Whole-brain Analysis Research Articles

Investigating Functional Connectivity in Adolescent Depression and Suicide Attempt during Neurofeedback Sessions: A Multivariate Random Covariance Model Approach

Background A recent neurofeedback functional magnetic resonance imaging (NF, fMRI) study on depressed vs. healthy adolescents elicited differential functional connectivity (FC) amongst brain regions of interest (ROIs). Previous results employed univariate methods and included only two seed areas of FC (amygdala and hippocampus). In this study, we propose a new multivariate analysis for whole-network FC estimation. Methods Primary analyses concerned a pre-identified network of 17 salient ROIs reflecting key regions in self-processing and emotion regulation. A random covariance model (RCM) was applied to jointly estimate participant- and group-specific connectivity, where FC was measured by partial correlation conditioned on or adjusted for rest-of-network connectivity patterns. Secondary analyses concerned participant-specific network association with mental functioning changes and the AAL3 whole-brain atlas. Results New findings suggested that depressed adolescents with a suicide attempt expressed significantly higher positive FC between the left temporal gyrus and the left amygdala during NF, compared to negative FC in non-attempting depressed youth, while healthy controls displayed negative FC between the insula, inferior frontal gyrus to inferior parietal lobe connection, compared to mild negative connectivity in depressed adolescents. Previous cross-hemispheric findings in depressed vs. healthy adolescents were corroborated. Conclusion A multivariate RCM uncovered key ROI-pairwise connections differentiating FC patterns between depressed youth vs. healthy controls and among depressed youth, with and without a suicide attempt. Findings were strengthened by enhanced inference vs. univariate methods, and corroboration of previous NF secondary analyses demonstrated future utility for participant-specific study in association with clinical outcomes and/or whole-brain analyses with larger sample sizes.

A Novel Directed Seed-Based Connectivity Analysis Toolbox Applied to Human and Marmoset Resting-State FMRI

Estimating the direction of functional connectivity (FC) can help further elucidate complex brain function. However, the estimation of directed FC at the voxel level in fMRI data, and evaluating its performance, has yet to be done. We therefore developed a novel directed seed-based connectivity analysis (SCA) method based on normalized pairwise Granger causality that provides greater detail and accuracy over ROI-based methods. We evaluated its performance against 145 cortical retrograde tracer injections in male and female marmosets that were used as ground truth cellular connectivity on a voxel-by-voxel basis. The receiver operating characteristic (ROC) curve was calculated for each injection, and we achieved area under the ROC curve of 0.95 for undirected and 0.942 for directed SCA in the case of high cell count threshold. This indicates that SCA can reliably estimate the strong cellular connections between voxels in fMRI data. We then used our directed SCA method to analyze the human default mode network (DMN) and found that dlPFC (dorsolateral prefrontal cortex) and temporal lobe were separated from other DMN regions, forming part of the language-network that works together with the core DMN regions. We also found that the cerebellum (Crus I-II) was strongly targeted by the posterior parietal cortices and dlPFC, but reciprocal connections were not observed. Thus, the cerebellum may not be a part of, but instead a target of, the DMN and language-network. Summarily, our novel directed SCA method, visualized with a new functional flat mapping technique, opens a new paradigm for whole-brain functional analysis.

Immunomodulatory treatment may change functional and structural brain imaging in severe mental disorders

Neuroinflammation has been implicated in the pathophysiology of schizophrenia and obsessive-compulsive disorder (OCD) and deviations in brain structure and connectivity are seen in these disorders. Here, we explore the effects of a potent immunomodulatory treatment on neuroimaging. In a pilot study of rituximab treatment in schizophrenia and OCD, a subgroup (n = 13) underwent structural and functional magnetic resonance imaging before and 5 months after treatment, to study longitudinal changes in resting-state functional connectivity (rsFC) and voxel-based morphometry (VBM).A hypothesis-free exploratory whole-brain analysis was performed twice to assess changes in rsFC, using anterior cingulate cortex, anterior insula, posterior insula and nucleus accumbens as seed regions. There were significant interactions (diagnosis x time) in connectivity between right posterior insula and two clusters encompassing basal ganglia and anterior frontal pole, and between left anterior insula and a cluster in basal ganglia, where connectivity decreased in OCD and increased in schizophrenia. The increase of connectivity after rituximab, between left anterior insula and parts of cerebellum and lingual gyrus and between left posterior insula and parts of cerebellum, correlated with improved global psychosocial functioning according to the Personal and Social Performance Scale, especially in schizophrenia. VBM analysis identified two clusters with increased grey matter volumes (GMV) after rituximab, one in right insula overlapping one of the seed regions with significant rsFC changes. This pilot study implies that rituximab may influence both brain structure and connectivity and that GMV changes and rsFC changes are regionally associated.

