Association between degree centrality and neurocognitive impairments in patients with Schizophrenia: A Longitudinal rs-fMRI Study.

BACKGROUND: Evidence indicates that patients with schizophrenia (SZ) experience significant changes in their functional connectivity during antipsychotic treatment. Despite previous reports of changes in brain network degree centrality (DC) in patients with schizophrenia, the relationship between brain DC changes and neurocognitive improvement in patients with SZ after antipsychotic treatment remains elusive. METHODS: A total of 74 patients with acute episodes of chronic SZ and 53 age- and sex-matched healthy controls were recruited. The Positive and Negative Syndrome Scale (PANSS), Symbol Digit Modalities Test, digital span test (DST), and verbal fluency test were used to evaluate the clinical symptoms and cognitive performance of the patients with SZ. Patients with SZ were treated with antipsychotics for six weeks starting at baseline and underwent MRI and clinical interviews at baseline and after six weeks, respectively. We then divided the patients with SZ into responding (RS) and non-responding (NRS) groups based on the PANSS scores (reduction rate of PANSS ≥50%). DC was calculated and analyzed to determine its correlation with clinical symptoms and cognitive performance. RESULTS: After antipsychotic treatment, the patients with SZ showed significant improvements in clinical symptoms, semantic fluency performance. Correlation analysis revealed that the degree of DC increase in the left anterior inferior parietal lobe (aIPL) after treatment was negatively correlated with changes in the excitement score (r = -0.256, p = 0.048, adjusted p = 0.080), but this correlation failed the multiple test correction. Patients with SZ showed a significant negative correlation between DC values in the left aIPL and DST scores after treatment, which was not observed at the baseline (r = -0.359, p = 0.005, adjusted p = 0.047). In addition, we did not find a significant difference in DC between the RS and NRS groups, neither at baseline nor after treatment. CONCLUSIONS: The results suggested that DC changes in patients with SZ after antipsychotic treatment are correlated with neurocognitive performance. Our findings provide new insights into the neuropathological mechanisms underlying antipsychotic treatment of SZ.

Enhanced brain functional connectivity and activation after 12-week Tai Chi-based action observation training in patients with Parkinson's disease.

Introduction: Motor-cognitive interactive interventions, such as action observation training (AOT), have shown great potential in restoring cognitive function and motor behaviors. It is expected that an advanced AOT incorporating specific Tai Chi movements with continuous and spiral characteristics can facilitate the shift from automatic to intentional actions and thus enhance motor control ability for early-stage PD. Nonetheless, the underlying neural mechanisms remain unclear. The study aimed to investigate changes in brain functional connectivity (FC) and clinical improvement after 12 weeks of Tai Chi-based action observation training (TC-AOT) compared to traditional physical therapy (TPT). Methods: Thirty early-stage PD patients were recruited and randomly assigned to the TC-AOT group (N = 15) or TPT group (N = 15). All participants underwent resting-state functional magnetic resonance imaging (rs-fMRI) scans before and after 12 weeks of training and clinical assessments. The FCs were evaluated by seed-based correlation analysis based on the default mode network (DMN). The rehabilitation effects of the two training methods were compared while the correlations between significant FC changes and clinical improvement were investigated. Results: The results showed that the TC-AOT group exhibited significantly increased FCs between the dorsal medial prefrontal cortex and cerebellum crus I, between the posterior inferior parietal lobe and supramarginal gyrus, and between the temporal parietal junction and clusters of middle occipital gyrus and superior temporal. Moreover, these FC changes had a positive relationship with patients' improved motor and cognitive performance. Discussion: The finding supported that the TC-AOT promotes early-stage PD rehabilitation outcomes by promoting brain neuroplasticity where the FCs involved in the integration of sensorimotor processing and motor learning were strengthened.

Using gamma-band transcranial alternating current stimulation (tACS) to improve sleep quality and cognition in patients with mild neurocognitive disorders due to Alzheimer's disease: A study protocol for a randomized controlled trial.

