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.

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.

Implicit threat learning involves the dorsolateral prefrontal cortex and the cerebellum

Background/Objective: Most studies investigating the neural correlates of threat learning were carried out using an explicit Pavlovian conditioning paradigm where declarative knowledge on contingencies between conditioned (CS) and unconditioned stimuli (US) is acquired. The current study aimed at understanding the neural correlates of threat conditioning when contingency awareness is limited or even absent. Method: We conducted an fMRI report of threat learning in an implicit associative learning paradigm called multi-CS conditioning, in which a number of faces were associated with aversive screams (US) such that participants could not report contingencies between the faces and the screams. Results: The univariate results showed support for the recruitment of threat-related regions including the dorsolateral prefrontal cortex (dlPFC) and the cerebellum during acquisition. Further analyses by the multivariate representational similarity technique identified learning-dependent changes in the bilateral dlPFC. Conclusion: Our findings support the involvement of the dlPFC and the cerebellum in threat conditioning that occurs with highly limited or even absent contingency awareness. (AU)

Cognitive bias modification for paranoia (CBM-pa): a randomised controlled feasibility study in patients with distressing paranoid beliefs.

BACKGROUND: Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose-response and (iv) select primary outcomes for future trials. METHODS: In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment. RESULTS: A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30-40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = -0.48 to -0.76), improved symptoms of paranoia (d = -0.19 to -0.38), and lower depressed and anxious mood (d = -0.03 to -0.29). The intervention effect was evident after the third session. CONCLUSIONS: CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.

Implicit threat learning involves the dorsolateral prefrontal cortex and the cerebellum.

Background/Objective: Most studies investigating the neural correlates of threat learning were carried out using an explicit Pavlovian conditioning paradigm where declarative knowledge on contingencies between conditioned (CS) and unconditioned stimuli (US) is acquired. The current study aimed at understanding the neural correlates of threat conditioning when contingency awareness is limited or even absent. Method: We conducted an fMRI report of threat learning in an implicit associative learning paradigm called multi-CS conditioning, in which a number of faces were associated with aversive screams (US) such that participants could not report contingencies between the faces and the screams. Results: The univariate results showed support for the recruitment of threat-related regions including the dorsolateral prefrontal cortex (dlPFC) and the cerebellum during acquisition. Further analyses by the multivariate representational similarity technique identified learning-dependent changes in the bilateral dlPFC. Conclusion: Our findings support the involvement of the dlPFC and the cerebellum in threat conditioning that occurs with highly limited or even absent contingency awareness.

Preoperative brain connectome predicts postoperative changes in processing speed in moyamoya disease.

Moyamoya disease is a rare cerebrovascular disorder associated with cognitive dysfunction. It is usually treated by surgical revascularization, but research on the neurocognitive outcomes of revascularization surgery is controversial. Given that neurocognitive impairment could affect the daily activities of patients with moyamoya disease, early detection of postoperative neurocognitive outcomes has the potential to improve patient management. In this study, we applied a well-established connectome-based predictive modelling approach to develop machine learning models that used preoperative resting-state functional connectivity to predict postoperative changes in processing speed in patients with moyamoya disease. Twelve adult patients with moyamoya disease (age range: 23-49 years; female/male: 9/3) were recruited prior to surgery and underwent follow-up at 1 and 6 months after surgery. Twenty healthy controls (age range: 24-54 years; female/male: 14/6) were recruited and completed the behavioural test at baseline, 1-month follow-up and 6-month follow-up. Behavioural results indicated that the behavioural changes in processing speed at 1 and 6 months after surgery compared with baseline were not significant. Importantly, we showed that preoperative resting-state functional connectivity significantly predicted postoperative changes in processing speed at 1 month after surgery (negative network: ρ = 0.63, P corr = 0.017) and 6 months after surgery (positive network: ρ = 0.62, P corr = 0.010; negative network: ρ = 0.55, P corr = 0.010). We also identified cerebro-cerebellar and cortico-subcortical connectivities that were consistently associated with processing speed. The brain regions identified from our predictive models are not only consistent with previous studies but also extend previous findings by revealing their potential roles in postoperative neurocognitive functions in patients with moyamoya disease. Taken together, our findings provide preliminary evidence that preoperative resting-state functional connectivity might predict the post-surgical longitudinal neurocognitive changes in patients with moyamoya disease. Given that processing speed is a crucial cognitive ability supporting higher neurocognitive functions, this study's findings offer important insight into the clinical management of patients with moyamoya disease.

