The effect of transcranial direct current and magnetic stimulation on fear extinction and return of fear: A meta-analysis and systematic review.

BACKGROUND: We conducted a meta-analysis and qualitative review on the randomized controlled trials investigating the effects of transcranial direct current stimulation and transcranial magnetic stimulation on fear extinction and the return of fear in non-primate animals and humans. METHODS: The meta-analysis was conducted by searching PubMed, Web of science, PsycINFO, and Cochrane Library and extracting fear response in the active and sham groups in the randomized controlled trials. The pooled effect size was quantified by Hedges' g using a three-level meta-analytic model in R. RESULTS: We identified 18 articles on the tDCS effect and 5 articles on the TMS effect, with 466 animal subjects and 621 human subjects. Our findings show that tDCS of the prefrontal cortex significantly inhibit fear retrieval in animal models (Hedges' g = -0.50). In human studies, TMS targeting the dorsolateral/ventromedial prefrontal cortex has an inhibiting effect on the return of fear (Hedges' g = -0.24). LIMITATIONS: The limited number of studies and the heterogeneous designs of the selected studies made cross-study and cross-species comparison difficult. CONCLUSIONS: Our findings shed light on the optimal non-invasive brain stimulation protocols for targeting the neural circuitry of threat extinction in humans.

Acute stress impairs intentional memory suppression through aberrant prefrontal cortex activation in high trait ruminators.

Objective: Research shows that the effect of acute stress on intentional memory suppression could be modulated by individual differences in psychological traits. However, whether acute stress distinctly affects intentional memory suppression in high trait ruminators, a high at-risk group of stress-related disorders, and the neural correlations, remains unclear. Method: 55 healthy college students were divided into high and low trait ruminators (HTR and LTR), Following stress manipulation, a Think/No Think task assessed the memory suppression performance. Functional near-infrared spectroscopy was applied to explore the neural correlates. Psychophysiological interaction analyses were used to assess how the functional connectivity between a seed region and another brain region was modulated by tasks during memory suppression, further mediating memory suppression performance and state rumination. Results: The HTR exhibited poorer memory suppression performance than the LTR under the stress condition. Aberrant activation patterns and task-modulated functional connectivity in the dorsal prefrontal cortex (DLPFC) and superior temporal gyrus (STG) were observed only in the HTR during memory suppression under the stress condition. The effect of memory suppression performance on the state rumination of individuals was significantly mediated by the task-modulated functional connectivity between the DLPFC and STG. Conclusions: The findings could provide insights for prevention or early intervention in the development of stress-related disorders in HTR.

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.

Aberrant positive affect dynamics in individuals with subthreshold depression: Evidence from laboratory and real-world assessments / Dinámica aberrante del afecto positivo en individuos con depresión subumbral: evidencia de evaluaciones de laboratorio y del mundo real

Background/Objective: Reduced positive affect (PA) is a core feature of major depressive disorder (MDD). However, the precursor of MDD, subthreshold depression (StD), has received less attention in this regard. Therefore, we examined PA dynamics in StD, integrating laboratory-based and ecological momentary assessment (EMA) approaches. Method: Participants were college students recruited from Chinese universities (31 with StD, and 39 healthy controls (HC)). Positive mood was induced in the laboratory by an eight-minute comedy clip used to assess PA reactivity and maintenance. To extend findings to the real world and explore mechanisms of PA maintenance, 53 participants with StD and 64 HC reported their emotional states 14 times daily for one week via EMA. Multilevel models were used to test for predictors of PA inertia. Results: In the laboratory, participants with StD achieved the same PA reactivity as HC when facing positive stimuli, yet the curve-fitting revealed difficulties for the StD group in maintaining PA over time. Such reduced capacity was further observed in real-world settings, manifesting in significantly greater PA inertia. Conclusions: High PA inertia in daily life may reflect resistance to mood change in StD, explaining anhedonia and difficulties with emotional maintenance, and highlighting the need for early identification.(AU)

P3b correlates of inspection time.