Cortical and subcortical substrates of working memory in the right hemisphere: A connectome-based lesion-symptom mapping study

Working Memory (WM) is a cognitive system whose crucial role is to temporarily hold and manipulate information. Early studies suggest that verbal WM is typically associated with left hemisphere (LH) brain regions, while the processing of visuospatial information in WM more specifically depends on the right hemisphere (RH). However, recent evidence suggests a more complex network involving both hemispheres' prefrontal and posterior parietal cortices in these processes. Unfortunately, previous lesion studies often examined only one modality (either verbal, or visuospatial) or one hemisphere, which limits the possible conclusions regarding non-lateralized hemispheric involvement. Using connectome-based lesion-symptom mapping on a large sample of patients with left (LBD) and right (RBD) focal brain damage, we examined whether gray matter damage and white matter disconnections predict deficits of WM updating in an N-back task. Patients were examined with two WM tasks that differed regarding modality (verbal, spatial) and cognitive load (1-back, 2-back). Behavioral outcomes indicated that RBD patients showed significant deficits in WM updating, regardless of task modality or load. This observation was supported by whole-brain voxel-based analysis, revealing associations between WM deficits and gray matter clusters in the RH. Specifically, damage to the right lateral frontal cortex including the brain region homologous to Broca's area was associated with verbal WM deficits, while damage to the right inferior parietal lobe and posterior temporal cortex predicted spatial WM deficits. Additionally, white matter analyses identified severely impacted tracts in the RH, predicting deficits in both verbal and spatial WM. Our findings suggest that the mental manipulation of both verbal and visuospatial information in WM updating relies on the integrity of the RH, irrespective of the specific type of information held in mind.

Task-based functional neural correlates of social cognition across autism and schizophrenia spectrum disorders

BackgroundAutism and schizophrenia spectrum disorders (SSDs) both feature atypical social cognition. Despite evidence for comparable group-level performance in lower-level emotion processing and higher-level mentalizing, limited research has examined the neural basis of social cognition across these conditions. Our goal was to compare the neural correlates of social cognition in autism, SSDs, and typically developing controls (TDCs).MethodsData came from two harmonized studies in individuals diagnosed with autism or SSDs and TDCs (aged 16–35 years), including behavioral social cognitive metrics and two functional magnetic resonance imaging (fMRI) tasks: a social mirroring Imitate/Observe (ImObs) task and the Empathic Accuracy (EA) task. Group-level comparisons, and transdiagnostic analyses incorporating social cognitive performance, were run using FSL’s PALM for each task, covarying for age and sex (1000 permutations, thresholded at p < 0.05 FWE-corrected). Exploratory region of interest (ROI)-based analyses were also conducted.ResultsImObs and EA analyses included 164 and 174 participants, respectively (autism N = 56/59, SSD N = 50/56, TDC N = 58/59). EA and both lower- and higher-level social cognition scores differed across groups. While canonical social cognitive networks were activated, no significant whole-brain or ROI-based group-level differences in neural correlates for either task were detected. Transdiagnostically, neural activity during the EA task, but not the ImObs task, was associated with lower- and higher-level social cognitive performance.LimitationsDespite attempting to match our groups on age, sex, and race, significant group differences remained. Power to detect regional brain differences is also influenced by sample size and multiple comparisons in whole-brain analyses. Our findings may not generalize to autism and SSD individuals with co-occurring intellectual disabilities.ConclusionsThe lack of whole-brain and ROI-based group-level differences identified and the dimensional EA brain-behavior relationship observed across our sample suggest that the EA task may be well-suited to target engagement in novel intervention testing. Our results also emphasize the potential utility of cross-condition approaches to better understand social cognition across autism and SSDs.

Brain white matter pathways of resilience to chronic back pain: a multisite validation.

