Dorsolateral Prefrontal Cortex Regions Research Articles

Neural response during prefrontal theta burst stimulation: Interleaved TMS-fMRI of full iTBS protocols

BackgroundLeft prefrontal intermittent theta-burst stimulation (iTBS) has emerged as a safe and effective transcranial magnetic stimulation (TMS) treatment protocol in depression. Though network effects after iTBS have been widely studied, the deeper mechanistic understanding of target engagement is still at its beginning. Here, we investigate the feasibility of a novel integrated TMS-fMRI setup and accelerated echo planar imaging protocol to directly observe the immediate effects of full iTBS treatment sessions. Objective/hypothesisIn our effort to explore interleaved iTBS-fMRI feasibility, we hypothesize that TMS will induce acute BOLD signal changes in both the stimulated area and interconnected neural regions. MethodsConcurrent TMS-fMRI with full sessions of neuronavigated iTBS (i.e. 600 pulses) of the left dorsolateral prefrontal cortex (DLPFC) was investigated in 18 healthy participants. In addition, we conducted four TMS-fMRI sessions in a single patient on long-term maintenance iTBS for bipolar depression to test the transfer to clinical cases. ResultsConcurrent TMS-fMRI was feasible for iTBS sequences with 600 pulses. During interleaved iTBS-fMRI, an increase of the BOLD signal was observed in a network including bilateral DLPFC regions. In the clinical case, a reduced BOLD response was found in the left DLPFC and the subgenual anterior cingulate cortex, with high variability across individual sessions. ConclusionsFull iTBS sessions as applied for the treatment of depressive disorders can be established in the interleaved iTBS-fMRI paradigm. In the future, this experimental approach could be valuable in clinical samples, for demonstrating target engagement by iTBS protocols and investigating their mechanisms of therapeutic action.

Can Brain Volume-Driven Characteristic Features Predict the Response of Alzheimer's Patients to Repetitive Transcranial Magnetic Stimulation? A Pilot Study.

This study is a post-hoc examination of baseline MRI data from a clinical trial investigating the efficacy of repetitive transcranial magnetic stimulation (rTMS) as a treatment for patients with mild-moderate Alzheimer's disease (AD). Herein, we investigated whether the analysis of baseline MRI data could predict the response of patients to rTMS treatment. Whole-brain T1-weighted MRI scans of 75 participants collected at baseline were analyzed. The analyses were run on the gray matter (GM) and white matter (WM) of the left and right dorsolateral prefrontal cortex (DLPFC), as that was the rTMS application site. The primary outcome measure was the Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog). The response to treatment was determined based on ADAS-Cog scores and secondary outcome measures. The analysis of covariance showed that responders to active treatment had a significantly lower baseline GM volume in the right DLPFC and a higher GM asymmetry index in the DLPFC region compared to those in non-responders. Logistic regression with a repeated five-fold cross-validated analysis using the MRI-driven features of the initial 75 participants provided a mean accuracy of 0.69 and an area under the receiver operating characteristic curve of 0.74 for separating responders and non-responders. The results suggest that GM volume or asymmetry in the target area of active rTMS treatment (DLPFC region in this study) may be a weak predictor of rTMS treatment efficacy. These results need more data to draw more robust conclusions.

Glucose-oxygen coupling can serve as a biomarker for neuroinflammation-related genetic variants.

Abstract The single-nucleotide polymorphism rs3197999 in the macrophage-stimulating protein 1 gene is a missense variant. Studies have indicated that macrophage-stimulating protein 1 mediates neuronal loss and synaptic plasticity damage, and overexpression of the macrophage-stimulating protein 1 gene leads to the excessive activation of microglial cells, thereby resulting in an elevation of cerebral glucose metabolism. Traditional diagnostic models may be disrupted by neuroinflammation, making it difficult to predict the pathological status of patients solely based on single-modal images. We hypothesize that the macrophage-stimulating protein 1 rs3197999 single-nucleotide polymorphism may lead to imbalances in glucose and oxygen metabolism, thereby influencing cognitive resilience and the progression of Alzheimer’s disease. In this study, we found that among 121 patients with mild cognitive impairment, carriers of the macrophage-stimulating protein 1 rs3197999 risk allele showed a significant reduction in the coupling of glucose and oxygen metabolism in the dorsolateral prefrontal cortex region. However, the rs3197999 variant did not induce significant differences in glucose metabolism and neuronal activity signals. Furthermore, the rs3197999 risk allele correlated with a higher rate of increase in clinical dementia score, mediated by the coupling of glucose and oxygen metabolism. Highlight

Top-down modulation of DLPFC in visual search: a study based on fMRI and TMS.

