Clinical and neuropsychological correlates of theta-band functional excitation-inhibition ratio in autism: An EEG study.

OBJECTIVE: How abnormal brain signaling impacts cognition in autism spectrum disorder (ASD) remained elusive. This study aimed to investigate the local and global brain signaling in ASD indicated by theta-band functional excitation-inhibition (fE/I) ratio and explored psychophysiological relationships between fE/I, cognitive deficits, and ASD symptomatology. METHODS: A total of 83 ASD and typically developing (TD) individuals participated in this study. Participants' interference control and set-shifting abilities were assessed. Resting-state electroencephalography (EEG) was used for estimating theta-band fE/I ratio. RESULTS: ASD individuals (n = 31 without visual EEG abnormality; n = 22 with visual EEG abnormality) generally performed slower in a cognitive task tapping interference control and set-maintenance abilities, but only ASD individuals with visually abnormal EEG performed significantly slower than their TD counterparts (Bonferroni-corrected ps < .001). Heightened theta-band fE/I ratios at the whole-head level, left and right hemispheres were observed in the ASD subgroup without visual EEG abnormality only (Bonferroni-corrected ps < .001), which remained highly significant when only data from medication-naïve participants were analyzed. In addition, higher left hemispheric fE/I ratios in ASD individuals without visual EEG abnormality were significantly correlated with faster interference control task performance, in turn faster reaction time was significantly associated with less severe restricted, repetitive behavior (Bonferroni-corrected ps ≤ .0017). CONCLUSIONS: Differential theta-band fE/I within the ASD population. Heightened theta-band fE/I in ASD without visual EEG abnormality may be associated with more efficient filtering of distractors and a less severe ASD symptom manifestation. SIGNIFICANCE: Brain signaling, indicated by theta-band fE/I, was different in ASD subgroups. Only ASD with visually-normal EEG showed heightened theta-band fE/I, which was associated with faster processing of visual distractors during a cognitive task. More efficient distractor filtering was associated with less restricted, repetitive behaviors.

Effects of multisession cathodal transcranial direct current stimulation with cognitive training on sociocognitive functioning and brain dynamics in autism: A double-blind, sham-controlled, randomized EEG study.

BACKGROUND: Few treatment options are available for targeting core symptoms of autism spectrum disorder (ASD). The development of treatments that target common neural circuit dysfunctions caused by known genetic defects, namely, disruption of the excitation/inhibition (E/I) balance, is promising. Transcranial direct current stimulation (tDCS) is capable of modulating the E/I balance in healthy individuals, yet its clinical and neurobiological effects in ASD remain elusive. OBJECTIVE: This double-blind, randomized, sham-controlled trial investigated the effects of multisession cathodal prefrontal tDCS coupled with online cognitive remediation on social functioning, information processing efficiency and the E/I balance in ASD patients aged 14-21 years. METHODS: Sixty individuals were randomly assigned to receive either active or sham tDCS (10 sessions in total, 20 min/session, stimulation intensity: 1.5 mA, cathode: F3, anode: Fp2, size of electrodes: 25 cm2) combined with 20 min of online cognitive remediation. Social functioning, information processing efficiency during cognitive tasks, and theta- and gamma-band E/I balance were measured one day before and after the treatment. RESULTS: Compared to sham tDCS, active cathodal tDCS was effective in enhancing overall social functioning [F(1, 58) = 6.79, p = .012, ηp2 = 0.105, 90% CI: (0.013, 0.234)] and information processing efficiency during cognitive tasks [F(1, 58) = 10.07, p = .002, ηp2 = 0.148, 90% CI: (0.034, 0.284)] in these individuals. Electroencephalography data showed that this cathodal tDCS protocol was effective in reducing the theta-band E/I ratio of the cortical midline structures [F(1, 58) = 4.65, p = .035, ηp2 = 0.074, 90% CI: (0.010, 0.150)] and that this reduction significantly predicted information processing efficiency enhancement (b = -2.546, 95% BCa CI: [-4.979, -0.113], p = .041). CONCLUSION: Our results support the use of multisession cathodal tDCS over the left dorsolateral prefrontal cortex combined with online cognitive remediation for reducing the elevated theta-band E/I ratio in sociocognitive information processing circuits in ASD patients, resulting in more adaptive regulation of global brain dynamics that is associated with enhanced information processing efficiency after the intervention.

The neurobiological effects of mind-body exercise: a systematic review and meta-analysis of neuroimaging studies.