Chronic back pain (CBP) is a global health concern with significant societal and economic burden. While various predictors of back pain chronicity have been proposed, including demographic and psychosocial factors, neuroimaging studies have pointed to brain characteristics as predictors of CBP. However, large-scale, multisite validation of these predictors is currently lacking. In two independent longitudinal studies, we examined white matter diffusion imaging data and pain characteristics in patients with subacute back pain (SBP) over six- and 12-month periods. Diffusion data from individuals with CBP and healthy controls (HC) were analyzed for comparison. Whole-brain tract-based spatial statistics analyses revealed that a cluster in the right superior longitudinal fasciculus (SLF) tract had larger fractional anisotropy (FA) values in patients who recovered (SBPr) compared to those with persistent pain (SBPp), and predicted changes in pain severity. The SLF FA values accurately classified patients at baseline and follow-up in a third publicly available dataset (Area under the Receiver Operating Curve ∼ 0.70). Notably, patients who recovered had FA values larger than those of HC suggesting a potential role of SLF integrity in resilience to CBP. Structural connectivity-based models also classified SBPp and SBPr patients from the three data sets (validation accuracy 67%). Our results validate the right SLF as a robust predictor of CBP development, with potential for clinical translation. Cognitive and behavioral processes dependent on the right SLF, such as proprioception and visuospatial attention, should be analyzed in subacute stages as they could prove important for back pain chronicity.

No significant alteration in white matter microstructure in first-degree relatives of patients with obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is characterized by structural alteration within white matter tissues of cortico-striato-thalamo-cortical, temporal and occipital circuits. However, the presence of microstructural changes in the white matter tracts of unaffected first-degree relatives of patients with OCD as a vulnerability marker remains unclear. Therefore, here, diffusion-tensor magnetic resonance imaging (DTI) data were obtained from 29 first-degree relatives of patients with OCD and 59 healthy controls. We investigated the group differences in FA using whole-brain analysis (DTI analysis). For additional regions of interest (ROI) analysis, we focused on the posterior thalamic radiation and sagittal stratum, shown in recent meta-analysis of patients with OCD. In both whole-brain and ROI analyses, using a strict statistical threshold (family-wise error rate [FWE] corrected p<.05 for whole-brain analyses, and p<.0125 (0.05/4) with Bonferroni correction for ROI analyses), we found no significant group differences in FA. Subtle reductions were observed in the anterior corona radiata, forceps minor, cingulum bundle, and corpus callosum only when a lenient statistical was applied (FWE corrected p<.20). These findings suggest that alterations in the white matter microstructure of first-degree relatives, as potential vulnerability markers for OCD, are likely subtle.

Relationships between serotonin 1A receptor DNA methylation, self-reported history of childhood abuse and gray matter volume in major depression

BackgroundEarly life adversity is a risk factor for psychopathology and is associated with epigenetic alterations in the 5-HT1A receptor gene promoter. The 5-HT1A receptor mediates neurotrophic effects, which could affect brain structure and function. We examined relationships between self-reported early childhood abuse, 5-HT1A receptor promoter DNA methylation, and gray matter volume (GMV) in Major Depressive Disorder (MDD). MethodsPeripheral DNA methylation of 5-HT1A receptor promoter CpG sites −681 and −1007 was assayed in 50 individuals with MDD, including 18 with a history of childhood abuse. T1-weighted structural magnetic resonance imaging (MRI) was performed. Voxel-based morphometry (VBM) was quantified in amygdala, hippocampus, insula, occipital lobe, orbitofrontal cortex, temporal lobe, parietal lobe, and at the voxel level. ResultsNo relationship was observed between DNA methylation and history of childhood abuse. We observed regional heterogeneity comparing −681 CpG site methylation and GMV (p = 0.014), with a positive relationship to GMV in orbitofrontal cortex (p = 0.035). Childhood abuse history was associated with higher GMV considering all ROIs simultaneously (p < 0.01). In whole-brain analyses, childhood abuse history was positively correlated with GMV in multiple clusters, including insula and orbitofrontal cortex (pFWE = 0.005), and negatively in intracalcarine cortex (pFWE = 0.001). LimitationsSmall sample size, childhood trauma assessment instrument used, and assay of peripheral, rather than CNS, methylation. ConclusionsThese cross-sectional findings support hypotheses of 5-HT1A receptor-related neurotrophic effects, and of increased regional GMV as a potential regulatory mechanism in the setting of childhood abuse. Orbitofrontal cortex was uniquely associated with both childhood abuse history and 5-HT1A receptor methylation.

Diffusion tensor imaging in Behcet's disease with and without neurological involvement patients: evaluation of microstructural white matter abnormality with a tract-based spatial statistical analysis.