BACKGROUND: Sleep disturbances are highly prevalent in patients with age-related neurodegenerative diseases, which severely affect cognition and even lead to accumulated ß-amyloid. Encouraging results from recent studies on transcranial direct current stimulation (tDCS) showed moderate positive effects on sleep quality in preclinical Alzheimer's disease (AD). Compared to tDCS, transcranial alternating current stimulation (tACS) enables the entrainment of neuronal activity with optimized focality through injecting electric current with a specific frequency and has significant enhancement effects on slow wave activities. METHODS AND DESIGN: This is a randomized, double-blind, sham-controlled clinical trial comparing 40 Hz tACS with tDCS in mild neurocognitive disorders due to AD with sleep disturbances. Magnetic resonance imaging (MRI) data is used to construct personalized realistic head model. Treatment outcomes, including sleep quality, cognitive performance and saliva Aß levels will be conducted at baseline, 4th week, 8th week, 12th week and 24th week. CONCLUSIONS: It is expected that the repeated gamma-band tACS will show significant improvements in sleep quality and cognitive functions compared to tDCS and sham tDCS. The findings will provide high-level evidence and guide further advanced studies in the field of neurodegenerative diseases and sleep medicine. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05544201.

Pinpointing the precise stimulation targets for brain rehabilitation in early-stage Parkinson's disease.

BACKGROUND: Transcranial magnetic stimulation (TMS) is increasingly used as a promising non-pharmacological treatment for Parkinson's disease (PD). Scalp-to-cortex distance (SCD), as a key technical parameter of TMS, plays a critical role in determining the locations of treatment targets and corresponding dosage. Due to the discrepancies in TMS protocols, the optimal targets and head models have yet to be established in PD patients. OBJECTIVE: To investigate the SCDs of the most popular used targets in left dorsolateral prefrontal cortex (DLPFC) and quantify its impact on the TMS-induced electric fields (E-fields) in early-stage PD patients. METHODS: Structural magnetic resonance imaging scans from PD patients (n = 47) and normal controls (n = 36) were drawn from the NEUROCON and Tao Wu datasets. SCD of left DLPFC was measured by Euclidean Distance in TMS Navigation system. The intensity and focality of SCD-dependent E-fields were examined and quantified using Finite Element Method. RESULTS: Early-stage PD patients showed an increased SCDs, higher variances in the SCDs and SCD-dependent E-fields across the seven targets of left DLPFC than normal controls. The stimulation targets located on gyral crown had more focal and homogeneous E-fields. The SCD of left DLPFC had a better performance in differentiating early-stage PD patients than global cognition and other brain measures. CONCLUSION: SCD and SCD-dependent E-fields could determine the optimal TMS treatment targets and may also be used as a novel marker to differentiate early-stage PD patients. Our findings have important implications for developing optimal TMS protocols and personalized dosimetry in real-world clinical practice.

Diversity in verbal fluency performance and its associations with MRI-informed brain age matrices in normal ageing and neurocognitive disorders.

INTRODUCTION: Category verbal fluency test (CVFT) has been widely used to assess and monitor the cognitive capacities in epidemiological studies and clinical trials. Pronounced discrepancy in CVFT performance has been found in individuals with different cognitive statuses. This study aimed to combine the psychometric and morphometric approaches to decode the complex verbal fluency performance in senior adults with normal ageing and neurocognitive disorders. METHODS: This study adopted a two-stage cross-sectional design involving quantitative analyses of neuropsychological and neuroimaging data. In study I, capacity- and speed-based measures of CVFT were developed to evaluate the verbal fluency performance in normal ageing seniors (n = 261), those with mild cognitive impairment (n = 204), and those with dementia (n = 23) whose age range is from 65 to 85 years. In study II, structural magnetic resonance imaging-informed gray matter volume (GMV) and brain age matrices were calculated in a subsample (n = 52) from Study I through surface-based morphometry analysis. With age and gender as covariates, Pearson's correlation analysis was used to examine the associations of CVFT measures, GMV, and brain age matrices. RESULTS: Speed-based measures showed extensive and stronger associations with other cognitive functions than capacity-based measures. The component-specific CVFT measures showed shared and unique neural underpinnings with lateralized morphometric features. Moreover, the increased CVFT capacity was significantly correlated with younger brain age in mild neurocognitive disorder (NCD) patients. CONCLUSION: We found that the diversity of verbal fluency performance in normal ageing and NCD patients could be explained by a combination of memory, language, and executive abilities. The component-specific measures and related lateralized morphometric correlates also highlight the underlying theoretical meaning of verbal fluency performance and its clinical utility in detecting and tracing the cognitive trajectory in individuals with accelerated ageing.