The neurobiological effects of mind-body exercise on brain activation, functional neural connections and structural changes in the brain remain elusive. This systematic review and coordinate-based meta-analysis investigated the changes in resting-state and task-based brain activation, as well as structural brain changes before and after mind-body exercise compared to waitlist or active controls based on published structural or functional magnetic resonance imaging randomized controlled trials or cross-sectional studies. Electronic database search and manual search in relevant publications yielded 34 empirical studies with low-to-moderate risk of bias (assessed by Cochrane risk-of-bias tool for randomized trials or Joanna Briggs Institute's critical appraisal checklist for analytical cross-sectional studies) that fulfilled the inclusion criteria, with 26 studies included in the narrative synthesis and 8 studies included in the meta-analysis. Coordinate-based meta-analysis showed that, while mind-body exercise enhanced the activation of the left anterior cingulate cortex within the default mode network (DMN), it induced more deactivation in the left supramarginal gyrus within the ventral attention network (uncorrected ps < 0.05). Meta-regression with duration of mind-body practice as a factor showed that, the activation of right inferior parietal gyrus within the DMN showed a positive association with increasing years of practice (voxel-corrected p < 0.005). Although mind-body exercise is shown to selectively modulate brain functional networks supporting attentional control and self-awareness, the overall certainty of evidence is limited by small number of studies. Further investigations are needed to understand the effects of both short-term and long-term mind-body exercise on structural changes in the brain.PROSPERO registration number: CRD42021248984.

Neural substrates underlying effortful control deficit in autism spectrum disorder: a meta-analysis of fMRI studies.

Effortful control comprises attentional control, inhibitory control, and cognitive flexibility subprocesses. Effortful control is impaired in individuals with autism spectrum disorder, yet its neural underpinnings remain elusive. By conducting a coordinate-based meta-analysis, this study compared the brain activation patterns between autism and typically developing individuals and examined the effect of age on brain activation in each effortful control subprocesses. Meta-analytic results from 22 studies revealed that, individuals with autism showed hypoactivation in the default mode network for tasks tapping inhibitory control functioning (threshold-free cluster enhancement p < 0.001). When these individuals perform tasks tapping attentional control and cognitive flexibility, they exhibited aberrant activation in various brain networks including default mode network, dorsal attention, frontoparietal, visual and somatomotor networks (uncorrected ps < 0.005). Meta-regression analyses revealed that brain regions within the default mode network showed a significant decreasing trend in activation with increasing age (uncorrected p < 0.05). In summary, individuals with autism showed aberrant activation patterns across multiple brain functional networks during all cognitive tasks supporting effortful control, with some regions showing a decrease in activation with increasing age.

Aberrant prefrontal functional connectivity during verbal fluency test is associated with reading comprehension deficits in autism spectrum disorder: An fNIRS study.

Children with autism spectrum disorder (ASD) show marked difficulties in reading comprehension, a complex cognitive skill fundamental to successful daily functioning that is associated with core executive functions. However, the neurophysiological mechanisms underlying reading comprehension deficits in these children remain elusive. Twenty-one right-handed males with high-functioning ASD (mean age = 10.24 years) and 23 age-, IQ-, educational level-, sex- and handedness-matched typically developing (TD; mean age = 10.14 years) individuals underwent a reading comprehension test and the semantic verbal fluency test that tapped core executive functions underlying reading comprehension during concurrent prefrontal functional near-infrared spectroscopy (fNIRS) measurement. Participants' information processing efficiency was also assessed. High-functioning ASD children exhibited general reading comprehension [main effect of group: F (1,40) = 7.58, p = 0.009], selective verbal fluency deficits [Group × category interaction: F (1,42) = 4.90, p = 0.032] and slower processing speed (t 42 = 2.36, p = 0.023). Regarding the hemodynamics of the prefrontal cortex (PFC), although ASD individuals showed comparable patterns of PFC brain activation to their healthy counterparts, lower PFC intrahemispheric [main effect of group: F (1,42) = 11.36, p = 0.002] and interhemispheric [main effect of group: F (1,42) = 7.79, p = 0.008] functional connectivity were evident during the semantic verbal fluency test. At the whole-group level, poorer reading comprehension performance was associated with poorer performance in the semantic verbal fluency test (r 42 = 0.508, p < 0.001). Moreover, poorer semantic verbal fluency test performance was associated with slower information processing speed (r 42 = -0.312, p = 0.044), which is associated with reduced left medial PFC functional connectivity (r 42 = -0.319, p = 0.040). Abnormal intrahemispheric and interhemispheric prefrontal hypoconnectivity is associated with deficits in executive processes essential for reading comprehension in ASD. Our study has provided important implications for the neuropsychological and neurophysiological mechanisms underlying reading comprehension deficits in ASD.