Effective visual search is essential for daily life, and attention orientation as well as inhibition of return play a significant role in visual search. Researches have established the involvement of dorsolateral prefrontal cortex in cognitive control during selective attention. However, neural evidence regarding dorsolateral prefrontal cortex modulates inhibition of return in visual search is still insufficient. In this study, we employed event-related functional magnetic resonance imaging and dynamic causal modeling to develop modulation models for two types of visual search tasks. In the region of interest analyses, we found that the right dorsolateral prefrontal cortex and temporoparietal junction were selectively activated in the main effect of search type. Dynamic causal modeling results indicated that temporoparietal junction received sensory inputs and only dorsolateral prefrontal cortex →temporoparietal junction connection was modulated in serial search. Such neural modulation presents a significant positive correlation with behavioral reaction time. Furthermore, theta burst stimulation via transcranial magnetic stimulation was utilized to modulate the dorsolateral prefrontal cortex region, resulting in the disappearance of the inhibition of return effect during serial search after receiving continuous theta burst stimulation. Our findings provide a new line of causal evidence that the top-down modulation by dorsolateral prefrontal cortex influences the inhibition of return effect during serial search possibly through the retention of inhibitory tagging via working memory storage.

Non-linear processing and reinforcement learning to predict rTMS treatment response in depression

BackgroundForecasting the efficacy of repetitive transcranial magnetic stimulation (rTMS) therapy can lead to substantial time and cost savings by preventing futile treatments. To achieve this objective, we've formulated a machine learning approach aimed at categorizing patients with major depressive disorder (MDD) into two groups: individuals who respond (R) positively to rTMS treatment and those who do not respond (NR). MethodsPreceding the commencement of treatment, we obtained resting-state EEG data from 106 patients diagnosed with MDD, employing 32 electrodes for data collection. These patients then underwent a 7-week course of rTMS therapy, and 54 of them exhibited positive responses to the treatment. Employing Independent Component Analysis (ICA) on the EEG data, we successfully pinpointed relevant brain sources that could potentially serve as markers of neural activity within the dorsolateral prefrontal cortex (DLPFC). These identified sources were further scrutinized to estimate the sources of activity within the sensor domain. Then, we integrated supplementary physiological data and implemented specific criteria to yield more realistic estimations when compared to conventional EEG analysis. In the end, we selected components corresponding to the DLPFC region within the sensor domain. Features were derived from the time-series data of these relevant independent components. To identify the most significant features, we used Reinforcement Learning (RL). In categorizing patients into two groups – R and NR to rTMS treatment – we utilized three distinct classification algorithms including K-Nearest Neighbor (KNN), Support Vector Machine (SVM), and Multilayer Perceptron (MLP). We assessed the performance of these classifiers through a ten-fold cross-validation method. Additionally, we conducted a statistical test to evaluate the discriminative capacity of these features between responders and non-responders, opening the door for further exploration in this field. ResultsWe identified EEG features that can anticipate the response to rTMS treatment. The most robust discriminators included EEG beta power, the sum of bispectrum diagonal elements in the delta and beta frequency bands. When these features were combined into a single vector, the classification of responders and non-responders achieved impressive performance, with an accuracy of 95.28 %, specificity at 94.23 %, sensitivity reaching 96.29 %, and precision standing at 94.54 %, all achieved using SVM. ConclusionsThe results of this study suggest that the proposed approach, utilizing power, non-linear, and bispectral features extracted from relevant independent component time-series, has the capability to forecast the treatment outcome of rTMS for MDD patients based solely on a single pre-treatment EEG recording session. The achieved findings demonstrate the superior performance of our method compared to previous techniques.