Decoding the radiomic features of dorsolateral prefrontal cortex in individuals with accelerated cortical changes: implications for personalized transcranial magnetic stimulation.

Purpose: Image-guided transcranial magnetic stimulation (TMS) is an emerging research field in neuroscience and rehabilitation medicine. Cortical morphometry, as a radiomic phenotype of aging, plays a vital role in developing personalized TMS model, yet few studies are afoot to examine the aging effects on region-specific morphometry and use it in the estimation of TMS-induced electric fields. Our study was aimed to investigate the radiomic features of bilateral dorsolateral prefrontal cortex (DLPFC) and quantify the TMS-induced electric fields during aging. Approach: Baseline, 1-year and 3-year structural magnetic resonance imaging (MRI) scans from normal aging (NA) adults ( n = 32 ) and mild cognitive impairment (MCI) converters ( n = 22 ) were drawn from the Open Access Series of Imaging Studies. The quantitative measures of radiomics included cortical thickness, folding, and scalp-to-cortex distance. Realistic head models were developed to simulate the impacts of radiomic features on TMS-induced E-fields using the finite-element method. Results: A pronounced aging-related decrease was found in the gyrification of left DLPFC in MCI converters ( t = 2.21 , p = 0.035 ), which could predict the decline of global cognition at 3-year follow up. Along with the decreased gyrification in left DLPFC, the magnitude of TMS-induced E-fields was rapidly decreased in MCI converters ( t = 2.56 , p = 0.018 ). Conclusions: MRI-informed radiomic features of the treatment targets have significant effects on the intensity and distribution of the stimulation-induced electric fields in prodromal dementia patients. Our findings highlight the importance of region-specific radiomics when conducting the transcranial brain stimulation in individuals with accelerated cortical changes, such as Alzheimer's disease.

Study protocol of a double-blind randomized control trial of transcranial direct current stimulation in post-stroke fatigue.

Rationale: Post-stroke fatigue (PSF) is a frequent problem in stroke survivors and often hinders their rehabilitation. PSF is difficult to treat, and pharmacological therapy is often ineffective. Transcranial direct current stimulation (tDCS) can modulate motor, sensory, cognitive and behavioral responses, as it alters neuronal activity by delivering a small amount of current via the scalp to the cortex, resulting in prolonged alterations to brain function. tDCS has been studied for the treatment of fatigue associated with other neurological diseases, namely, multiple sclerosis, Parkinson's disease and post-polio syndrome. Aims: This proposed project will examine the effect of tDCS on PSF. Sample size estimates: We will recruit 156 participants aged 18 to 80 with chronic stroke and allocate them equally to two groups (i.e., n = 78 per group). Methods and design: This proposed project will be a double-blind randomized control trial. The participants will be randomly divided into two groups. The control group will receive sham tDCS, and the treatment group will receive active tDCS. The latter treatment will involve application of a constant 2-mA current via one 5 × 5-cm anodal electrode positioned on the scalp over the C3 or C4 positions (motor cortex) of the lesioned hemisphere and one cathodal electrode positioned at the ipsilateral shoulder in two 20-min sessions per day for 5 days. The period of follow-up will be 4 weeks. Study outcomes: The primary outcome measure will be a change in fatigue severity, as measured using the modified fatigue impact scale (MFIS). The participants' scores on the MFIS (total score and physical, cognitive and psychosocial subscores) will be collected before treatment (T0), after 10 treatment sessions, i.e., 1 day after the fifth treatment day (T1), and 1 week (T2), 2 weeks (T3) and 4 weeks (T4) thereafter. Both per-protocol analysis and intention-to-treat analysis will be performed. Discussion: This proposed project will provide proof-of-concept, i.e., demonstrate the benefits of tDCS for the treatment of PSF. The beneficiaries are the subjects participated in the study. This will stimulate further research to optimize tDCS parameters for the treatment of PSF. Clinical trial registration: www.Chictr.org.cn, identifier: ChiCTR2100052515.