Abnormal Prefrontal Functional Connectivity Is Associated with Inflexible Information Processing in Patients with Autism Spectrum Disorder (ASD): An fNIRS Study.

Individuals with autism spectrum disorder (ASD) are characterized by impairments in flexibly acquiring and maintaining new information, as well as in applying learned information for problem solving. However, the neural mechanism underpinning such impairments remains unclear. This study investigated the flexibility in the acquisition and application of visual information in ASD (aged 14−21) when they performed the Wisconsin Card Sorting Test (WCST). Behavioral data including response accuracy and latency, and prefrontal hemodynamic data measured by functional near-infrared spectroscopy (fNIRS), were collected when individuals performed WCST. Canonical general linear model and functional connectivity analyses were performed to examine the prefrontal activation and synchronization patterns, respectively. Results showed that although ASD individuals (n = 29) achieved comparable accuracy rates when compared with age- and intelligence quotient (IQ)-matched typically developing (TD; n = 26) individuals (F1,53 = 3.15, p = 0.082), ASD individuals needed significantly more time to acquire and apply WCST card sorting rules (F1,53 = 17.92, p < 0.001). Moreover, ASD individuals showed significantly lower prefrontal functional connectivity than TD individuals during WCST (F1,42 = 9.99, p = 0.003). The hypoconnectivity in ASD individuals was highly significant in the right lateral PFC in the acquisition condition (p = 0.005) and in the bilateral lateral PFC in the application condition (ps = 0.006). Furthermore, slower WCST reaction time was correlated with lower bilateral lateral PFC functional connectivity only in the application condition (ps = 0.003) but not the acquisition condition. Impairment in information acquisition and application is evident in ASD individuals and is mediated by processing speed, which is associated with lower functional connectivity in the bilateral lateral PFC when these individuals apply learned rules to solve novel problems.

Altered Cytokine and BDNF Levels in Individuals with Autism Spectrum Disorders.

Previous studies have shown that immunological factors are involved in the pathogenesis of autism spectrum disorders (ASDs). The present study examined whether immunological abnormalities are associated with cognitive and behavioral deficits in children with ASD and whether children with ASD show different immunological biomarkers and brain-derived neurotrophic factor BDNF levels than typically developing (TD) children. Sixteen children with TD and 18 children with ASD, aged 6-18 years, voluntarily participated in the study. Participants' executive functions were measured using neuropsychological tests, and behavioral measures were measured using parent ratings. Immunological measures were assessed by measuring the participants' blood serum levels of chemokine ligand 2 (CCL2) and chemokine ligand 5 (CCL5). Children with ASD showed greater deficits in cognitive functions as well as altered levels of immunological measures when compared to TD children, and their cognitive functions and behavioral deficits were significantly associated with increased CCL5 levels and decreased BDNF levels. These results provide evidence to support the notion that altered immune functions and neurotrophin deficiency are involved in the pathogenesis of ASD.

Neurophysiological and behavioral effects of multisession prefrontal tDCS and concurrent cognitive remediation training in patients with autism spectrum disorder (ASD): A double-blind, randomized controlled fNIRS study.

BACKGROUND: The clinical effects and neurophysiological mechanisms of prefrontal tDCS and concurrent cognitive remediation training in individuals with autism spectrum disorder (ASD) remain unclear. OBJECTIVE: This two-armed, double-blind, randomized, sham-controlled trial aimed to investigate the beneficial effects of tDCS combined with concurrent cognitive remediation training on adolescents and young adults with ASD. METHODS: Participants were randomly assigned to either active or sham tDCS groups and received 1.5 mA prefrontal tDCS with left dorsolateral prefrontal cortex (dlPFC) cathode placement and right supraorbital region anode placement for 20 minutes over two consecutive weeks. tDCS was delivered concurrently with a computerized cognitive remediation training program. Social functioning and its underlying cognitive processes, as well as prefrontal resting-state functional connectivity (rsFC), were measured. RESULTS: The results from 41 participants indicated that multisession prefrontal tDCS, compared to sham tDCS, significantly enhanced the social functioning of ASD individuals [F(1,39) = 4.75, p = .035, ηp2 = 0.11]. This improvement was associated with enhanced emotion recognition [F(1,39) = 8.34, p = .006, ηp2 = 0.18] and cognitive flexibility [F(1,39) = 4.91, p = .033, ηp2 = 0.11]. Specifically, this tDCS protocol optimized information processing efficiency [F(1,39) = 4.43, p = .042, ηp2 = 0.10], and the optimization showed a trend to be associated with enhanced rsFC in the right medial prefrontal cortex (ρ = 0.339, pFDR = .083). CONCLUSION: Multisession tDCS with left dlPFC cathode placement and right supraorbital region anode placement paired with concurrent cognitive remediation training promoted social functioning in individuals with ASD. This appeared to be associated with the enhancement of the functional connectivity of the right medial PFC, a major hub for flexible social information processing, allowing these individuals to process information more efficiently in response to different social situations. TRIAL REGISTRATION: ClinicalTrials.gov (ID: NCT03814083).