The connectivity of the human frontal pole cortex, and a theory of its involvement in exploit versus explore.

The frontal pole is implicated in humans in whether to exploit resources versus explore alternatives. Effective connectivity, functional connectivity, and tractography were measured between six human frontal pole regions and for comparison 13 dorsolateral and dorsal prefrontal cortex regions, and the 360 cortical regions in the Human Connectome Project Multi-modal-parcellation atlas in 171 HCP participants. The frontal pole regions have effective connectivity with Dorsolateral Prefrontal Cortex regions, the Dorsal Prefrontal Cortex, both implicated in working memory; and with the orbitofrontal and anterior cingulate cortex reward/non-reward system. There is also connectivity with temporal lobe, inferior parietal, and posterior cingulate regions. Given this new connectivity evidence, and evidence from activations and damage, it is proposed that the frontal pole cortex contains autoassociation attractor networks that are normally stable in a short-term memory state, and maintain stability in the other prefrontal networks during stable exploitation of goals and strategies. However, if an input from the orbitofrontal or anterior cingulate cortex that expected reward, non-reward, or punishment is received, this destabilizes the frontal pole and thereby other prefrontal networks to enable exploration of competing alternative goals and strategies. The frontal pole connectivity with reward systems may be key in exploit versus explore.

Side-by-side regions in dorsolateral prefrontal cortex estimated within the individual respond differentially to domain-specific and domain-flexible processes.

A recurring debate concerns whether regions of primate prefrontal cortex (PFC) support domain-flexible or domain-specific processes. Here we tested the hypothesis with functional MRI (fMRI) that side-by-side PFC regions, within distinct parallel association networks, differentially support domain-flexible and domain-specialized processing. Individuals (N = 9) were intensively sampled, and all effects were estimated within their own idiosyncratic anatomy. Within each individual, we identified PFC regions linked to distinct networks, including a dorsolateral PFC (DLPFC) region coupled to the medial temporal lobe (MTL) and an extended region associated with the canonical multiple-demand network. We further identified an inferior PFC region coupled to the language network. Exploration in separate task data, collected within the same individuals, revealed a robust functional triple dissociation. The DLPFC region linked to the MTL was recruited during remembering and imagining the future, distinct from juxtaposed regions that were modulated in a domain-flexible manner during working memory. The inferior PFC region linked to the language network was recruited during sentence processing. Detailed analysis of the trial-level responses further revealed that the DLPFC region linked to the MTL specifically tracked processes associated with scene construction. These results suggest that the DLPFC possesses a domain-specialized region that is small and easily confused with nearby (larger) regions associated with cognitive control. The newly described region is domain specialized for functions traditionally associated with the MTL. We discuss the implications of these findings in relation to convergent anatomical analysis in the monkey.NEW & NOTEWORTHY Competing hypotheses link regions of prefrontal cortex (PFC) to domain-flexible or domain-specific processes. Here, using a precision neuroimaging approach, we identify a domain-specialized region in dorsolateral PFC, coupled to the medial temporal lobe and recruited for scene construction. This region is juxtaposed to, but distinct from, broader PFC regions recruited flexibly for cognitive control. Region distinctions align with broader network differences, suggesting that PFC regions gain dissociable processing properties via segregated anatomical projections.

Correlation between cerebral hemodynamic functional near-infrared spectroscopy and positron emission tomography for assessing mild cognitive impairment and Alzheimer's disease: An exploratory study.