Efficacy and acceptability of transcranial direct current stimulation for treating depression: A meta-analysis of randomized controlled trials.

BACKGROUND: Transcranial direct current stimulation (tDCS) is a promising nonpharmacological intervention for treating depression. We aimed to provide an updated meta-analysis assessing the anti-depressant efficacy of tDCS. METHODS: We searched the literature from the first available date to 30 December 2020 to identify relevant randomized controlled trials (RCTs). RESULTS: 27 RCTs (N = 1204 patients, 653 in active tDCS and 551 in sham tDCS) were included. Active tDCS was superior to sham tDCS (g = 0.46, 95 % CI 0.15-0.76) in modulating depressive symptoms measured by depression rating scales. Active tDCS was also superior to sham tDCS in reducing response and remission rates, but these differences did not reach statistically significant levels (ORresponse = 1.75, 95 % CI 0.85-3.58; ORremission = 1.29, 95 % CI 0.59-2.83). The two groups had comparable dropout rates (OR = 1.28, 95 % CI 0.62-1.64). CONCLUSION: For treatments of depressive episodes, tDCS may be efficacious. Specific tDCS parameters (e.g., a 2-mA stimulation current and 30-min sessions) and clinical characteristics (e.g., antidepressant-free) may augment the treatment efficacy of tDCS.

Anxiety mediates the relationship between interpretation bias and paranoia in patients with persistent persecutory beliefs.

Background and Objectives: The role of interpretation bias in generating and maintaining persecutory beliefs/paranoid ideation is becoming established in the literature, but how negative mood affects this relationship remains unclear. The current study investigated the mediating role of anxiety and depression in the association between interpretation bias and paranoia in patients with persistent paranoia. Methods/Design: We applied the mediation model to clinical data gathered from patients with persistent paranoia (N = 62), and compared how levels of depression and anxiety affected the association between interpretation bias and paranoia. Results: Interpretation bias and anxiety accounted for 43% of the variance in paranoia, while interpretation bias and depression explained 31% of this variance. Levels of anxiety, but not depression, partially mediated the relationship between interpretation bias and paranoid beliefs. Our data suggest that the association between interpretation bias and paranoid beliefs takes effect partly, although not completely, through heightened levels of anxiety. Conclusions: The current study highlighted the role of anxiety as a mediator in the association between interpretation bias and paranoid beliefs in patients with distressing paranoia. These findings inform the potential mechanism underlying cognitive interventions for pathological paranoia. Trial registration: Current Controlled Trials ISRCTN: 90749868. Retrospectively registered on 12 May 2016.

Positive affect is inversely related to the salience and emotion network's connectivity.

Increasing evidence has shown that positive affect enhances many aspects of daily functioning. Yet, how dispositional positive affect is represented in the intrinsic brain networks remains unclear. Here, we used resting-state functional Magnetic Resonance Imaging to test how trait positive and negative affect of an individual were associated with the intrinsic connectivity of brain regions within the salience and emotion network and the default mode network in 70 healthy young adults. We observed that positive affect was negatively associated with connectivity within the salience and emotion network, particularly with the bidirectional connections spanning the left anterior insula and left nucleus accumbens. For connections between the salience and emotion network and the rest of the brain, we observed that positive affect was negatively related to the connectivity between the right amygdala and the right middle temporal gyrus. Affect-based modulations of connectivity were specific to positive affect and to the salience and emotion network. Our findings highlight the critical role of salience and emotion network in the neural relations of positive affect, and lay the groundwork for future studies on modeling the connectivity of salience and emotion network to predict mental well-being.

The implication of cognitive processes in emotional bias.