Effects of working memory load on frontal connectivity in children with autism spectrum disorder: a fNIRS study.

Individuals with autism spectrum disorder (ASD) perform poorly in working memory (WM) tasks, with some literature suggesting that their impaired performance is modulated by WM load. While some neuroimaging and neurophysiological studies have reported altered functional connectivity during WM processing in individuals with autism, it remains largely unclear whether such alterations are moderated by WM load. The present study aimed to examine the effect of WM load on functional connectivity within the prefrontal cortex (PFC) in ASD using functional near-infrared spectroscopy (fNIRS). Twenty-two children with high-functioning ASD aged 8-12 years and 24 age-, intelligent quotient (IQ)-, sex- and handedness-matched typically developing (TD) children performed a number n-back task with three WM loads (0-back, 1-back, and 2-back). Hemodynamic changes in the bilateral lateral and medial PFC during task performance were monitored using a multichannel NIRS device. Children with ASD demonstrated slower reaction times, specifically during the "low load" condition, than TD children. In addition, the ASD and TD groups exhibited differential load-dependent functional connectivity changes in the lateral and medial PFC of the right but not the left hemisphere. These findings indicate that WM impairment in high-functioning ASD is paralleled by load-dependent alterations in right, but not left, intrahemispheric connectivity during WM processing in children with ASD. A disruption of functional neural connections that support different cognitive processes may underlie poor performance in WM tasks in ASD.

The functional brain networks activated by music listening: A neuroimaging meta-analysis and implications for treatment.

OBJECTIVE: Previous behavioral studies show that music listening enhances attention and working memory in both healthy and clinical populations. However, how music listening engages brain functional networks remains elusive due to inconsistent results from previous findings. METHOD: A meta-analysis of functional magnetic resonance imaging data using seed-based d mapping (SDM) with permutation of subject images was performed. Studies that presented music listening paradigms to healthy individuals were included. Subgroup analyses were performed to investigate the effects of music genres on brain activation. To examine functional network correlates, voxels that were significantly activated by music listening were overlaid onto cortical, subcortical, and striatal network parcellations. RESULTS: Whole-group analysis showed that ventral attention, somatomotor, default, dorsal attention, frontoparietal, and limbic networks significantly coactivated during music listening (familywise error-corrected p < .01). Specifically, music listening activated multiple frontal, temporal, subcortical, and cerebellar regions. Subgroup analyses revealed that classical music, but not songs or simple tunes, activated the limbic network. Meta-regression analysis revealed nonsignificant correlations between years of music training and all brain regions activated during music listening. CONCLUSIONS: Music listening bilaterally activated multiple cortical, subcortical, and cerebellar regions encompassing multiple brain networks that were not modulated by music training experience. It is recommended that music listening can be applied to people with neurological disorders to modulate the disordered functional brain networks known to underlie the pathophysiology of these diseases, while future studies may help delineate the effects of music preferences on brain activation patterns among these patients to promote the development of evidence-based medicine. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The neurobiology of prefrontal transcranial direct current stimulation (tDCS) in promoting brain plasticity: A systematic review and meta-analyses of human and rodent studies.