This study was performed to investigate the usefulness of functional near-infrared spectroscopy (fNIRS) by conducting a comparative analysis of hemodynamic activation detected by fNIRS and positron emission tomography (PET) and magnetic resonance imaging (MRI) in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD). Participants were divided into four groups: the subjective memory impairment (SMI), amnestic MCI (aMCI), non-amnestic MCI (naMCI), and AD groups. We recorded the hemodynamic response during the semantic verbal fluency task (SVFT) using a commercial wireless continuous-wave NIRS system. The correlation between the parameters of the neuroimaging assessments among the groups was analyzed. Region of interest-based comparisons showed that the four groups had significantly different hemodynamic responses during SVFT in the bilateral dorsolateral prefrontal cortex (DLPFC). The linear mixed effect model result indicates that the mean ΔHbO2 from the bilateral DLPFC regions showed a significant positive correlation to the overall FDG-PET after controlling for age and group differences in the fNIRS signals. Amyloid PET signals tended to better differentiate the AD group from other groups, and fNIRS signals tended to better differentiate the SMI group from other groups. In addition, a comparison between the group pairs revealed a mirrored pattern between the hippocampal volume and hemodynamic response in the DLPFC. The hemodynamic response detected by fNIRS showed a significant correlation with metabolic and anatomical changes associated with disease progression. Therefore, fNIRS may be considered as a screening tool to predict the hemodynamic and metabolic statuses of the brain in patients with MCI and AD.

Causally informed activity flow models provide mechanistic insight into network-generated cognitive activations

Brain activity flow models estimate the movement of task-evoked activity over brain connections to help explain network-generated task functionality. Activity flow models have been shown to accurately generate task-evoked brain activations across a wide variety of brain regions and task conditions. However, these models have had limited explanatory power, given known issues with causal interpretations of the standard functional connectivity measures used to parameterize activity flow models. We show here that functional/effective connectivity (FC) measures grounded in causal principles facilitate mechanistic interpretation of activity flow models. We progress from simple to complex FC measures, with each adding algorithmic details reflecting causal principles. This reflects many neuroscientists’ preference for reduced FC measure complexity (to minimize assumptions, minimize compute time, and fully comprehend and easily communicate methodological details), which potentially trades off with causal validity. We start with Pearson correlation (the current field standard) to remain maximally relevant to the field, estimating causal validity across a range of FC measures using simulations and empirical fMRI data. Finally, we apply causal-FC-based activity flow modeling to a dorsolateral prefrontal cortex region (DLPFC), demonstrating distributed causal network mechanisms contributing to its strong activation during a working memory task. Notably, this fully distributed model is able to account for DLPFC working memory effects traditionally thought to rely primarily on within-region (i.e., not distributed) recurrent processes. Together, these results reveal the promise of parameterizing activity flow models using causal FC methods to identify network mechanisms underlying cognitive computations in the human brain.

The Relationship between Depression Severity and Prefrontal Hemodynamic Changes in Adolescents with Major Depression Disorder: A Functional Near-infrared Spectroscopy Study.

: Numerous studies have identified hemodynamic changes in adults with major depressive disorder (MDD) by using functional near-infrared spectroscopy (fNIRS). However, studies on adolescents with MDD are limited. As adolescence is a stage of rapid brain development, differences may occur depending on age. This study used fNIRS as an objective tool to investigate hemodynamic changes in the frontal lobe according to depression severity and age in adolescents with MDD. : Thirty adolescents (12 aged 12-15 years and 18 aged 16-18 years) were retrospectively investigated. The Children's Depression Inventory was used as a psychiatric evaluation scale, fNIRS was used as an objective brain function evaluation tool, and the Verbal Fluency Test was performed. : During the Verbal Fluency Test, in the younger MDD group, oxygenated-hemoglobin concentration increased in the right dorsolateral prefrontal cortex region as the severity of depression increased. In the older MDD group, the oxygenated-hemoglobin concentration decreased in the right dorsolateral prefrontal cortex region as the severity of depression increased. : These results suggest that fNIRS may be an objective tool for identifying age differences among adolescents with MDD. To generalize the results and verify fNIRS as a potential biomarker tool, follow-up studies with a larger sample group should be conducted.