Recently, Yuan et al. (2019) quantitatively reviewed emotional bias studies with P3 event-related potential amplitudes and demonstrated that emotional bias varies with stimulus parameters, such as type, arousal, and task setting. We believe that emotional biases might profitably be studied together with cognitive processes in order to understand the affective dysregulation underpinning various mental illnesses. In this commentary, we highlighted the role of attention bias and interpretation bias as examples of cognitive processes affecting emotional bias in anxiety disorders. We discussed the potential synergy of examining cognitive processes alongside emotional bias to understand the psychopathology underlying various prevalent forms of mental disorders and potentially disentangle the intricate mechanisms for further interventions.

Multi-Session Anodal Prefrontal Transcranial Direct Current Stimulation does not Improve Executive Functions among Older Adults.

OBJECTIVE: Findings from single-session online studies highlighted the potential of using anodal prefrontal transcranial direct current stimulation (tDCS) to enhance executive functions (EF) in the context of aging. However, tDCS must be executed as a multi-session offline intervention to ascertain its viability in this context. Relatedly, findings from multi-session studies remained inconclusive. To this end, we examined the effects of multi-session anodal prefrontal tDCS on EF in an intervention. METHOD: The intervention consisted of 15 sessions; in each, healthy older participants (Agemean = 66.7) received either 15 min of 1.5 mA tDCS (Ncompleted = 35) or sham stimulation (Ncompleted = 33) while performing EF training tasks. EF measures were assessed at baseline, post-intervention, and 1-month follow-up. Hierarchical linear models were used to examine the effect of tDCS on EF outcomes. RESULTS: Both groups of participants did not differ significantly in side effect ratings and attendance. There were no significant tDCS-associated gains in any EF outcomes in the intervention. CONCLUSIONS: Multi-session prefrontal tDCS did not lead to any significant gains in EF in the current intervention. More research is needed to optimize the use of tDCS before it can be effectively used to enhance EF among older adults.

The neural correlates of perceived energy levels in older adults with late-life depression.

Late-life depression is common among older adults. Although white-matter abnormality is highly implicated, the extent to which the corticospinal tract is associated with the pathophysiology of late-life depression is unclear. The current study aims to investigate the white-matter structural integrity of the corticospinal tract and determine its cognitive and functional correlates in older adults with late-life depression. Twenty-eight older adults with clinical depression and 23 healthy age-matched older adults participated in the study. The white matter volume and the white matter hyperintensities (WMHs) of the corticospinal tract, as well as the global WMHs, were measured. Psychomotor processing speed, severity of depression, perceived levels of energy and physical functioning were measured to examine the relationships among the correlates in the depressed participants. The right corticospinal tract volume was significantly higher in depressed older adults relative to healthy controls. Moreover, the right corticospinal tract volume was significantly associated with the overall severity of depression and accounted for 17% of its variance. It further attenuated the relationship between the severity of depression and perceived levels of energy. Our findings suggested that higher volume in the right corticospinal tract is implicated in LLD and may relate to lower perceived levels of energy experienced by older adults with depression.

White matter microstructural abnormalities in amnestic mild cognitive impairment: A meta-analysis of whole-brain and ROI-based studies.

Studies that examined white matter (WM) alterations in amnestic mild cognitive impairment (aMCI) abound. This timely meta-analysis aims to synthesize the results of these studies. Seventy-seven studies (totalNaMCI=1844) were included. Fourteen region-of-interest-based (ROI-based) (k≥8;NaMCI≥284 per ROI) and two activation likelihood estimation (ALE) meta-analyses (fractional anisotropy [FA]: k=15;NaMCI=463; mean diffusivity [MD]: k=8;NaMCI=193) were carried out. Among the many significant ROI-related findings, reliable FA and MD alterations in the fornix, uncinate fasciculus, and parahippocampal cingulum were observed in aMCI. Larger effects were observed in MD relative to FA. The ALE meta-analysis revealed a significant FA decrease among aMCI subjects in the posterior corona radiata. These results provide robust evidence of the presence of WM abnormalities in aMCI. Our findings also highlight the importance of carrying out both ROI-based and whole-brain-based research to obtain a complete picture of WM microstructural alterations associated with the condition..

Imaging and neuropsychological correlates of white matter lesions in different subtypes of Mild Cognitive Impairment: A systematic review.