This study aims to assess the microstructural abnormalities in white matter (WM) among Behcet's disease (BD) patients, both with and without neurological involvement, utilising tract-based spatial statistics (TBSS) to elucidate the underlying causes of WM microstructural changes. This prospective study comprised 43 BD patients without neurological involvement, 15 neuro-Behcet's disease (NBD) patients with normal conventional MRI, and 54 healthy controls matched for age and sex. TBSS was applied in this diffusion tensor imaging study to conduct a whole-brain voxel-wise analysis of fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) of WM. Compared to the control group, BD patients exhibited decreased FA and increased MD and RD in nearly all WM tracts, along with increased AD in the left corticospinal tract (CST), left inferior longitudinal fasciculus (ILF), and left superior longitudinal fasciculus (SLF). NBD patients also showed a widespread decrease in FA and increased MD and RD, similar to BD patients without neurological involvement. Additionally, NBD patients had increased AD in the left CST, left ILF, left SLF, left inferior fronto-occipital fasciculus (IFOF), and right CST. Compared to BD patients without neurological involvement, NBD patients exhibited a greater reduction in FA and an increase in MD and RD in WM tracts, with no significant differences in AD. These results suggest that the main mechanism of microstructural changes in the WM of BD patients may be related to impaired fibre integrity, demyelination, and decreased myelin sheath integrity. This study demonstrated BD patients without neurological involvement and NBD patients a decrease in FA and an increase in MD and RD were observed in larger areas of major WM tracts, while an increase in AD values was observed in fewer tracts. Our findings may be useful in understanding the pathophysiology underlying subclinical parenchymal involvement and neurological dysfunction in BD patients and the management of BD patients.

Independent replications reveal anterior and posterior cingulate cortex activation underlying state anxiety-attenuated face encoding

Anxiety involves the anticipation of aversive outcomes and can impair neurocognitive processes, such as the ability to recall faces encoded during the anxious state. It is important to precisely delineate and determine the replicability of these effects using causal state anxiety inductions in the general population. This study therefore aimed to replicate prior research on the distinct impacts of threat-of-shock-induced anxiety on the encoding and recognition stage of emotional face processing, in a large asymptomatic sample (n = 92). We successfully replicated previous results demonstrating impaired recognition of faces encoded under threat-of-shock. This was supported by a mega-analysis across three independent studies using the same paradigm (n = 211). Underlying this, a whole-brain fMRI analysis revealed enhanced activation in the posterior cingulate cortex (PCC), alongside previously seen activity in the anterior cingulate cortex (ACC) when combined in a mega-analysis with the fMRI findings we aimed to replicate. We further found replications of hippocampus activation when the retrieval and encoding states were congruent. Our results support the notion that state anxiety disrupts face recognition, potentially due to attentional demands of anxious arousal competing with affective stimuli processing during encoding and suggest that regions of the cingulate cortex play pivotal roles in this.

Differential neural mechanisms for movement adaptations following neuromuscular training in young female athletes with a history of sports-related concussion

Sports-related concussion (SRC) in adolescent athletes is associated with an increased risk of subsequent lower extremity injury. Neuromuscular training (NMT) has shown promise for reducing lower extremity injuries following SRC, however, neural adaptations in response to changes in lower extremity biomechanics following NMT in athletes with a history of SRC (HxSRC) remains poorly understood. Therefore, the purpose of this study was to identify changes in neural activity associated with lower extremity movement adaptations following a six-week NMT intervention in athletes with a HxSRC. Thirty-two right-hand/foot-dominant female adolescent athletes (16 with self-reported HxSRC, 16 age- and anthropometrically-matched controls) completed a bilateral leg press task with 3D motion analysis during functional magnetic resonance imaging (fMRI). Movement adaptations were defined as a change in frontal and sagittal plane range of motion (ROM) during the fMRI bilateral leg press task. Significant pre- to post-NMT reductions were observed in the non-dominant (left) mean frontal plane ROM. Whole-brain neural correlate analysis revealed that increased cerebellar activity was significantly associated with reduced mean left-knee frontal ROM for matched controls. Exploratory within group analyses identified neural correlates in the postcentral gyrus for the HxSRC group which was associated with reduced mean left-knee frontal plane ROM. These distinct longitudinal changes provide preliminary evidence of differential neural activity associated with NMT to support knee frontal plane control in athletes with and without a HxSRC.

Optimization and validation of low-field MP2RAGE T1 mapping on 0.35T MR-Linac: Toward adaptive dose painting with hypoxia biomarkers.

