechanisms quintessentially yield positive or negative social outcomes may vary depending on contextual or person-specific characteristics (21). An alternative view holds that emotional valence may be the key in guiding the social effects of OXT, with it facilitating social approach to positive cues and inhibiting...

The specific neural systems underlying the subjective feeling of fear are debated in affective neuroscience. Here, we combine functional MRI with machine learning to identify and evaluate a sensitive and generalizable neural signature predictive of the momentary self-reported subjective fear experience across discovery (n = 67), validation (n = 20) and generalization (n = 31) cohorts. We systematically demonstrate that accurate fear prediction crucially requires distributed brain systems, with important contributions from cortical (e.g., prefrontal, midcingulate and insular cortices) and subcortical (e.g., thalamus, periaqueductal gray, basal forebrain and amygdala) regions. We further demonstrate that the neural representation of subjective fear is distinguishable from the representation of conditioned threat and general negative affect. Overall, our findings suggest that subjective fear, which exhibits distinct neural representation with some other aversive states, is encoded in distributed systems rather than isolated ‘fear centers’.

Previous research on gaming disorder (GD) has highlighted key methodological and conceptual hindrances stemming from the heterogeneity of nomenclature and the use of nonstandardized psychometric tools to assess this phenomenon. The recent recognition of GD as an official mental health disorder and behavioral addiction by the World Health Organization (WHO) in the 11th Revision of the International Classification of Diseases (ICD-11) opens up new possibilities to investigate further the psychosocial and mental health implications due to excessive and disordered gaming. However, before further research on GD can be conducted in a reliable way and within a robust cross-cultural context, a valid and reliable standardized psychometric tool to assess the construct as defined by the WHO should be developed. The aim of this study was to develop The Gaming Disorder Test (GDT), a brief four-item measure to assess GD and to further explore its psychometric properties. A sample of 236 Chinese (47% male, mean age 19.22 years, SD = 1.57) and 324 British (49.4% male, mean age 26.74 years, SD = 7.88) gamers was recruited online. Construct validity of the GDT was examined via factorial validity, nomological validity, alongside convergent and discriminant validity. Concurrent validity was also examined using the Internet Gaming Disorder Scale-Short-Form (IGDS9-SF). Finally, reliability indicators involving the Cronbach's alpha and composite reliability coefficients were estimated. Overall, the results indicated that GDT is best conceptualized within a single-factor structure. Additionally, the four items of the GDT are valid, reliable, and proved to be highly suitable for measuring GD within a cross-cultural context.

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