Altered Associations Between Task Performance and Dorsolateral Prefrontal Cortex Activation During Cognitive Control in Schizophrenia

BackgroundDysfunctional cognitive control processes are now well understood to be core features of schizophrenia (SZ). A body of work suggests that the dorsolateral prefrontal cortex (DLPFC) plays a critical role in explaining cognitive control disruptions in SZ. Here, we examined relationships between DLPFC activation and drift rate (DR), a model-based performance measure that combines reaction time and accuracy, in people with SZ and healthy control (HC) participants. MethodsOne hundred fifty-one people with recent-onset SZ spectrum disorders and 118 HC participants performed the AX–Continuous Performance Task during functional magnetic resonance imaging scanning. Proactive cognitive control–associated activation was extracted from left and right DLPFC regions of interest. Individual behavior was fit using a drift diffusion model, allowing DR to vary between task conditions. ResultsBehaviorally, people with SZ showed significantly lower DRs than HC participants, particularly during high proactive control trial types (“B” trials). Recapitulating previous findings, the SZ group also demonstrated reduced cognitive control–associated DLPFC activation compared with HC participants. Furthermore, significant group differences were also observed in the relationship between left and right DLPFC activation with DR, such that positive relationships between DR and activation were found in HC participants but not in people with SZ. ConclusionsThese results suggest that DLPFC activation is less associated with cognitive control–related behavioral performance enhancements in SZ. Potential mechanisms and implications are discussed.

Modelling the differential effects of age on transcranial magnetic stimulation induced electric fields

Objective. The therapeutic application of noninvasive brain stimulation modalities such as transcranial magnetic stimulation (TMS) has expanded in terms of indications and patient populations. Often neurodevelopmental and neurodegenerative changes are not considered in research studies and clinical applications. This study sought to examine TMS dosing across time points in the life cycle. Approach. TMS induced electric fields with a figure-of-eight coil was simulated at left dorsolateral prefrontal cortex regions and taken in vertex as a control region. Realistic magnetic resonance imaging-based head models (N = 48) were concurrently examined in a cross-sectional study of three different age groups (children, adults, and elderlies). Main results. Age had a negative correlation with electric field peaks in white matter, grey matter and cerebrospinal fluid (P < 0.001). Notably, the electric field map in children displayed the widest cortical surface spread of TMS induced electric fields. Significance. Age-related anatomical geometry beneath the coil stimulation site had a significant impact on the TMS induced electric fields for different age groups. Safety considerations for TMS applications and protocols in children are warranted based on the present electric field findings.

The Evaluation of Effects of Electrical Stimulation in Treatment of Patients with Chronic Tinnitus with Normal Hearing Sensitivity.

Tinnitus is usually associated with different comorbidities such as anxiety, annoyance and depression. Evidences have targeted two main places for tinnitus treatment, namely the auditory cortex and the dorsolateral prefrontal cortex (DLPFC). Transcranial direct current stimulation (tDCS) has been reportedly associated with improvement of cognitive functions in individuals. This study was conducted to evaluate the therapeutic effects of repeated sessions of anodal bifrontal tDCS on tinnitus symptoms. Furthermore, the tDCS impacts on the comorbid depression and anxiety of the patients were investigated. Forty-two voluntaries that suffers from chronic tinnitus were randomly assigned into "real tDCS" (n = 21) and "sham tDCS" (n = 21) groups. The tDCS group, received tDCS with the protocol consisted of 2mA current, daily one session of 20min, 6 consecutive days per week and for 4 consecutive weeks. The tinnitus handicap inventory (THI) scale, was measured before the first tDCS session and at one-week and two weeks follow-up. With the same intervals; the distress-related tinnitus was evaluated using visual analogue scale. Depression and anxiety scores were also measured using the Beck depression inventory and Beck anxiety inventory scales, respectively. Our findings indicated that THI score, depression and anxiety level has been gradually diminished across subsequent measurement intervals. We also find significant reduction of distress-related tinnitus in the real-tDCS group after treatment. We conclude that application of tDCS to the bilateral DLPFC region alleviates chronic tinnitus and it should be considered in patients with refractory tinnitus.

Prefrontal and somatosensory-motor cortex effective connectivity in humans.