Stereotactic MR-guided Adaptive Radiation Therapy (SMART) dose painting for hypoxia has potential to improve treatment outcomes, but clinical implementation on low-field MR-Linac faces substantial challenges due to dramatically lower signal-to-noise ratio (SNR) characteristics. While quantitative MRI and T1 mapping of hypoxia biomarkers show promise, T1-to-noise ratio (T1NR) optimization at low fields is paramount, particularly for the clinical implementation of oxygen-enhanced (OE)-MRI. The 3D Magnetization Prepared (2) Rapid Gradient Echo (MP2RAGE) sequence stands out for its ability to acquire homogeneous T1-weighted contrast images with simultaneous T1 mapping. To optimize MP2RAGE for low-field T1 mapping; conduct experimental validation in a ground-truth phantom; establish feasibility and reproducibility of low-field MP2RAGE acquisition and T1 mapping in healthy volunteers. The MP2RAGE optimization was performed to maximize the contrast-to-noise ratio (CNR) of T1 values in white matter (WM) and gray matter (GM) brain tissues at 0.35T. Low-field MP2RAGE images were acquired on a 0.35T MR-Linac (ViewRay MRIdian) using a multi-channel head coil. Validation of T1 mapping was performed with a ground-truth Eurospin phantom, containing inserts of known T1 values (400-850ms), with one and two average (1A and 2A) MP2RAGE scans across four acquisition sessions, resulting in eight T1 maps. Mean (±SD) T1 relative error, T1NR, and intersession coefficient of variation (CV) were determined. Whole-brain MP2RAGE scans were acquired in 5 healthy volunteers across two sessions (A and B) and T1 maps were generated. Mean (±SD) T1 values for WM and GM were determined. Whole-brain T1 histogram analysis was performed, and reproducibility was determined with the CV between sessions. Voxel-by-voxel T1 difference maps were generated to evaluate 3D spatial variation. Low-field MP2RAGE optimization resulted in parameters: MP2RAGETR of 3250ms, inversion times (TI1/TI2) of 500/1200ms, and flip angles (α1/α2) of 7/5°. Eurospin T1 maps exhibited a mean (±SD) relative error of 3.45%±1.30%, T1NR of 20.13±5.31, and CV of 2.22%±0.67% across all inserts. Whole-brain MP2RAGE images showed high anatomical quality with clear tissue differentiation, resulting in mean (±SD) T1 values: 435.36±10.01ms for WM and 623.29±14.64ms for GM across subjects, showing excellent concordance with literature. Whole-brain T1 histograms showed high intrapatient and intersession reproducibility with characteristic intensity peaks consistent with voxel-level WM and GM T1 values. Reproducibility analysis revealed a CV of 0.46%±0.31% and 0.35%±0.18% for WM and GM, respectively. Voxel-by-voxel T1 difference maps show a normal 3D spatial distribution of noise in WM and GM. Low-field MP2RAGE proved effective in generating accurate, reliable, and reproducible T1 maps with high T1NR in phantom studies and in vivo feasibility established in healthy volunteers. While current work is focused on refining the MP2RAGE protocol to enable clinically efficient OE-MRI, this study establishes a foundation for TOLD T1 mapping for hypoxia biomarkers. This advancement holds the potential to facilitate a paradigm shift toward MR-guided biological adaptation and dose painting by leveraging 3D hypoxic spatial distributions and improving outcomes in conventionally challenging-to-treat cancers.

Brain mechanisms underlying the modulation of heart rate variability when accepting and reappraising emotions

Heart rate variability (HRV) has been linked to resilience and emotion regulation (ER). How HRV and brain processing interact during ER, however, has remained elusive. Sixty-two subjects completed the acquisition of resting HRV and task HRV while performing an ER functional Magnetic Resonance Imaging (fMRI) paradigm, which included the differential strategies of ER reappraisal and acceptance in the context of viewing aversive pictures. We found high correlations of resting and task HRV across all emotion regulation strategies. Furthermore, individuals with high levels of resting, but not task, HRV showed numerically lower distress during ER with acceptance. Whole-brain fMRI parametrical modulation analyses revealed that higher task HRV covaried with dorso-medial prefrontal activation for reappraisal, and dorso-medial prefrontal, anterior cingulate and temporo-parietal junction activation for acceptance. Subjects with high resting HRV, compared to subjects with low resting HRV, showed higher activation in the pre-supplementary motor area during ER using a region of interest approach. This study demonstrates that while resting and task HRV exhibit a positive correlation, resting HRV seems to be a better predictor of ER capacity. Resting and task HRV were associated with ER brain activation in mid-line frontal cortex (i.e. DMPFC).

