Childhood adversities characterize the heterogeneity in the brain pattern of individuals during neurodevelopment.

BACKGROUND: Several factors shape the neurodevelopmental trajectory. A key area of focus in neurodevelopmental research is to estimate the factors that have maximal influence on the brain and can tip the balance from typical to atypical development. METHODS: Utilizing a dissimilarity maximization algorithm on the dynamic mode decomposition (DMD) of the resting state functional MRI data, we classified subjects from the cVEDA neurodevelopmental cohort (n = 987, aged 6-23 years) into homogeneously patterned DMD (representing typical development in 809 subjects) and heterogeneously patterned DMD (indicative of atypical development in 178 subjects). RESULTS: Significant DMD differences were primarily identified in the default mode network (DMN) regions across these groups (p < 0.05, Bonferroni corrected). While the groups were comparable in cognitive performance, the atypical group had more frequent exposure to adversities and faced higher abuses (p < 0.05, Bonferroni corrected). Upon evaluating brain-behavior correlations, we found that correlation patterns between adversity and DMN dynamic modes exhibited age-dependent variations for atypical subjects, hinting at differential utilization of the DMN due to chronic adversities. CONCLUSION: Adversities (particularly abuse) maximally influence the DMN during neurodevelopment and lead to the failure in the development of a coherent DMN system. While DMN's integrity is preserved in typical development, the age-dependent variability in atypically developing individuals is contrasting. The flexibility of DMN might be a compensatory mechanism to protect an individual in an abusive environment. However, such adaptability might deprive the neural system of the faculties of normal functioning and may incur long-term effects on the psyche.

Maximizing dissimilarity in resting state detects heterogeneous subtypes in healthy population associated with high substance use and problems in antisocial personality.

Patterns in resting-state fMRI (rs-fMRI) are widely used to characterize the trait effects of brain function. In this aspect, multiple rs-fMRI scans from single subjects can provide interesting clues about the rs-fMRI patterns, though scan-to-scan variability pose challenges. Therefore, rs-fMRI's are either concatenated or the functional connectivity is averaged. This leads to loss of information. Here, we use an alternative way to extract the rs-fMRI features that are common across all the scans by applying common-and-orthogonal-basis-extraction (COBE) technique. To address this, we employed rs-fMRI of 788 subjects from the human connectome project and estimated the common-COBE-component of each subject from the four rs-fMRI runs. Since the common-COBE-component is specific to a subject, the pattern was used to classify the subjects based on the similarity/dissimilarity of the features. The subset of subjects (n = 107) with maximal-COBE-dissimilarity (MCD) was extracted and the remaining subjects (n = 681) formed the COBE-similarity (CS) group. The distribution of weights of the common-COBE-component for the two groups across rs-fMRI networks and subcortical regions was evaluated. We found the weights in the default mode network to be lower in the MCD compared to the CS. We compared the scores of 69 behavioral measures and found six behaviors related to the use of marijuana, illicit drugs, alcohol, and tobacco; and including a measure of antisocial personality to differentiate the two groups. Gender differences were also significant. Altogether the findings suggested that subtypes exist even in healthy control population, and comparison studies (case vs. control) need to be mindful of it.

Individual-specific fMRI-Subspaces improve functional connectivity prediction of behavior.

There is significant interest in using resting-state functional connectivity (RSFC) to predict human behavior. Good behavioral prediction should in theory require RSFC to be sufficiently distinct across participants; if RSFC were the same across participants, then behavioral prediction would obviously be poor. Therefore, we hypothesize that removing common resting-state functional magnetic resonance imaging (rs-fMRI) signals that are shared across participants would improve behavioral prediction. Here, we considered 803 participants from the human connectome project (HCP) with four rs-fMRI runs. We applied the common and orthogonal basis extraction (COBE) technique to decompose each HCP run into two subspaces: a common (group-level) subspace shared across all participants and a subject-specific subspace. We found that the first common COBE component of the first HCP run was localized to the visual cortex and was unique to the run. On the other hand, the second common COBE component of the first HCP run and the first common COBE component of the remaining HCP runs were highly similar and localized to regions within the default network, including the posterior cingulate cortex and precuneus. Overall, this suggests the presence of run-specific (state-specific) effects that were shared across participants. By removing the first and second common COBE components from the first HCP run, and the first common COBE component from the remaining HCP runs, the resulting RSFC improves behavioral prediction by an average of 11.7% across 58 behavioral measures spanning cognition, emotion and personality.