Both P3b and the inspection time (IT) are related with intelligence, yet the P3b correlates of IT are not well understood. This event-related potential study addressed this question by asking participants (N = 28) to perform an IT task. There were three IT conditions with different levels of discriminative stimulus duration, i.e., 33 ms, 67 ms, and 100 ms, and a control condition with no target presentation (0 ms condition). We also measured participants' processing speed with four Elementary Cognitive Tests (ECTs), including a Simple Reaction Time task (SRT), two Choice Reaction Time tasks (CRTs), and a Pattern Discrimination task (PD). Results revealed that an increase in P3b latency with longer duration of the discriminative stimulus. Moreover, the P3b latency was negatively correlated with the accuracy of the IT task in the 33 ms condition, but not evident in the 67 and 100 ms conditions. Furthermore, the P3b latency of the 33 ms condition was positively correlated with the RT of the SRT, but not related with the RTs of CRTs or PD. A significant main effect of duration on the amplitude of P1 was also found. We conclude that the present study provides the neurophysiological correlates of the IT task, and those who are able to accurately perceive and process very briefly presented stimuli have a higher speed of information process, reflected by the P3b latency, yet this relationship is more obvious in the most difficult condition. Combined, our results suggest that P3b is related with the closure of a perceptual epoch to form the neural representation of a stimulus, in support of the "context closure" hypothesis.

Multimodal digital assessment of depression with actigraphy and app in Hong Kong Chinese.

There is an emerging potential for digital assessment of depression. In this study, Chinese patients with major depressive disorder (MDD) and controls underwent a week of multimodal measurement including actigraphy and app-based measures (D-MOMO) to record rest-activity, facial expression, voice, and mood states. Seven machine-learning models (Random Forest [RF], Logistic regression [LR], Support vector machine [SVM], K-Nearest Neighbors [KNN], Decision tree [DT], Naive Bayes [NB], and Artificial Neural Networks [ANN]) with leave-one-out cross-validation were applied to detect lifetime diagnosis of MDD and non-remission status. Eighty MDD subjects and 76 age- and sex-matched controls completed the actigraphy, while 61 MDD subjects and 47 controls completed the app-based assessment. MDD subjects had lower mobile time (P = 0.006), later sleep midpoint (P = 0.047) and Acrophase (P = 0.024) than controls. For app measurement, MDD subjects had more frequent brow lowering (P = 0.023), less lip corner pulling (P = 0.007), higher pause variability (P = 0.046), more frequent self-reference (P = 0.024) and negative emotion words (P = 0.002), lower articulation rate (P < 0.001) and happiness level (P < 0.001) than controls. With the fusion of all digital modalities, the predictive performance (F1-score) of ANN for a lifetime diagnosis of MDD was 0.81 and 0.70 for non-remission status when combined with the HADS-D item score, respectively. Multimodal digital measurement is a feasible diagnostic tool for depression in Chinese. A combination of multimodal measurement and machine-learning approach has enhanced the performance of digital markers in phenotyping and diagnosis of MDD.

Predicting suicidality in late-life depression by 3D convolutional neural network and cross-sample entropy analysis of resting-state fMRI.

BACKGROUND: Predicting suicide is a pressing issue among older adults; however, predicting its risk is difficult. Capitalizing on the recent development of machine learning, considerable progress has been made in predicting complex behavior such as suicide. As depression remained the strongest risk for suicide, we aimed to apply deep learning algorithms to identify suicidality in a group with late-life depression (LLD). METHODS: We enrolled 83 patients with LLD, 35 of which were non-suicidal and 48 were suicidal, including 26 with only suicidal ideation and 22 with past suicide attempts, for resting-state functional magnetic resonance imaging (MRI). Cross-sample entropy (CSE) analysis was conducted to examine the complexity of MRI signals among brain regions. Three-dimensional (3D) convolutional neural networks (CNNs) were used, and the classification accuracy in each brain region was averaged to predict suicidality after sixfold cross-validation. RESULTS: We found brain regions with a mean accuracy above 75% to predict suicidality located mostly in default mode, fronto-parietal, and cingulo-opercular resting-state networks. The models with right amygdala and left caudate provided the most reliable accuracy in all cross-validation folds, indicating their neurobiological importance in late-life suicide. CONCLUSION: Combining CSE analysis and the 3D CNN, several brain regions were found to be associated with suicidality.

Age-related positive emotional reactivity decline associated with the anterior insula based resting-state functional connectivity.