Right anterior insula ASL hypoperfusion as a diagnostic biomarker of prodromal and mild dementia with Lewy bodies: preliminary evidence using a Bayesian approach.

Identifying and validating a biomarker with high specificity in early-stage dementia with Lewy bodies (DLB) using a feasible method is crucial to enhance the current suboptimal diagnostic procedure. Previous research revealed abnormalities, including hypoperfusion in the right anterior insular cortex at group level, in prodromal DLB. Exploring hypoperfusion of the right anterior insula, at an individual-level and assessing its relevance as a potential imaging biomarker in early DLB, has, to our knowledge, not been investigated. Our preliminary study aims to assess the feasibility of the technique and to provide a methodological framework for further investigation. We assessed the feasibility and accuracy of the hypoperfusion of the right anterior insula per arterial spin labelling magnetic resonance imaging (ASL-MRI) as a diagnostic biomarker in early DLB and provided rough estimates of its sensitivity and specificity. Defining the region of interest based on previous research, we established the biomarker as the hypoperfusion of the right anterior insula. Discriminative and analytical performances were assessed in comparison to a control group of treatment-resistant depression patients. Bayesian diagnostic reasoning was employed to assess the biomarker diagnostic usability in early DLB in two scenarios: healthy elderly controls and mild cognitive impairment. Additionally, we updated probabilities by integrating data from the Mayo-clinic cognitive fluctuations scale and real-time quaking-induced conversion (RT-QuIC) α-synuclein data. Lastly, a whole-brain perfusion analysis of DLB patients was conducted to identify further brain regions with discriminative abilities. We successfully replicated the right anterior insular hypoperfusion (RAI-Hypo) in all DLB patients at the individual level. The overall sensitivity of the biomarker was 96%, and the specificity was 92%. Bayesian testing revealed the biomarker's highest performance in early-stage DLB with cognitive fluctuations, showcasing a diagnostic potential associated with a high precision and moderate accuracy. In a cognitively non-impaired population, the RAI-Hypo showed a limited usability and lacked in selectivity to qualify as a screening tool. The exploratory whole-brain analysis revealed perfect discriminative capacities in the bilateral anterior insulae and the left inferior parietal lobule. Further studies are needed to confirm our preliminary results. If performance is maintained in subsequent studies and is compared to a more suitable control population, the proposed biomarker may be eventually sufficient to discriminate early-stage DLB from non-DLB.

Unravelling the origin of the reward positivity: a human intracranial event-related brain potential study.

The reward positivity (RewP) is an event-related brain potential (ERP) component that emerges approximately 250 to 350 milliseconds (ms) after receiving reward-related feedback stimuli and is believed to be important for reinforcement learning and reward processing. Although numerous localization studies have indicated that the anterior cingulate cortex (ACC) is the neural generator of this component, other studies have identified sources outside of the ACC, fuelling a debate about its origin. Because the results of EEG and MEG source localization studies are severely limited by the inverse problem, we addressed this question by leveraging the high spatial and temporal resolution of intracranial EEG. We predicted that we would identify a neural generator of the RewP in the caudal ACC. We recorded intracranial EEG in 19 refractory epilepsy patients who underwent invasive video-EEG monitoring at Ghent University Hospital, Belgium. Participants engaged in the virtual T-maze task (vTMT), a trial-and-error task known to elicit a canonical RewP, while scalp and intracranial EEG were simultaneously recorded. The RewP was identified using a difference wave approach for both scalp and intracranial EEG. The data were aggregated across participants to create a virtual "meta-participant" that contained all the recorded intracranial ERPs (iERPs) with respect to their intracranial contact locations. We used both a hypothesis-driven (focused on ACC) and exploratory (whole-brain analysis) approach to segment the brain into regions of interest (ROI). For each ROI, we evaluated the degree to which the time course of the absolute current density (ACD) activity mirrored the time course of the RewP, and confirmed the statistical significance of the results using permutation analysis. The grand average waveform of the scalp data revealed a RewP at 309 ms after reward feedback with a frontocentral scalp distribution, consistent with the identification of this component as the RewP. The meta-participant contained iERPs recorded from 582 intracranial contacts in total. The ACD activity of the aggregated iERPs were most similar to the RewP in left caudal ACC, left dorsolateral prefrontal cortex, left frontomedial cortex, and left white matter, with the highest score attributed to caudal ACC, as predicted. To our knowledge, this is the first study that uses intracranial EEG aggregated across multiple human epilepsy patients and current source density analysis to identify the neural generator(s) of the RewP. These results provide direct evidence that the ACC is a neural generator of the RewP.