BACKGROUND: White matter lesions (WML) are prevalent in older adults. The association between WML and cognition in different subtypes of Mild Cognitive Impairment (MCI) is inconsistent in the literature. OBJECTVES: We aim to provide a systematic review on the impact of WML in different subtypes of MCI, and discuss the recent findings on white matter plasticity. METHODS: We reviewed peer-reviewed articles from January 2011 to August 2016 and identified 12 studies investigating the association between WML and subtypes of MCI with both neuroimaging and cognitive measures. RESULTS: Our review shows that 1) WM abnormality was identified between different subtypes of MCI and healthy controls on diffusion imaging; 2) neither visual ratings of WML nor its volumetry differentiate different subtypes of MCI or its prognosis to dementia; and 3) cognitive correlates of WML were evident in the Amnestic-type MCI in the domains of memory, language, psychomotor speed, attention and executive functions. CONCLUSION: Cognitive reserve and the plasticity of white matter may modulate the impact of WML on the manifestation of the neurodegenerative disease. Further research is needed to study the plasticity of white matter in the MCI population to evaluate its potential clinical application.

Perceived loneliness and general cognitive status in community-dwelling older adults: the moderating influence of depression.

The relationship between depression, loneliness, and cognitive functioning among the elderly is not well understood in the literature. In the present study, we tested the moderating influence of depressive symptoms on loneliness and cognitive functioning. We recruited 100 community-dwelling older adults in Hong Kong. Demographic information, perceived loneliness, depressed mood, and general cognitive status were assessed. Results indicated that married participants reported lower levels of perceived loneliness (t (96) = 2.26, p = .03). We found a significant moderating effect of depressive symptoms on the relationship between perceived loneliness and general cognitive status (B = -.05, p = .002). Perceived loneliness correlated negatively with general cognitive status only in participants with higher levels of depressed mood (B = -.16, p = .01). Together, these findings suggest that perceived loneliness combined with depressed mood is related to poorer general cognitive status in older adults. The implications of these findings are discussed.

Perceived loneliness among older adults with mild cognitive impairment.

BACKGROUND: The high prevalence of mild cognitive impairment (MCI) in Hong Kong, as previously reported, requires verification. Furthermore, the relationship between loneliness, depression, and cognitive impairment with regards to MCI are unclear. The present study aims to establish the prevalence of MCI in a community sample in Hong Kong and determine if participants with MCI feel significantly lonelier, even after depression has been taken into consideration. METHODS: Participants from a community sample (N = 376) were assessed with subjective and objective measures of cognitive impairments to determine whether the criteria had been met for MCI. The MCI cases are then compared with age, sex, and education-matched controls on subjective measures of loneliness and depression. RESULTS: A total of 66 (17.6%) participants were diagnosed with MCI. These participants reported significantly higher levels of perceived loneliness and depression compared to the matched controls. Differences between groups in loneliness remained significant, even after depression levels have been controlled. CONCLUSIONS: Loneliness is implicated in MCI. The relationship between loneliness and MCI is, at least, partially independent of depression. The implications of these finding are discussed.

Age-related difference in relationships between cognitive processing speed and general cognitive status.

General cognitive status (GCS) is a composite of cognitive abilities reflecting full function. The literature suggests a relationship between cognitive processing speed and GCS, as well as age-related changes of processing speed on cognitive performance. Therefore, this study recruited 34 younger and 39 older adults to verify age-related differences in relationships between cognitive processing speed and GCS. We measured cognitive processing speed with the Processing Speed Index of the Wechsler Adult Intelligence Scale. Findings indicated that cognitive processing speed predicted GCS in older but not younger adults. Future research may be needed to verify the training effect of processing speed on GCS. This study also further examined cognitive factors related to processing speed in aging and the relationships between cognitive processing speed and verbal fluency, cognitive inhibition, and divided attention. A stepwise regression analysis indicated that only verbal fluency contributed significantly to cognitive processing speed in older adults, accounting for 21% of the variance. These observations suggest that age-related changes of prefrontal regions may not fully explain age-related decline in cognitive processing speed.