Clinical and radiomic features for predicting the treatment response of repetitive transcranial magnetic stimulation in major neurocognitive disorder: Results from a randomized controlled trial.

Image-guided repetitive transcranial magnetic stimulation (rTMS) has shown clinical effectiveness in senior adults with co-occurring depression and cognitive impairment, yet the imaging markers for predicting the treatment response are less investigated. In this clinical trial, we examined the efficacy and sustainability of 10 Hz rTMS for the treatment of depression and cognitive impairment in major neurocognitive disorder (NCD) patients and tested the predictive values of imaging-informed radiomic features in response to rTMS treatment. Fifty-five major NCD patients with depression were randomly assigned to receive a 3-week rTMS treatment of either active 10 Hz rTMS (n = 27) or sham rTMS (n = 28). Left dorsolateral prefrontal cortex (DLPFC) was the predefined treatment target. Based on individual structural magnetic resonance imaging scans, surface-based analysis was conducted to quantitatively measure the baseline radiomic features of left DLPFC. Severity of depression, global cognition and the serum brain-derived neurotrophic factor (BDNF) level were evaluated at baseline, 3-, 6- and 12-week follow-ups. Logistic regression analysis revealed that advanced age, higher baseline cognition and randomized group were associated with the remission of depression. Increased cortical thickness and gyrification in left DLPFC were the significant predictors of clinical remission and cognitive enhancement. A 3-week course of 10 Hz rTMS is an effective adjuvant treatment for rapid ameliorating depressive symptoms and enhancing cognitive function. Pre-treatment radiomic features of the stimulation target can predict the response to rTMS treatment in major NCD. Cortical thickness and folding of treatment target may serve as imaging markers to detect the responders. ChiCTR-IOR-16008191, registered on March 30, 2016.

Increasing participation in habitual intellectual activities on modulating functional connectivity of default mode network among older adults at risk of dementia: study protocol of a randomized controlled trial.

BACKGROUND: Active participation in intellectual leisure activities such as calligraphy helps prevent cognitive decline and dementia, but the underlying mechanisms are not fully understood. With disrupted functional connectivity (FC) of default mode network (DMN) associated with cognitive decline, we speculate that intellectual activities might optimize cognitive function through modulating FC of DMN. This two-arm single-blind randomized controlled trial aims to identify the effects of increasing practice of calligraphy on cognitive function and FC of DMN in people with subjective cognitive decline (SCD). METHODS: One hundred twelve community-living Chinese aged 55 to 75 years old with SCD but without mild cognitive impairment or dementia and with prior practice of calligraphy as defined by 1 h of calligraphy per week will be recruited through elderly social centres in Hong Kong and randomized into either control or intervention group. The control group will continue with their usual practice of calligraphy, whereas the intervention group will double their practice of calligraphy. Measurement of cognitive outcomes and neuroimaging on resting-state FC will be performed at baseline and in 6 months. Repeated measures analysis of variance will be used to assess cognitive and FC changes, with time being the within-group factor, control/intervention as the between-group measure, and important covariates (age, sex, educational and occupational attainment, health, and other lifestyle factors) controlled for. DISCUSSION: This study will shed light on the underlying neurocognitive mechanisms of how intellectual activities promotes cognitive maintenance. Our anticipated findings will provide evidence that reversing or slowing FC disruption by actively participating in intellectual activities is still possible for the at-risk individuals. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR1900024433 . Registered on 11 July 2019.

Selectively disrupted sensorimotor circuits in chronic stroke with hand dysfunction.