Recent studies have suggested that emotional reactivity changes with age, but the neural basis is still unclear. The insula may be critical for the emotional reactivity. The current study examined how ageing affects emotional reactivity using the emotional reactivity task data from a human sample (Cambridge Center for Age and Neuroscience, N = 243, age 18-88 years). The resting-state magnetic resonance measurements from the same sample were used to investigate the potential mechanisms of the insula. In the initial analysis, we conducted partial correlation assessments to examine the associations between emotional reactivity and age, as well as between the gray matter volume (GMV) of the insula and age. Our results revealed that emotional reactivity, especially positive emotional reactivity, decreased with age and that the GMV of the insula was negatively correlated with age. Subsequently, the bilateral insula was divided into six subregions to calculate the whole brain resting-state functional connectivity (rsFC). The mediating effect of the rsFC on age and emotional reactivity was then calculated. The results showed that the rsFC of the left anterior insula (AI) with the right hippocampus, and the rsFCs of the right AI with the striatum and the thalamus were mediated the relationship between positive emotional reactivity and age. Our findings suggest that attenuating emotional reactivity with age may be a strategic adaptation fostering emotional stability and diminishing emotional vulnerability. Meanwhile, the findings implicate a key role for the AI in the changes in positive emotional reactivity with age.

Aberrant positive affect dynamics in individuals with subthreshold depression: Evidence from laboratory and real-world assessments.

Background/Objective: Reduced positive affect (PA) is a core feature of major depressive disorder (MDD). However, the precursor of MDD, subthreshold depression (StD), has received less attention in this regard. Therefore, we examined PA dynamics in StD, integrating laboratory-based and ecological momentary assessment (EMA) approaches. Method: Participants were college students recruited from Chinese universities (31 with StD, and 39 healthy controls (HC)). Positive mood was induced in the laboratory by an eight-minute comedy clip used to assess PA reactivity and maintenance. To extend findings to the real world and explore mechanisms of PA maintenance, 53 participants with StD and 64 HC reported their emotional states 14 times daily for one week via EMA. Multilevel models were used to test for predictors of PA inertia. Results: In the laboratory, participants with StD achieved the same PA reactivity as HC when facing positive stimuli, yet the curve-fitting revealed difficulties for the StD group in maintaining PA over time. Such reduced capacity was further observed in real-world settings, manifesting in significantly greater PA inertia. Conclusions: High PA inertia in daily life may reflect resistance to mood change in StD, explaining anhedonia and difficulties with emotional maintenance, and highlighting the need for early identification.

Consensus Paper: Cerebellum and Ageing.

Given the key roles of the cerebellum in motor, cognitive, and affective operations and given the decline of brain functions with aging, cerebellar circuitry is attracting the attention of the scientific community. The cerebellum plays a key role in timing aspects of both motor and cognitive operations, including for complex tasks such as spatial navigation. Anatomically, the cerebellum is connected with the basal ganglia via disynaptic loops, and it receives inputs from nearly every region in the cerebral cortex. The current leading hypothesis is that the cerebellum builds internal models and facilitates automatic behaviors through multiple interactions with the cerebral cortex, basal ganglia and spinal cord. The cerebellum undergoes structural and functional changes with aging, being involved in mobility frailty and related cognitive impairment as observed in the physio-cognitive decline syndrome (PCDS) affecting older, functionally-preserved adults who show slowness and/or weakness. Reductions in cerebellar volume accompany aging and are at least correlated with cognitive decline. There is a strongly negative correlation between cerebellar volume and age in cross-sectional studies, often mirrored by a reduced performance in motor tasks. Still, predictive motor timing scores remain stable over various age groups despite marked cerebellar atrophy. The cerebello-frontal network could play a significant role in processing speed and impaired cerebellar function due to aging might be compensated by increasing frontal activity to optimize processing speed in the elderly. For cognitive operations, decreased functional connectivity of the default mode network (DMN) is correlated with lower performances. Neuroimaging studies highlight that the cerebellum might be involved in the cognitive decline occurring in Alzheimer's disease (AD), independently of contributions of the cerebral cortex. Grey matter volume loss in AD is distinct from that seen in normal aging, occurring initially in cerebellar posterior lobe regions, and is associated with neuronal, synaptic and beta-amyloid neuropathology. Regarding depression, structural imaging studies have identified a relationship between depressive symptoms and cerebellar gray matter volume. In particular, major depressive disorder (MDD) and higher depressive symptom burden are associated with smaller gray matter volumes in the total cerebellum as well as the posterior cerebellum, vermis, and posterior Crus I. From the genetic/epigenetic standpoint, prominent DNA methylation changes in the cerebellum with aging are both in the form of hypo- and hyper-methylation, and the presumably increased/decreased expression of certain genes might impact on motor coordination. Training influences motor skills and lifelong practice might contribute to structural maintenance of the cerebellum in old age, reducing loss of grey matter volume and therefore contributing to the maintenance of cerebellar reserve. Non-invasive cerebellar stimulation techniques are increasingly being applied to enhance cerebellar functions related to motor, cognitive, and affective operations. They might enhance cerebellar reserve in the elderly. In conclusion, macroscopic and microscopic changes occur in the cerebellum during the lifespan, with changes in structural and functional connectivity with both the cerebral cortex and basal ganglia. With the aging of the population and the impact of aging on quality of life, the panel of experts considers that there is a huge need to clarify how the effects of aging on the cerebellar circuitry modify specific motor, cognitive, and affective operations both in normal subjects and in brain disorders such as AD or MDD, with the goal of preventing symptoms or improving the motor, cognitive, and affective symptoms.