The neurobiological mechanisms underlying prefrontal transcranial direct current stimulation (tDCS) remain elusive. Randomized, sham-controlled trials in humans and rodents applying in vivo prefrontal tDCS were included to explore whether prefrontal tDCS modulates resting-state and event-related functional connectivity, neural oscillation and synaptic plasticity. Fifty studies were included in the systematic review and 32 in the meta-analyses. Neuroimaging meta-analysis indicated anodal prefrontal tDCS significantly enhanced bilateral median cingulate activity [familywise error (FWE)-corrected p < .005]; meta-regression revealed a positive relationship between changes in median cingulate activity after tDCS and current density (FWE-corrected p < .005) as well as electric current strength (FWE-corrected p < .05). Meta-analyses of electroencephalography and magnetoencephalography data revealed nonsignificant changes (ps > .1) in both resting-state and event-related oscillatory power across all frequency bands. Applying anodal tDCS over the rodent hippocampus/prefrontal cortex enhanced long-term potentiation and brain-derived neurotrophic factor expression in the stimulated brain regions (ps <.005). Evidence supporting prefrontal tDCS administration is preliminary; more methodologically consistent studies evaluating its effects on cognitive function that include brain activity measurements are needed.

Differential mirror neuron system (MNS) activation during action observation with and without social-emotional components in autism: a meta-analysis of neuroimaging studies.

BACKGROUND: Impaired imitation has been found to be an important factor contributing to social communication deficits in individuals with autism spectrum disorder (ASD). It has been hypothesized that the neural correlate of imitation, the mirror neuron system (MNS), is dysfunctional in ASD, resulting in imitation impairment as one of the key behavioral manifestations in ASD. Previous MNS studies produced inconsistent results, leaving the debate of whether "broken" mirror neurons in ASD are unresolved. METHODS: This meta-analysis aimed to explore the differences in MNS activation patterns between typically developing (TD) and ASD individuals when they observe biological motions with or without social-emotional components. Effect size signed differential mapping (ES-SDM) was adopted to synthesize the available fMRI data. RESULTS: ES-SDM analysis revealed hyperactivation in the right inferior frontal gyrus and left supplementary motor area in ASD during observation of biological motions. Subgroup analysis of experiments involving the observation of stimuli with or without emotional component revealed hyperactivation in the left inferior parietal lobule and left supplementary motor during action observation without emotional components, whereas hyperactivation of the right inferior frontal gyrus was found during action observation with emotional components in ASD. Subgroup analyses of age showed hyperactivation of the bilateral inferior frontal gyrus in ASD adolescents, while hyperactivation in the right inferior frontal gyrus was noted in ASD adults. Meta-regression within ASD individuals indicated that the right cerebellum crus I activation increased with age, while the left inferior temporal gyrus activation decreased with age. LIMITATIONS: This meta-analysis is limited in its generalization of the findings to individuals with ASD by the restricted age range, heterogeneous study sample, and the large within-group variation in MNS activation patterns during object observation. Furthermore, we only included action observation studies which might limit the generalization of our results to the imitation deficits in ASD. In addition, the relatively small sample size for individual studies might also potentially overestimate the effect sizes. CONCLUSION: The MNS is impaired in ASD. The abnormal activation patterns were found to be modulated by the nature of stimuli and age, which might explain the contradictory results from earlier studies on the "broken mirror neuron" debate.

Effects of Transcranial Direct Current Stimulation (tDCS) in the Normalization of Brain Activation in Patients with Neuropsychiatric Disorders: A Systematic Review of Neurophysiological and Neuroimaging Studies.

Background: People with neuropsychiatric disorders have been found to have abnormal brain activity, which is associated with the persistent functional impairment found in these patients. Recently, transcranial direct current stimulation (tDCS) has been shown to normalize this pathological brain activity, although the results are inconsistent. Objective: We explored whether tDCS alters and normalizes brain activity among patients with neuropsychiatric disorders. Moreover, we examined whether these changes in brain activity are clinically relevant, as evidenced by brain-behavior correlations. Methods: A systematic review was conducted according to PRISMA guidelines. Randomized controlled trials that studied the effects of tDCS on brain activity by comparing experimental and sham control groups using either electrophysiological or neuroimaging methods were included. Results: With convergent evidence from 16 neurophysiological/neuroimaging studies, active tDCS was shown to be able to induce changes in brain activation patterns in people with neuropsychiatric disorders. Importantly, anodal tDCS appeared to normalize aberrant brain activation in patients with schizophrenia and substance abuse, and the effect was selectively correlated with reaction times, task-specific accuracy performance, and some symptom severity measures. Limitations and Conclusions. Due to the inherent heterogeneity in brain activity measurements for tDCS studies among people with neuropsychiatric disorders, no meta-analysis was conducted. We recommend that future studies investigate the effect of repeated cathodal tDCS on brain activity. We suggest to clinicians that the prescription of 1-2 mA anodal stimulation for patients with schizophrenia may be a promising treatment to alleviate positive symptoms. This systematic review is registered with registration number CRD42020183608.