Repetition priming effects for famous faces through dynamic causal modelling of latency-corrected event-related brain potentials.

Repetition priming, that is, the repeated processing of a stimulus, facilitates performance. However, the neural underpinnings of repetition priming for famous faces in terms of effective connectivity are not known. Here we investigated this problem using dynamic causal modelling of latency-corrected event-related brain potentials (RERPs). Source waveforms of RERP-derived sources in the Occipital Lobe, Fusiform Gyrus, Mediotemporal Lobe, Prefrontal Cortex and Anterotemporal Lobe of each hemisphere entered into models with only forward (F) or also with backward (FB) connections. Based on the framework of predictive coding formulated for repetition suppression, modulations of F and FB connections were expected for sources that displayed priming effects in their source waveforms. Hence, neural sources in each hemisphere were fitted with either F or FB connections. Inter-hemispheric connections were considered between homologous areas and were allowed to be modulated in an incremental manner resulting in a model space that comprised of 24 models. Bayesian model averaging across models revealed effective bidirectional connectivity between the Fusiform Gyrus (face perception) and Prefrontal Cortex (decision-making) in both hemispheres to be modulated by priming. In the left hemisphere, there is also a substantial involvement from the Mediotemporal Lobe, indicating the facilitation of automatic retrieval of the famous person's name. Furthermore, there is evidence that the priming is supported by connections from the right to the left Fusiform Gyri possibly in the service of inter-hemispheric cooperation. Altogether, the study indicates that along with top-down modulations, efficient processing within and across the two hemispheres is crucial for famous face priming.

Sex difference in tDCS current mediated by changes in cortical anatomy: A study across young, middle and older adults.

INTRODUCTION: The observed variability in the effects of transcranial direct current stimulation (tDCS) is influenced by the amount of current reaching the targeted region-of-interest (ROI). Age and sex might affect current density at target ROI due to their impact on cortical anatomy. The present tDCS simulation study investigates the effects of cortical anatomical parameters (volumes, dimension, and torque) on simulated tDCS current density in healthy young, middle-aged, and older males and females. METHODOLOGY: Individualized head models from 240 subjects (120 males, 18-87 years of age) were used to identify the estimated current density (2 mA current intensity, 25 cm2 electrode) from two simulated tDCS montages (CP5_CZ and F3_FP2) targeting the inferior parietal lobule (IPL) and middle frontal gyrus (MFG), respectively. Cortical parameters including segmented brain volumes (cerebrospinal fluid [CSF], grey and white matter), cerebral-dimensions (length/width &length/height) and brain-torque (front and back shift, petalia, and bending) were measured using the magnetic resonance images (MRIs) from each subject. The present study estimated sex differences in current density at these target ROIs mediated by these cortical parameters within each age group. RESULTS: For both tDCS montages, females in the older age group received higher current density than their male counterparts at the target ROIs. No sex differences were observed in the middle-aged group. Males in the younger age group had a higher current density than females, only for the parietal montage. Across all age groups, CSF, and grey matter volumes significantly predicted the current intensity estimated at the target sites. In the older age group only, brain-torque was a significant mediator of the sex difference. CONCLUSIONS: Our findings demonstrate the presence of sex differences in the simulated tDCS current density, however this pattern differed across age groups and stimulation locations. Future studies should consider influence of age and sex on individual cortical anatomy and tailor tDCS stimulation parameters accordingly.

Variation of cerebrospinal fluid in specific regions regulates focality in transcranial direct current stimulation.