AIM: To investigate the directional and selective disconnection of the sensorimotor cortex (SMC) subregions in chronic stroke patients with hand dysfunction. METHODS: We mapped the resting-state fMRI effective connectivity (EC) patterns for seven SMC subregions in each hemisphere of 65 chronic stroke patients and 40 healthy participants and correlated these patterns with paretic hand performance. RESULTS: Compared with controls, patients demonstrated disrupted EC in the ipsilesional primary motor cortex_4p, ipsilesional primary somatosensory cortex_2 (PSC_2), and contralesional PSC_3a. Moreover, we found that EC values of the contralesional PSC_1 to contralesional precuneus, the ipsilesional inferior temporal gyrus to ipsilesional PSC_1, and the ipsilesional PSC_1 to contralesional postcentral gyrus were correlated with paretic hand performance across all patients. We further divided patients into partially (PPH) and completely (CPH) paretic hand subgroups. Compared with CPH patients, PPH patients demonstrated decreased EC in the ipsilesional premotor_6 and ipsilesional PSC_1. Interestingly, we found that paretic hand performance was positively correlated with seven sensorimotor circuits in PPH patients, while it was negatively correlated with five sensorimotor circuits in CPH patients. CONCLUSION: SMC neurocircuitry was selectively disrupted after chronic stroke and associated with diverse hand outcomes, which deepens the understanding of SMC reorganization.

Personalized prediction of repetitive transcranial magnetic stimulation clinical response in medication-refractory depression data.

This article describes a dataset that was generated as part of the article: Personalized prediction of transcranial magnetic stimulation clinical response in patients with treatment-refractory depression using neuroimaging biomarkers and machine learning (DOI: 10.1016/j.jad.2021.04.081). We collected resting-state functional Magnetic Resonance Imaging data from 70 medication-refractory depressed subjects before undergoing four weeks of repetitive transcranial magnetic stimulation targeting the left dorsolateral prefrontal cortex. The data presented here include information about the seed-based analyses such as regions of interest, individual/group functional connectivity maps and contrast maps. The contrast maps are controlled for age, gender, duration of the current depressive episode, duration since the first depressive episode, and symptom scores. Demographics, clinical characteristics, and categorical treatment response variables are reported as well. Further, the individual connectivity values of the identified neuroimaging biomarkers of long-term clinical response were used as features in the support vector machine models are presented in combination with the trained classifiers of the support vector machine models. Post hoc analyses that were not published in the original analyses are presented as well. Finally, the R or MATLAB code scripts for all figures published in the co-submitted paper are included.

Cortical Morphometric Abnormality and Its Association with Working Memory in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children and adolescents. The present study investigated the cortical morphology features and their relationship with working memory (WM). METHODS: In the present study, a total of 36 medication naïve children with ADHD (aged from 8 to 15 years) and 36 age- and gendermatched healthy control (HC) children were included. The digit span test was used to evaluate WM. The magnetic resonance imaging (MRI) was used to examine the characteristics of cortical morphology. Firstly, we compared the cortical morphology features between two groups to identify the potential structural alterations of cortical volume, surface, thickness, and curvature in children with ADHD. Then, the correlation between the brain structural abnormalities and WM was further explored in children with ADHD. RESULTS: Compared with the HC children, the children with ADHD showed reduced cortical volumes in the left lateral superior temporal gyrus (STG) (p=6.67×10-6) and left anterior cingulate cortex (ACC) (p=3.88×10-4). In addition, the cortical volume of left lateral STG was positively correlated with WM (r=0.36, p=0.029). CONCLUSION: Though preliminary, these findings suggest that the reduced cortical volumes of left lateral STG may contribute to the pathogenesis of ADHD and correlate with WM in children with ADHD.

The Effects of Repetitive Transcranial Magnetic Stimulation Antidepressant Response on Cold Cognition: A Single-Arm Prospective Longitudinal Study.