Mental Health of Children With Special Educational Needs and the Return to In-Person Learning After the COVID-19 Pandemic.

Importance: There is limited evidence on whether the quality of life and behavior of children with special educational needs (SEN) have improved or worsened since schools reopened after COVID-19-related school closures. Objective: To describe the changes in the mental well-being of children and adolescents with SEN during the initial 6 months of resuming in-person learning after COVID-19-related school closures. Design, Setting, and Participants: This repeated cross-sectional study reported data from surveys completed by parents and caregivers of children and adolescents aged 3 to 18 years with SEN studying at special schools in Hong Kong. The first cohort was obtained during COVID-19-related school closure in April 2020 (wave 1) and the second cohort was obtained 6 months after school resumption with data collection between July and October 2021 (wave 2). Data analysis occurred from January to June 2022. Exposure: Diagnosis of a disability or disorder that required school-based special educational programming. Main Outcomes and Measures: Children's emotional and behavioral difficulties (measured with the Strengths and Difficulties Questionnaire [SDQ]), quality of life (measured with the Pediatric Quality of Life Inventory [PedsQL]), lifestyle habits, parental stress, and parental well-being (measured with the PedsQL Family Impact Module) were assessed. Cross-sectional comparisons of well-being between the 2 waves were conducted using analysis of covariance, and multiple regression analysis was performed to identify factors associated with mental health outcomes in wave 2. Results: In wave 1, a total of 456 parents and caregivers of children with SEN (mean [SD] age, 7.44 [3.98] years; 315 boys [69.1%]; 141 girls [30.9%]) responded to the surveys. In wave 2, 519 parents and caregivers of children with SEN (mean [SD] age, 8.16 [4.47] years; 365 boys [70.3%]; 154 girls [29.7%]) responded. After school resumption, preschoolers aged 3 to 5 years with SEN had significantly fewer emotional difficulties (mean [SD] SDQ score, 3.26 [2.39] vs 2.68 [2.03]; standardized mean difference [SMD] = 0.26; 95% CI, 0.07-0.46; Bonferroni-corrected P = .04) and conduct difficulties (mean [SD] SDQ score, 2.88 [1.89] vs 2.41 [1.91]; SMD = 0.25; 95% CI, 0.05-0.44; Bonferroni-corrected P = .01), whereas adolescents had more conduct difficulties (mean [SD] SDQ score, 1.62 [1.50] vs 2.37 [3.02]; SMD = 0.41; 95% CI, 0.13-0.70; Bonferroni-corrected P = .049). The overall quality of life of school-aged children with SEN aged 6 to 11 years worsened after school resumption (mean [SD] PedsQL score, 67.52 [17.45] vs 60.57 [16.52]; SMD = 0.41; 95% CI, 0.19-0.62; Bonferroni-corrected P = .002). Conclusions and Relevance: The findings of this repeated cross-sectional study suggest that preschoolers with SEN had improved emotional and behavioral functioning when school resumed after COVID-19-related closures. School-aged children with SEN, adolescents with SEN, and children with intellectual disabilities were at risk of reduced quality of life, indicating that additional support should be offered to vulnerable groups as they return to schools.