Background: Conventionally, transcranial direct current stimulation (tDCS) aims to focalize the current reaching the target region-of-interest (ROI). The focality can be quantified by the dose-target-determination-index (DTDI). Despite having a uniform tDCS setup, some individuals receive focal stimulation (high DTDI) while others show reduced focality ("non-focal"). The volume of cerebrospinal fluid (CSF), gray matter (GM), and white matter (WM) underlying each ROI govern the tDCS current distribution inside the brain, thereby regulating focality. Aim: To determine the regional volume parameters that differentiate the focal and non-focal groups. Methods: T1-weighted images of the brain from 300 age-sex matched adults were divided into three equal groups- (a) Young (20 ≤ × < 40 years), (b) Middle (40 ≤ × < 60 years), and (c) Older (60 ≤ × < 80 years). For each group, inter and intra-hemispheric montages with electrodes at (1) F3 and right supraorbital region (F3-RSO), and (2) CP5 and Cz (CP5-Cz) were simulated, targeting the left- Dorsolateral Prefrontal Cortex (DLPFC) and -Inferior Parietal Lobule (IPL), respectively. Both montages were simulated for two current doses (1 and 2 mA). For each individual head simulated for a tDCS configuration (montage and dose), the current density at each region-of-interest (ROI) and their DTDI were calculated. The individuals were categorized into two groups- (1) Focal (DTDI ≥ 0.75), and (2) Non-focal (DTDI < 0.75). The regional volume of CSF, GM, and WM of all the ROIs was determined. For each tDCS configuration and ROI, three 3-way analysis of variance was performed considering- (i) GM, (ii) WM, and (iii) CSF as the dependent variable (DV). The age group, sex, and focality group were the between-subject factors. For a given ROI, if any of the 3 DV's showed a significant main effect or interaction involving the focality group, then that ROI was classified as a "focal ROI." Results: Regional CSF was the principal determinant of focality. For interhemispheric F3-RSO montage, interaction effect (p < 0.05) of age and focality was observed at Left Caudate Nucleus, with the focal group exhibiting higher CSF volume. The CSF volume of focal ROI correlated positively (r ∼ 0.16, p < 0.05) with the current density at the target ROI (DLPFC). For intrahemispheric CP5-Cz montage, a significant (p < 0.05) main effect was observed at the left pre- and post-central gyrus, with the focal group showing lower CSF volume. The CSF volume correlated negatively (r ∼ -0.16, p < 0.05) with current density at left IPL. The results were consistent for both current doses. Conclusion: The CSF channels the flow of tDCS current between electrodes with focal ROIs acting like reservoirs of current. The position of focal ROI in the channel determines the stimulation intensity at the target ROI. For focal stimulation in interhemispheric F3-RSO, the proximity of focal ROI reserves the current density at the target ROI (DLPFC). In contrast, for intrahemispheric montage (CP5-Cz), the far-end location of focal ROI reduces the current density at the target (IPL).

The Role of Primary Motor Cortex: More Than Movement Execution.

The predominant role of the primary motor cortex (M1) in motor execution is well acknowledged. However, additional roles of M1 are getting evident in humans owing to advances in noninvasive brain stimulation (NIBS) techniques. This review collates such studies in humans and proposes that M1 also plays a key role in higher cognitive processes. The review commences with the studies that have investigated the nature of connectivity of M1 with other cortical regions in light of studies based on NIBS. The review then moves on to discuss the studies that have demonstrated the role of M1 in higher cognitive processes such as attention, motor learning, motor consolidation, movement inhibition, somatomotor response, and movement imagery. Overall, the purpose of the review is to highlight the additional role of M1 in motor cognition besides motor control, which remains unexplored.

Focality-Oriented Selection of Current Dose for Transcranial Direct Current Stimulation.