Frontal pole iron deposition is associated with cognitive decline in patients with carotid atherosclerosis stenosis: a quantitative susceptibility mapping study

Objective: To investigate the correlation between brain iron deposition and cognitive function in patients with carotid atherosclerosis stenosis (CAS) based on quantitative susceptibility mapping (QSM). Methods: This single-center prospective study was performed at the Department of Vascular Surgery, Nanjing Drum Tower Hospital from January 2022 to June 2022. Patients who met the ataxation criteria were divided into the CAS group (n=16) and the CAS with mild cognitive impairment (CAS-MCI) group (n=17) according to the Montreal Cognitive Assessment (MoCA) scores. All patients completed QSM imaging and whole-brain analyses were performed for absolute susceptibility values in cortical regions. Age, sex, education years, hypertension, and diabetes mellitus were included as covariates in all analyses. Partial correlation analyses were used to determine the correlation between bilateral CAS degrees and cortical susceptibility values. Further, mediation analyses were performed to determine whether and how cortical susceptibility values affect cognition in CAS patients. Receiver operating characteristic (ROC) curve analysis was also performed to evaluate the predictive worth of differential brain region susceptibility values for cognitive decline. Independent sample t test and Mann-Whitney U test was used to compare quantitative variables. The comparison of categorical variables was conducted using χ2 test, Fisher's exact test or Wilcoxon rank sum test. Results: A total of 33 patients were included in the study, including 16 in the CAS group and 17 in the CAS-MCI group. There were 23 males and 10 females, aged (62.8±9.0) years (range: 48 to 88 years). CAS-MCI group showed higher right CAS grades (Z=-2.037, P=0.042). Whole-brain cortical QSM analyses showed higher susceptibility values in the frontal pole ((-0.210±0.080)×10-8 vs.(-0.130±0.120)×10-8;t=-2.187, P=0.037), superior frontal gyrus ((-0.604±0.243)×10-8 vs. (-0.428±0.203)×10-8;t=-2.223,P=0.034), and temporal pole ((-0.081±0.115)×10-8 vs. (0.054±0.190)×10-8;t=-2.417, P=0.022) in CAS-MCI group compared to CAS group. The susceptibility value of the frontal pole showed a positive correlation with the right CAS grade (r=0.424, P=0.009),while a quasi-significant positive correlation with the left CAS (r=0.313, P=0.070). The susceptibility values of the frontal and temporal poles were negatively correlated with the MoCA score (frontal pole: r=-0.391, P=0.027; temporal pole: r=-0.410, P=0.020). Mediation analysis showed the effect of right CAS on cognition was fully mediated by the susceptibility value of the frontal pole. The ROC curve revealed that the area under the curve of using hypertension combined with the susceptibility value of the frontal pole to predict cognitive decline was 0.882 (95% CI:0.763 to 0.989) with 82% of sensitivity and 83% of specificity. Conclusions: Multiple cortical regions show iron deposition in CAS-MCI patients. Right CAS plays an important role in cognitive decline, frontal pole iron deposition mediates the effect of right CAS on cognitive function. Quantified frontal pole susceptibility is useful for the diagnosis of cognitive decline in patients with CAS.

Interference of default mode on attention networks in adults with attention-deficit/hyperactivity disorder and its association with genetic variants and treatment outcomes.

Altered brain functional connectivity has been proposed as the neurobiological underpinnings of attention-deficit/hyperactivity disorder (ADHD), and the default mode interference hypothesis is one of the most popular neuropsychological models. Here, we explored whether this hypothesis is supported in adults with ADHD and the association with high-risk genetic variants and treatment outcomes. Voxel-based whole-brain connectome analysis was conducted on resting-state functional MRI data from 84 adults with ADHD and 89 healthy controls to identify functional connectivity substrates corresponding to ADHD-related alterations. The candidate genetic variants and 12-week cognitive behavioral therapy data were leveraged from the same population to assess these associations. We detected breakdowns of functional connectivity in the precuneus and left middle temporal gyrus in adults with ADHD, with exact contributions from decreased connectivity within the default mode, dorsal and ventral attention networks, as well as increased connectivity among them with the middle temporal gyrus serving as a crucial 'bridge'. Additionally, significant associations between the altered functional connectivity and genetic variants in both MAOA and MAOB were detected. Treatment restored brain function, with the amelioration of connectivity of the middle temporal gyrus, accompanied by improvements in ADHD core symptoms. These findings support the interference of default mode on attention in adults with ADHD and its association with genetic risk variants and clinical management, providing insights into the underlying pathogenesis of ADHD and potential biomarkers for treatment evaluation.