Item-specific neural representations during human sleep support long-term memory.

Understanding how individual memories are reactivated during sleep is essential in theorizing memory consolidation. Here, we employed the targeted memory reactivation (TMR) paradigm to unobtrusively replaying auditory memory cues during human participants' slow-wave sleep (SWS). Using representational similarity analysis (RSA) on cue-elicited electroencephalogram (EEG), we found temporally segregated and functionally distinct item-specific neural representations: the early post-cue EEG activity (within 0 to 2,000 ms) contained comparable item-specific representations for memory cues and control cues, signifying effective processing of auditory cues. Critically, the later EEG activity (2,500 to 2,960 ms) showed greater item-specific representations for post-sleep remembered items than for forgotten and control cues, indicating memory reprocessing. Moreover, these later item-specific neural representations were supported by concurrently increased spindles, particularly for items that had not been tested prior to sleep. These findings elucidated how external memory cues triggered item-specific neural representations during SWS and how such representations were linked to successful long-term memory. These results will benefit future research aiming to perturb specific memory episodes during sleep.

The role of consciousness in threat extinction learning.

Extinction learning is regarded as a core mechanism underlying exposure therapy. The extent to which learned threats can be extinguished without conscious awareness is a controversial and on-going debate. We investigated whether implicit vs. explicit exposure to a threatened stimulus can modulate defence responses measured using pupillometry. Healthy participants underwent a threat conditioning paradigm in which one of the conditioned stimuli (CS) was perceptually suppressed using continuous flash suppression (CFS). Participants' pupillary responses, CS pleasantness ratings, and trial-by-trial awareness of the CS were recorded. During Extinction, participants' pupils dilated more in the trials in which they were unaware of the CS than in those in which they were aware of it (Cohen's d = 0.57). After reinstatement, the percentage of fear recovery was greater for the CFS-suppressed CS than the CS with full awareness. The current study suggests that the modulation of fear responses by extinction with reduced visual awareness is weaker compared to extinction with full perceptual awareness.

The robust reciprocal relationship between loneliness and depressive symptoms among the general population: Evidence from a quantitative analysis of 37 studies.

BACKGROUND: Loneliness has long been associated with depressive symptoms, but there is no evidence on the question of "which comes first". To help us to answer this question, this study conducted a meta-analysis using a cross-lagged formula to examine the reciprocal relations between loneliness and depressive symptoms, as well as potential moderators. METHODS: The meta-analytic dataset consisted of 37 studies with sample sizes ranging from 52 to 5991. Effect sizes (including autoregressive effects and lagged coefficients) were included. We computed weighted mean effect sizes for the correlation effect and cross-lagged effect between loneliness and depressive symptoms. We also performed a meta-regression to investigate potential moderators. RESULTS: The results showed that loneliness and depressive symptoms reciprocally predicted each other over time with similar effect sizes. There was no moderation of our overall effect size in either direction by time interval between measurements, the proportion of female participants, mean age of the sample, or type of measurement. LIMITATIONS: Caution should be taken in drawing final conclusions about the relative strength of reciprocal effects between loneliness and depressive symptoms due to the potential influence of varied research focus in the included studies, which could affect the effect size. CONCLUSIONS: These findings advance the study of the relationship between loneliness and depressive symptoms by providing evidence that the link between them is symmetrically reciprocal and robust, which may help clinicians to develop effective intervention methods.

Effects of computerized cognitive training on structure‒function coupling and topology of multiple brain networks in people with mild cognitive impairment: a randomized controlled trial.