Background: In transcranial direct current stimulation (tDCS), the injected current becomes distributed across the brain areas. The objective is to stimulate the target region of interest (ROI) while minimizing the current in non-target ROIs (the 'focality' of tDCS). For this purpose, determining the appropriate current dose for an individual is difficult. Aim: To introduce a dose-target determination index (DTDI) to quantify the focality of tDCS and examine the dose-focality relationship in three different populations. Method: Here, we extended our previous toolbox i-SATA to the MNI reference space. After a tDCS montage is simulated for a current dose, the i-SATA(MNI) computes the average (over voxels) current density for every region in the brain. DTDI is the ratio of the average current density at the target ROI to the ROI with a maximum value (the peak region). Ideally, target ROI should be the peak region, so DTDI shall range from 0 to 1. The higher the value, the better the dose. We estimated the variation of DTDI within and across individuals using T1-weighted brain images of 45 males and females distributed equally across three age groups: (a) young adults (20 ≤ x ˂ 40 years), (b) mid adults (40 ≤ x ˂ 60 years), and (c) older adults (60 ≤ x ˂ 80 years). DTDI's were evaluated for the frontal montage with electrodes at F3 and the right supraorbital for three current doses of 1 mA, 2 mA, and 3 mA, with the target ROI at the left middle frontal gyrus. Result: As the dose is incremented, DTDI may show (a) increase, (b) decrease, and (c) no change across the individuals depending on the relationship (nonlinear or linear) between the injected tDCS current and the distribution of current density in the target ROI. The nonlinearity is predominant in older adults with a decrease in focality. The decline is stronger in males. Higher current dose at older age can enhance the focality of stimulation. Conclusion: DTDI provides information on which tDCS current dose will optimize the focality of stimulation. The recommended DTDI dose should be prioritized based on the age (>40 years) and sex (especially for males) of an individual. The toolbox i-SATA(MNI) is freely available.

Individual-fMRI-approaches reveal cerebellum and visual communities to be functionally connected in obsessive compulsive disorder.

There is significant interest in understanding the pathophysiology of Obsessive-Compulsive Disorder (OCD) using resting-state fMRI (rsfMRI). Previous studies acknowledge abnormalities within and beyond the fronto-striato-limbic circuit in OCD that require further clarifications. However, limited information could be inferred from the conventional way of investigating the functional connectivity differences between OCD and healthy controls. Here, we identified altered brain organization in patients with OCD by applying individual-based approaches to maximize the identification of underlying network-based features specific to the OCD group. rsfMRI of 20 patients with OCD and 22 controls were preprocessed, and individual-fMRI-subspace was derived for each subject within each group. We evaluated group differences in functional connectivity using individual-fMRI-subspace and established its advantage over conventional-fMRI methodology. We applied prediction-based approaches to highlight the group differences by evaluating the differences in functional connections that predicted the clinical scores (namely, the Obsessive-Compulsive Inventory-Revised (OCI-R) and Hamilton Anxiety Rating Scale). Then, we explored the brain network organization of both groups by estimating the subject-specific communities within each group. Lastly, we evaluated associations between the inter-individual variation of nodes in the communities to clinical measures using linear regression. Functional connectivity analysis using individual-fMRI-subspace detected 83 connections that were different between OCD and control groups, compared to none found using conventional-fMRI methodology. Connectome-based prediction analysis did not show significant overlap between the two groups in the functional connections that predicted the clinical scores. This suggests that the functional architecture in patients with OCD may be different compared to controls. Seven communities were found in both groups. Interestingly, within the OCD group but not controls, we observed functional connectivity between cerebellar and visual regions, and lack of connectivity between striato-limbic and frontal areas. Inter-individual variations in the community-size of these two communities were also associated with the OCI-R score (p < .005). Due to our small sample size, we further validated our results by (i) accounting for head motion, (ii) applying global signal regression (GSR) in data processing, and (iii) using an alternate atlas for parcellation. While the main results were consistently observed with accounting for head motion and using another atlas, the key findings were not reproduced with GSR application. The study demonstrated the existence of disconnectedness in fronto-striato-limbic community and connectedness between cerebellar and visual areas in OCD patients, which was also related to the clinical symptomatology of OCD.

i-SATA: A MATLAB based toolbox to estimate current density generated by transcranial direct current stimulation in an individual brain.

OBJECTIVE: Transcranial Direct Current Stimulation (tDCS) is a technique where a weak current is passed through the electrodes placed on the scalp. The distribution of the electric current induced in the brain due to tDCS is provided by simulation toolbox like Realistic volumetric Approach based Simulator for Transcranial electric stimulation (ROAST). However, the procedure to estimate the total current density induced at the target and the intermediary region of the cortex is complex. The Systematic-Approach-for-tDCS-Analysis (SATA) was developed to overcome this problem. However, SATA is limited to standardized (MNI152) headspace only. Here we develop individual-SATA (i-SATA) to extend it to individual head. APPROACH: T1-weighted images of 15 subjects were taken from two Magnetic Resonance Imaging scanners of different strengths. Across the subjects, the montages were simulated in ROAST. i-SATA converts the ROAST output to Talairach space. The x, y and z coordinates of the anterior commissure (AC), posterior commissure (PC), and Mid-Sagittal (MS) points are necessary for the conversion. AC and PC are detected using the acpcdetect toolbox. We developed a method to determine the MS in the image and cross-verified its location manually using BrainSight®. MAIN RESULTS: Determination of points with i-SATA is fast and accurate. The i-SATA provided estimates of the current-density induced across an individual's cortical lobes and gyri as tested on images from two different scanners. SIGNIFICANCE: Researchers can use i-SATA for customizing tDCS-montages. With i-SATA it is also easier to compute the inter-individual variation in current-density across the target and intermediary regions of the brain. The software is publicly available.