Effective connectivity, functional connectivity, and tractography were measured between 57 cortical frontal and somatosensory regions and the 360 cortical regions in the Human Connectome Project (HCP) multimodal parcellation atlas for 171 HCP participants. A ventral somatosensory stream connects from 3b and 3a via 1 and 2 and then via opercular and frontal opercular regions to the insula, which then connects to inferior parietal PF regions. This stream is implicated in "what"-related somatosensory processing of objects and of the body and in combining with visual inputs in PF. A dorsal "action" somatosensory stream connects from 3b and 3a via 1 and 2 to parietal area 5 and then 7. Inferior prefrontal regions have connectivity with the inferior temporal visual cortex and orbitofrontal cortex, are implicated in working memory for "what" processing streams, and provide connectivity to language systems, including 44, 45, 47l, TPOJ1, and superior temporal visual area. The dorsolateral prefrontal cortex regions that include area 46 have connectivity with parietal area 7 and somatosensory inferior parietal regions and are implicated in working memory for actions and planning. The dorsal prefrontal regions, including 8Ad and 8Av, have connectivity with visual regions of the inferior parietal cortex, including PGs and PGi, and are implicated in visual and auditory top-down attention.

Enhancing Immediate Memory, Potential Learning, and Working Memory with Transcranial Direct Current Stimulation in Healthy Older Adults.

Background: Transcranial direct current stimulation (tDCS) has emerged as a prevention method or minimizer of the normal cognitive deterioration that occurs during the aging process. tDCS can be used to enhance cognitive functions such as immediate memory, learning, or working memory in healthy subjects. The objective of this study was to analyze the effect of two 20-min sessions of anodal transcranial direct stimulation on immediate memory, learning potential, and working memory in healthy older adults. Methods: A randomized, single-blind, repeated-measures, sham-controlled design was used. The sample is made up of 31 healthy older adults, of whom 16 were in the stimulation group and 15 were in the sham group. The anode was placed on position F7, coinciding with the left dorsolateral prefrontal cortex region, and the cathode was placed on Fp2, the right supraorbital area (rSO). Results: When comparing the results of the treatment group and the sham group, differences were observed in working memory and learning potential; however, no differences in immediate memory were found. Conclusion: The results showed that tDCS is a non-invasive and safe tool to enhance cognitive processes in healthy older adults interested in maintaining some cognitive function.

Combined Effect of Repetitive Transcranial Magnetic Stimulation and Cognitive Rehabilitation on Working Memory of Patients with Chronic Stroke

Background: Working memory is one of the cognitive aspects that may be damaged in patients suffering from a stroke. According to evidence, repetitive Transcranial Magnetic Stimulation (rTMS) and cognitive interventions could affect cognitive function in healthy individuals or patients with neurological diseases. Objectives: This study aimed to evaluate the combined effect of high-frequency rTMS in the left Dorsolateral Prefrontal Cortex (DLPFC) region of the brain and cognitive rehabilitation on the working memory of stroke patients. Methods: In this double-blind, randomized clinical trial with a pretest-posttest design, 18 post-stroke chronic patients aged 55 to 75 years were randomly divided into two experimental and control groups. The working memory score was measured using the N-back test in the two groups before the interventions. Then, both groups participated in rTMS intervention sessions, except that in the control group, changing the coil angle prevented the waves from reaching the brain. The rTMS interventions were performed for each patient in 15 sessions of six minutes, three days a week. In addition, both groups received computer-based cognitive rehabilitation therapy immediately after each rTMS session for 30 to 40 minutes. These practices included working memory rehabilitation in Captain's Log software used at the adult level. Each level had 15 steps, and the difficulty of the exercises increased with increasing steps. Finally, the working memory was remeasured after the intervention sessions. Results: The use of rTMS on the left DLPFC region significantly improved the working memory of stroke people in the experimental group compared to the control group (P = 0.027). In addition, the difference before and after the interventions in both groups was significant for this variable (P &lt; 0.001), which indicates the positive effect of cognitive rehabilitation on reducing cognitive problems. Conclusions: Although cognitive rehabilitation using software is effective on working memory, using rTMS along with cognitive rehabilitation in the left DLPFC area has a more significant effect on improving working memory in people with chronic stroke.