BACKGROUND: People with mild cognitive impairment (MCI) experience a loss of cognitive functions, whose mechanism is characterized by aberrant structure‒function (SC-FC) coupling and topological attributes of multiple networks. This study aimed to reveal the network-level SC-FC coupling and internal topological changes triggered by computerized cognitive training (CCT) to explain the therapeutic effects of this training in individuals with MCI. METHODS: In this randomized block experiment, we recruited 60 MCI individuals and randomly divided them into an 8-week multidomain CCT group and a health education control group. The neuropsychological outcome measures were the Montreal Cognitive Assessment (MoCA), Chinese Auditory Verbal Learning Test (CAVLT), Chinese Stroop Color-Word Test (SCWT), and Rey-Osterrieth Complex Figure Test (Rey CFT). The brain imaging outcome measures were SC-FC coupling and topological attributes using functional MRI and diffusion tensor imaging methods. We applied linear model analysis to assess the differences in the outcome measures and identify the correspondence between the changes in the brain networks and cognitive functions before and after the CCT. RESULTS: Fifty participants were included in the analyses after the exclusion of three dropouts and seven participants with low-quality MRI scans. Significant group × time effects were found on the changes in the MoCA, CAVLT, and Rey CFT recall scores. The changes in the SC-FC coupling values of the default mode network (DMN) and somatomotor network (SOM) were higher in the CCT group than in the control group (P(unc.) = 0.033, P(unc.) = 0.019), but opposite effects were found on the coupling values of the visual network (VIS) (P(unc.) = 0.039). Increasing clustering coefficients in the functional DMN and SOM and subtle changes in the nodal degree centrality and nodal efficiency of the right dorsal medial prefrontal cortex, posterior cingulate cortex, left parietal lobe, somatomotor area, and visual cortex were observed in the CCT group (P < 0.05, Bonferroni correction). Significant correspondences were found between global cognitive function and DMN coupling values (P(unc.) = 0.007), between immediate memory and SOM as well as FPC coupling values (P(unc.) = 0.037, P(unc.) = 0.030), between delayed memory and SOM coupling values (P(unc.) = 0.030), and between visual memory and VIS coupling values (P(unc.) = 0.007). CONCLUSIONS: Eight weeks of CCT effectively improved global cognitive and memory functions; these changes were correlated with increases in SC-FC coupling and changes in the topography of the DMN and SOM in individuals with MCI. The CCT regimen also modulated the clustering coefficient and the capacity for information transformation in functional networks; these effects appeared to underlie the cognitive improvement associated with CCT. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2000034012. Registered on 21 June 2020.

The Chinese "Reading the Mind in the Eyes" Test: A study with normal adults, and adults with Asperger syndrome/high-functioning autism.

We developed a 28-item Chinese Eyes Test and tested its psychometric properties with a mixed sample of high-functioning adults with autism or Asperger syndrome and neurotypical adults. The Chinese Eyes Test showed good convergent and divergent validity, satisfactory known-group discrimination, and acceptable internal consistency. The identified cutoff score of 18 or below (Sensitivity: 66.7%; Specificity: 84.0%) should be useful for identifying clinically significant levels of social cognitive deficits, in terms of difficulty with the perceptual understanding of others' mental states, in high-functioning adults with autism or Asperger syndrome.

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).

A Pilot Study of Short-Course Oral Vitamin A and Aerosolised Diffuser Olfactory Training for the Treatment of Smell Loss in Long COVID.

Background: Olfactory dysfunction (OD) is a common neurosensory manifestation in long COVID. An effective and safe treatment against COVID-19-related OD is needed. Methods: This pilot trial recruited long COVID patients with persistent OD. Participants were randomly assigned to receive short-course (14 days) oral vitamin A (VitA; 25,000 IU per day) and aerosolised diffuser olfactory training (OT) thrice daily (combination), OT alone (standard care), or observation (control) for 4 weeks. The primary outcome was differences in olfactory function by butanol threshold tests (BTT) between baseline and end-of-treatment. Secondary outcomes included smell identification tests (SIT), structural MRI brain, and serial seed-based functional connectivity (FC) analyses in the olfactory cortical network by resting-state functional MRI (rs-fMRI). Results: A total of 24 participants were randomly assigned to receive either combination treatment (n = 10), standard care (n = 9), or control (n = 5). Median OD duration was 157 days (IQR 127-175). Mean baseline BTT score was 2.3 (SD 1.1). At end-of-treatment, mean BTT scores were significantly higher for the combination group than control (p < 0.001, MD = 4.4, 95% CI 1.7 to 7.2) and standard care (p = 0.009) groups. Interval SIT scores increased significantly (p = 0.009) in the combination group. rs-fMRI showed significantly higher FC in the combination group when compared to other groups. At end-of-treatment, positive correlations were found in the increased FC at left inferior frontal gyrus and clinically significant improvements in measured BTT (r = 0.858, p < 0.001) and SIT (r = 0.548, p = 0.042) scores for the combination group. Conclusions: Short-course oral VitA and aerosolised diffuser OT was effective as a combination treatment for persistent OD in long COVID.