Reading proficiency influences the effects of transcranial direct current stimulation: Evidence from selective modulation of dorsal and ventral pathways of reading in bilinguals.

INTRODUCTION: tDCS can modulate reading which is processed by lexical (ventral) and sub-lexical (dorsal) pathways. Previous research indicates that pathway recruitment in bilinguals depends on a script's orthographic depth and a reader's proficiency with it. The effect of tDCS on each reading pathway has not been investigated in bilinguals. We stimulated the left dorsal and ventral pathways separately in Chinese-English (C-E) bilinguals to understand whether pathway-specific modulation by tDCS is possible and, if so, how it is influenced by orthographic depth and script proficiency. METHODS: A double-blind, sham-controlled, within-subject experiment was designed wherein 16 balanced bilinguals received anodal tDCS in dorsal, ventral and sham sessions. Two tDCS montages of electrode sizes 5 × 5 cm2 with 1) anode at CP5 and cathode at CZ, and 2) anode at TP7 and cathode at nape of the neck, were applied for stimulating the dorsal and ventral pathways respectively. Bilinguals were asked to read word lists for each language before and after stimulation. RTs for accurate trials were analysed using linear mixed-effect modelling that included proficiency scores for reading English pseudo-words (PW) and Chinese pinyin. RESULTS: For both languages, word reading RTs were faster following dorsal pathway stimulation. The dorsal stimulation effect (change in RT) was negatively correlated with pseudoword reading and pinyin proficiency. Stimulation of the ventral pathway decreased RTs only for Chinese reading. CONCLUSION: Dorsal and ventral reading pathways can be selectively modulated by tDCS in bilingual readers with dorsal (sub-lexical) pathway stimulation affecting reading in both scripts and ventral (lexical) pathway stimulation selectively affecting Chinese reading. Dorsal pathway tDCS effects are modulated by sub-lexical reading proficiency.

Simulation Analyses of tDCS Montages for the Investigation of Dorsal and Ventral Pathways.

Modulating higher cognitive functions like reading with transcranial direct current stimulation (tDCS) can be challenging as reading involves regions in the dorsal and ventral cortical areas that lie in close proximity. If the two pathways are stimulated simultaneously, the function of dorsal pathway (predominantly used for graphophonological conversion) might interfere with the function of the ventral pathway (used for semantics), and vice-versa. To achieve functional specificity in tDCS for investigating the two pathways of reading, it is important to stimulate each pathway per session such that the spread of current across the cortical areas due to the two montages has minimal overlap. The present study intends to achieve this by introducing a systematic approach for tDCS analysis. We employed the COMETS2 software to simulate 10 montage configurations (5 for each pathway) for three electrode sizes: 5 × 5, 3 × 3, and 5 × 7 cm2. This diversity in montage configuration is chosen since previous studies found the position and the size of anode and cathode to play an important role. The values of the magnitude of current density (MCD) obtained from the configuration were used to calculate: (i) average MCD in each cortical lobe, (ii) number of overlapping coordinates, and (iii) cortical areas with high MCD. The measures (i) and (iii) ascertained the current spread by each montage within a cortical lobe, and (ii) verified the overlap of the spread of current between a pair of montages. The analyses show that a montage using the electrode size of 5 × 5 cm2 with the anode at CP5 and cathode at CZ, and another with anode at TP7 and cathode at nape of the neck are optimal choices for dorsal and ventral pathways, respectively. To verify, we cross-validated the results with ROAST. This systematic approach was helpful in reducing the ambiguity of montage selection prior to conducting a tDCS study.