Combined Effect of Repetitive Transcableranial Magnetic Stimulation and Cognitive Rehabilitation on Working Memory of Patients with Chronic Stroke

Background: Working memory is one of the cognitive aspects that may be damaged in patients suffering from a stroke. According to evidence, repetitive Transcranial Magnetic Stimulation (rTMS) and cognitive interventions could affect cognitive function in healthy individuals or patients with neurological diseases. Objectives: This study aimed to evaluate the combined effect of high-frequency rTMS in the left Dorsolateral Prefrontal Cortex (DLPFC) region of the brain and cognitive rehabilitation on the working memory of stroke patients. Methods: In this double-blind, randomized clinical trial with a pretest-posttest design, 18 post-stroke chronic patients aged 55 to 75 years were randomly divided into two experimental and control groups. The working memory score was measured using the N-back test in the two groups before the interventions. Then, both groups participated in rTMS intervention sessions, except that in the control group, changing the coil angle prevented the waves from reaching the brain. The rTMS interventions were performed for each patient in 15 sessions of six minutes, three days a week. In addition, both groups received computer-based cognitive rehabilitation therapy immediately after each rTMS session for 30 to 40 minutes. These practices included working memory rehabilitation in Captain's Log software used at the adult level. Each level had 15 steps, and the difficulty of the exercises increased with increasing steps. Finally, the working memory was remeasured after the intervention sessions. Results: The use of rTMS on the left DLPFC region significantly improved the working memory of stroke people in the experimental group compared to the control group (P = 0.027). In addition, the difference before and after the interventions in both groups was significant for this variable (P &lt; 0.001), which indicates the positive effect of cognitive rehabilitation on reducing cognitive problems. Conclusions: Although cognitive rehabilitation using software is effective on working memory, using rTMS along with cognitive rehabilitation in the left DLPFC area has a more significant effect on improving working memory in people with chronic stroke.

Reconfiguration of Functional Dynamics in Cortico-Thalamo-Cerebellar Circuit in Schizophrenia Following High-Frequency Repeated Transcranial Magnetic Stimulation.

Schizophrenia is a serious mental illness characterized by a disconnection between brain regions. Transcranial magnetic stimulation is a non-invasive brain intervention technique that can be used as a new and safe treatment option for patients with schizophrenia with drug-refractory symptoms, such as negative symptoms and cognitive impairment. However, the therapeutic effects of transcranial magnetic stimulation remain unclear and would be investigated using non-invasive tools, such as functional connectivity (FC). A longitudinal design was adopted to investigate the alteration in FC dynamics using a dynamic functional connectivity (dFC) approach in patients with schizophrenia following high-frequency repeated transcranial magnetic stimulation (rTMS) with the target at the left dorsolateral prefrontal cortex (DLPFC). Two groups of schizophrenia inpatients were recruited. One group received a 4-week high-frequency rTMS together with antipsychotic drugs (TSZ, n = 27), while the other group only received antipsychotic drugs (DSZ, n = 26). Resting-state functional magnetic resonance imaging (fMRI) and psychiatric symptoms were obtained from the patients with schizophrenia twice at baseline (t1) and after 4-week treatment (t2). The dynamics was evaluated using voxel- and region-wise FC temporal variability resulting from fMRI data. The pattern classification technique was used to verify the clinical application value of FC temporal variability. For the voxel-wise FC temporary variability, the repeated measures ANCOVA analysis showed significant treatment × time interaction effects on the FC temporary variability between the left DLPFC and several regions, including the thalamus, cerebellum, precuneus, and precentral gyrus, which are mainly located within the cortico-thalamo-cerebellar circuit (CTCC). For the ROI-wise FC temporary variability, our results found a significant interaction effect on the FC among CTCC. rTMS intervention led to a reduced FC temporary variability. In addition, higher alteration in FC temporal variability between left DLPFC and right posterior parietal thalamus predicted a higher remission ratio of negative symptom scores, indicating that the decrease of FC temporal variability between the brain regions was associated with the remission of schizophrenia severity. The support vector regression (SVR) results suggested that the baseline pattern of FC temporary variability between the regions in CTCC could predict the efficacy of high-frequency rTMS intervention on negative symptoms in schizophrenia. These findings confirm the potential relationship between the reduction in whole-brain functional dynamics induced by high-frequency rTMS and the improvement in psychiatric scores, suggesting that high-frequency rTMS affects psychiatric symptoms by coordinating the heterogeneity of activity between the brain regions. Future studies would examine the clinical utility of using functional dynamics patterns between specific brain regions as a biomarker to predict the treatment response of high-frequency rTMS.