Sleep quality mediates the relationship between systemic inflammation and neurocognitive performance.

Background: Systemic inflammation is a significant mechanism underpinning adverse cognitive changes. Sleep quality is a crucial factor associated with systemic inflammation and neurocognitive health. Elevated levels of pro-inflammatory cytokines in the periphery help mark inflammation. With this background, we examined the relationship between systemic inflammation, subjective sleep quality, and neurocognitive performance in adults. Method & Results: In 252 healthy adults, we measured the systemic inflammation reflected by serum levels of IL-6, IL-12, IL-18, TNF-α and IFN-γ, subjective sleep quality reflected by the global scores of the Pittsburgh Sleep Quality Index, and their neurocognitive performance measured by the Hong Kong Montreal Cognitive Assessment. We observed that neurocognitive performance was negatively related to IL-18 (p = 0.046) and positively related to sleep quality (p = 0.006). We did not observe significant associations between other cytokines and neurocognitive performance. Furthermore, we found that sleep quality as a mediator explained the relationship between IL-18 and neurocognitive performance depending on the levels of IL-12 (index of moderated mediation: 95% CI = [0.0047, 0.0664]). Better subjective sleep quality buffered the negative effect of IL-18 on neurocognitive performance when IL-12 was low (bootstrapping 95% CI: [- 0.0824, - 0.0018]). On the contrary, poor subjective sleep quality mediated the association between higher IL-18 and poorer neurocognitive performance when IL-12 was elevated (bootstrapping 95% CI: [0.0004, 0.0608]). Conclusion & Implications: Our findings indicate that systemic inflammation was negatively associated with neurocognitive performance. Sleep quality regulated by IL-18/IL-12 axis activation could be a potential mechanism underpinning neurocognitive changes. Our results illustrate the intricate relationships between immune functioning, sleep quality and neurocognitive performance. These insights are essential to understand the potential mechanisms underpinning neurocognitive changes, paving the way for the development of preventive interventions for the risk of cognitive impairment.

Computerized Cognitive Training Enhances Episodic Memory by Down-Modulating Posterior Cingulate-Precuneus Connectivity in Older Persons With Mild Cognitive Impairment: A Randomized Controlled Trial.

OBJECTIVE: The neural mechanisms underlying the beneficial effects of a computerized cognitive training (CCT) program for improving episodic memory in older persons with mild cognitive impairment (MCI) remain unclear. This study aimed to use both functional and structural brain changes to elucidate the treatment effects of CCT on enhancing episodic memory. DESIGN, SETTING, AND PARTICIPANTS: Single-blinded, multicenter randomized controlled trial on 60 older adults with MCI in Fuzhou, China. INTERVENTION: Participants were randomly assigned to either an 8-week 24-hour CCT program or a health education program as the control. MEASUREMENTS: Clinical outcomes included changes in scores on the immediate and/or delayed recall subtests of the Chinese auditory verbal learning test (CAVLT) and rey complex figure test (CFT), and changes in gray matter volume and the functional connectivity of the posterior cingulate cortex (PCC) and hippocampus in the Papez circuit on magnetic resonance imaging. RESULTS: Significant group-by-time effects showed greater improvements in both immediate and delayed recall scores of CAVLT and delayed recall scores of Rey CFT in participants receiving the CCT program compared to those in the health education program. Among the CCT participants, seed-based analyses revealed decreases in functional connectivity of the PCC and hippocampus with neural substrates in the parietal and occipital regions. The decreased PCC and precuneus connectivity were found to mediate patients' improvements in immediate recall function. CONCLUSION: An 8-week CCT program was effective for improving episodic memory in older individuals with MCI. The decrease in connectivity originating from the PCC and hippocampus is suggestive of potential plastic changes in the Papez circuit, which could have alleviated the age-related compensatory mechanism. The findings of this study also shed light on expanding the content and extending the frequency and duration of the CCT program in future studies.