PURPOSE: The cognitive neuropsychological model of depression suggests that the cognitive deficits observed in depressed subjects are the result of attenuated top-down cognitive control resulting in increased bottom-up emotional processing. Remediation of cognitive impairments in cold cognition has been proposed as a valuable treatment for depression. The study aimed to examine the effects of clinical response to repetitive transcranial magnetic stimulation (rTMS) on cold cognition over the course of 8 weeks in medication-refractory depressed subjects. MATERIALS AND METHODS: Twenty-two medication-refractory depressed subjects received twenty sessions of high-frequency rTMS targeting the left dorsolateral prefrontal cortex, one of the key nodes of the cognitive control network. Cold cognition and antidepressant treatment response were monitored at baseline, week 2, 4 and 8. Clinical response was defined as ≥50% reduction in Montgomery-Åsberg Depression Rating Scale score at week 8. Longitudinal changes in cold cognition were modeled using (generalized) linear mixed models. It was hypothesized that the excitatory effects of rTMS would improve cognition in the domains of executive function, memory, and attention. Additionally, responders were expected to show larger cognitive improvements than nonresponders. RESULTS: A decrease in median latency was observed on a task that measured executive function, irrespective of treatment response status. Further, responders showed significantly larger improvements in A-Prime (the ability to detect target sequences) on a sustained attention task. Post hoc analysis indicated higher levels of rumination in non-responders. CONCLUSION: Our findings suggest that distractions during tasks with low perceptual complexity affected nonresponders disproportionately possibly due to higher rumination levels. Overall, cold cognition in medication-resistant depressed subjects was minimally affected by rTMS, substantiating the safety of rTMS treatment. LIMITATIONS: The sample size was small, and the study did not include a control group.

Dynamic changes of region-specific cortical features and scalp-to-cortex distance: implications for transcranial current stimulation modeling.

BACKGROUND: Transcranial current stimulation in rehabilitation is a fast-growing field featured with computational and biophysical modeling. Cortical features and scalp-to-cortex distance (SCD) are key variables for determining the strength and distribution of the electric field, yet longitudinal studies able to capture these dynamic changes are missing. We sought to investigate and quantify the ageing effect on the morphometry and SCD of left primary motor cortex (M1) and dorsolateral prefrontal cortex (DLPFC) in normal ageing adults and mild cognitive impairment (MCI) converters. METHODS: Baseline, 1-year and 3-year follow-up structural magnetic resonance imaging scans from normal ageing adults (n = 32), and MCI converters (n = 22) were drawn from the Open Access Series of Imaging Studies. We quantified the changes of the cortical features and SCDs of left M1 and DLPFC, including grey matter volume, white matter volume, cortical thickness, and folding. Head model was developed to simulate the impact of SCD on the electric field induced by transcranial current stimulation. RESULTS: Pronounced ageing effect was found on the SCD of left DLPFC in MCI converters. The SCD change of left DLPFC from baseline to 3-year follow-up demonstrated better performance to discriminate MCI converters from normal ageing adults than the other morphometric measures. The strength of electric field was consequently decreased with SCD in MCI converters. CONCLUSION: Ageing has a prominent, but differential effect on the region-specific SCD and cortical features in older adults with cognitive impairments. Our findings suggest that SCD, cortical thickness, and folding of the targeted regions could be used as valuable imaging markers when conducting transcranial brain stimulation in individuals with brain atrophy.

Quantifying Age-Associated Cortical Complexity of Left Dorsolateral Prefrontal Cortex with Multiscale Measurements.

BACKGROUND: Cortical complexity plays a central role in the diagnosis and prognosis of age-related diseases. However, little is known about the regional cortical complexity in the context of brain atrophy. OBJECTIVE: We aimed to systematically examine the age-related changes of the cortical complexity of left dorsolateral prefrontal cortex (DLPFC) and its subregions. METHODS: Two hundred and fourteen cognitively normal adults drawn from the Open Access Series of Imaging Studies (OASIS) were divided into four age groups: young, middle-aged, young-old, and old-old. Based on structural magnetic resonance imaging (sMRI) scans, the multiscale measures of cortical complexity included cortical thickness (mm), surface area (mm2), grey matter volume (mm3), density, gyrification index (GI), and fractal dimension (FD). RESULTS: Advancing age was associated with reduced grey matter volume, pial surface area, density, and FD of left DLPFC, but correlated with increased cortical thickness and GI. Volumetric measures, cerebrospinal fluid volume in particular, showed better performance to discriminate young-old adults from old-old adults, while FD was more sensitive than the volumetric measures to discriminate young adults and middle-aged adults. CONCLUSION: This is the first demonstration that chronological age has a pronounced and differential effect on the cortical complexity of left DLPFC. Our findings suggest that surface-based measures of cortical region, thickness, and gyrification in particular, could be considered as valuable imaging markers for the studies of aging brain and neurodegenerative diseases.