Expansion of Schizophrenia Gene Network Knowledge Using Machine Learning Selected Signals From Dorsolateral Prefrontal Cortex and Amygdala RNA-seq Data.

It is widely accepted, given the complex nature of schizophrenia (SCZ) gene networks, that a few or a small number of genes are unlikely to represent the underlying functional pathways responsible for SCZ pathogenesis. Several studies from large cohorts have been performed to search for key SCZ network genes using different analytical approaches, such as differential expression tests, genome-wide association study (GWAS), copy number variations, and differential methylations, or from the analysis of mutations residing in the coding regions of the genome. However, only a small portion (<10%) of candidate genes identified in these studies were considered SCZ disease-associated genes in SCZ pathways. RNA sequencing (RNA-seq) has been a powerful method to detect functional signals. In this study, we used RNA-seq data from the dorsolateral prefrontal cortex (DLPFC) from 254 individuals and RNA-seq data from the amygdala region from 46 individuals. Analysis was performed using machine learning methods, including random forest and factor analysis, to prioritize the numbers of genes from previous SCZ studies. For genes most differentially expressed between SCZ and healthy controls, 18 were added to known SCZ-associated pathways. These include three genes (GNB2, ITPR1, and PLCB2) for the glutamatergic synapse pathway, six genes (P2RX6, EDNRB, GHR, GRID2, TSPO, and S1PR1) for neuroactive ligand–receptor interaction, eight genes (CAMK2G, MAP2K1, RAF1, PDE3A, RRAS2, VAV1, ATP1B2, and GLI3) for the cAMP signaling pathway, and four genes (GNB2, CAMK2G, ITPR1, and PLCB2) for the dopaminergic synapse pathway. Besides the previously established pathways, 103 additional gene interactions were expanded to SCZ-associated networks, which were shared among both the DLPFC and amygdala regions. The novel knowledge of molecular targets gained from this study brings opportunities for a more complete picture of the SCZ pathogenesis. A noticeable fact is that hub genes, in the expanded networks, are not necessary differentially expressed or containing hotspots from GWAS studies, indicating that individual methods, such as differential expression tests, are not enough to identify the underlying SCZ pathways and that more integrative analysis is required to unfold the pathobiology of SCZ.

Blue light exposure increases functional connectivity between dorsolateral prefrontal cortex and multiple cortical regions.

ObjectiveBlue light is a powerful environmental stimulus that can produce significant phase shifts in the circadian rhythm of melatonin and sleep propensity as well as acute effects on alertness of neurobehavioral performance. Here, we undertook an expansion and reanalysis of our previously published findings to examine the effect of acute blue light exposure on the strength of resting-state functional connectivity (rsFC) between a previously identified region of the left dorsolateral prefrontal cortex (DLPFC) and 106 cortical and subcortical regions.MethodsTwenty-nine healthy adults (16 men and 13 women; age 18–32 years) completed a psychomotor vigilance test (PVT) before and after a single 30-min exposure to either blue (λ = 469 nm; n = 17) or amber wavelength (λ = 578 nm; n = 12) light, immediately followed by an rsFC scan.ResultsCompared with amber light, blue light exposure produced significantly greater functional connectivity between the left DLPFC seed region and 30 cortical and subcortical regions (P < 0.05; false discovery rate–corrected). Although neurobehavioral performance did not differ between light conditions, only those exposed to blue light showed a significant association between rsFC and sustained PVT performance. Better sustained PVT performance was associated with greater connectivity between the left DLPFC and regions associated with visuospatial awareness/motion detection (right temporal-occipital middle temporal gyrus) and memory (left hippocampus), as well as reduced connectivity in a circuit associated with cognitive rumination and distraction (left parahippocampal gyrus).ConclusionFindings suggest that blue-wavelength light may facilitate acute alertness and improved cognitive performance through enhanced rsFC between the left DLPFC and cortical regions associated with visuospatial awareness.