Impact of trauma type on neural mechanisms of threat conditioning and its extinction

Trauma type moderates the impact of trauma exposure on clinical symptomatology; however, the impact of trauma type on the neural correlates of emotion regulation is not as well understood. This study examines how violent and nonviolent trauma differentially influence the neural correlates of conditioned fear and extinction. We aggregated psychophysiological and fMRI data from three studies; we categorized reported trauma as violent or nonviolent, and subdivided violent trauma as sexual or nonsexual. We examined skin conductance responses (SCR) during a fear conditioning and extinction paradigm. For fMRI data analyses, we conducted region-specific and whole-brain analyses. We examined associations between beta weights from specific brain regions and CAPS scores. The group exposed to violent trauma showed significantly higher SCR during extinction recall. Those exposed to nonviolent trauma showed significantly higher functional activation during late extinction learning. The group exposed to violent trauma showed higher functional connectivity within the default mode network (DMN) and between the DMN and frontoparietal control network. For secondary analyses of sexual vs nonsexual trauma, we did not observe any between-group differences in SCR. During late extinction learning, the group exposed to sexual trauma showed significantly higher activation in the prefrontal cortex and precuneus. During extinction recall, the group exposed to nonsexual trauma showed significantly higher activation in the insular cortex. Violent trauma significantly impacts functional brain activations and connectivity in brain areas important for perception and attention with no significant impact on brain areas that modulate emotion regulation. Sexual trauma impacts brain areas important for internal perception.

Stress in Musicians with and Without Focal Dystonia Is Not Reflected in Limbic Circuit Activation.

Musicians' dystonia (MD) is a movement disorder with several established risk factors, but the exact pathophysiology remains unknown. Recent research suggests dysfunction in sensory-motor, basal ganglia, cerebellar, and limbic loops as potential causes. Adverse childhood experiences are also considered risk factors. This study aimed to investigate whether MD patients have experienced more childhood trauma, leading to increased stress reactivity and neural vulnerability to movement disorders. Using functional magnetic resonance imaging and the Montreal Imaging Stress Task, 40 MD patients were compared with 39 healthy musicians (HMs). Whole-brain analysis and regions of interest analysis were performed. Parameter estimates and subjective stress levels were compared between groups and correlated with the Childhood Trauma Questionnaire. MD patients reported significantly higher childhood trauma scores than healthy control subjects, but they did not differ in their subjective stress experiences. Stress-related activity of limbic areas was neither found in the whole sample nor between the two groups. Instead, increased activity of visual association and temporal areas was observed, but this activation did not differ between patients and HMs. However, patients showed a tendency toward reduced precuneus activity under stress. Adverse childhood experiences were negatively correlated with precuneus, thalamus, and substantia nigra activity across all participants. Overall, MD patients and HMs had similar subjective and neurological reactions to stress but differed in childhood trauma experiences and precuneus activity under stress. Further research about the functional connectivity between precuneus, cerebellum, thalamus, and basal ganglia in musicians is needed. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Intergenerational effects of racism on amygdala and hippocampus resting state functional connectivity

Racism is an insidious problem with far-reaching effects on the lives of Black, Indigenous, and People of Color (BIPOC). The pervasive negative impact of racism on mental health is well documented. However, less is known about the potential downstream impacts of maternal experiences of racism on offspring neurodevelopment. This study sought to examine evidence for a biological pathway of intergenerational transmission of racism-related trauma. This study examined the effects of self-reported maternal experiences of racism on resting state functional connectivity (rsFC) in n = 25 neonates (13 female, 12 male) birthed by BIPOC mothers. Amygdala and hippocampus are brain regions involved in fear, memory, and anxiety, and are central nodes in brain networks associated with trauma-related change. We used average scores on the Experiences of Racism Scale as a continuous, voxel-wise regressor in seed-based, whole-brain connectivity analysis of anatomically defined amygdala and hippocampus seed regions of interest. All analyses controlled for infant sex and gestational age at the 2-week scanning session. More maternal racism-related experiences were associated with (1) stronger right amygdala rsFC with visual cortex and thalamus; and (2) stronger hippocampus rsFC with visual cortex and a temporo-parietal network, in neonates. The results of this research have implications for understanding how maternal experiences of racism may alter neurodevelopment, and for related social policy.