Electric Field Modeling in Personalizing Transcranial Magnetic Stimulation Interventions.

The modeling of transcranial magnetic stimulation (TMS)-induced electric fields (E-fields) is a versatile technique for evaluating and refining brain targeting and dosing strategies, while also providing insights into dose-response relationships in the brain. This review outlines the methodologies employed to derive E-field estimations, covering TMS physics, modeling assumptions, and aspects of subject-specific head tissue and coil modeling. We also summarize various numerical methods for solving the E-field and their suitability for various applications. Modeling methodologies have been optimized to efficiently execute numerous TMS simulations across diverse scalp coil configurations, facilitating the identification of optimal setups or rapid cortical E-field visualization for specific brain targets. These brain targets are extrapolated from neurophysiological measurements and neuroimaging, enabling precise and individualized E-field dosing in experimental and clinical applications. This necessitates the quantification of E-field estimates using metrics that enable the comparison of brain target engagement, functional localization, and TMS intensity adjustments across subjects. The integration of E-field modeling with empirical data has the potential to uncover pivotal insights into the aspects of E-fields responsible for stimulating and modulating brain function and states, enhancing behavioral task performance, and impacting the clinical outcomes of personalized TMS interventions.

Lack of reproducibility of resting-state functional MRI findings in migraine with aura.

BACKGROUND: Several studies have applied resting-state functional MRI to examine whether functional brain connectivity is altered in migraine with aura patients. These studies had multiple limitations, including small sample sizes, and reported conflicting results. Here, we performed a large, cross-sectional brain imaging study to reproduce previous findings. METHODS: We recruited women aged 30-60 years from the nationwide Danish Twin Registry. Resting-state functional MRI of women with migraine with aura, their co-twins, and unrelated migraine-free twins was performed at a single centre. We carried out an extensive series of brain connectivity data analyses. Patients were compared to migraine-free controls and to co-twins. RESULTS: Comparisons were based on data from 160 patients, 30 co-twins, and 136 controls. Patients were similar to controls with regard to age, and several lifestyle characteristics. We replicated clear effects of age on resting-state networks. In contrast, we failed to detect any differences, and to replicate previously reported differences, in functional connectivity between migraine patients with aura and non-migraine controls or their co-twins in any of the analyses. CONCLUSION: Given the large sample size and the unbiased population-based design of our study, we conclude that women with migraine with aura have normal resting-state brain connectivity outside of migraine attacks.

Characterising the covariance pattern between lifestyle factors and structural brain measures: a multivariable replication study of two independent ageing cohorts.

Modifiable lifestyle factors have been shown to promote healthy brain ageing. However, studies have typically focused on a single factor at a time. Given that lifestyle factors do not occur in isolation, multivariable analyses provide a more realistic model of the lifestyle-brain relationship. Here, canonical correlation analyses (CCA) examined the relationship between nine lifestyle factors and seven MRI-derived indices of brain structure. The resulting covariance pattern was further explored with Bayesian regressions. CCA analyses were first conducted on a Danish cohort of older adults (n = 251) and then replicated in a British cohort (n = 668). In both cohorts, the latent factors of lifestyle and brain structure were positively correlated (UK: r = .37, p < 0.001; Denmark: r = .27, p < 0.001). In the cross-validation study, the correlation between lifestyle-brain latent factors was r = .10, p = 0.008. However, the pattern of associations differed between datasets. These findings suggest that baseline characterisation and tailoring towards the study sample may be beneficial for achieving targeted lifestyle interventions.

Volumetric measurements of weak current-induced magnetic fields in the human brain at high resolution.

PURPOSE: Clinical use of transcranial electrical stimulation (TES) requires accurate knowledge of the injected current distribution in the brain. MR current density imaging (MRCDI) uses measurements of the TES-induced magnetic fields to provide this information. However, sufficient sensitivity and image quality in humans in vivo has only been documented for single-slice imaging. METHODS: A recently developed, optimally spoiled, acquisition-weighted, gradient echo-based 2D-MRCDI method has now been advanced for volume coverage with densely or sparsely distributed slices: The 3D rectilinear sampling (3D-DENSE) and simultaneous multislice acquisition (SMS-SPARSE) were optimized and verified by cable-loop experiments and tested with 1-mA TES experiments for two common electrode montages. RESULTS: Comparisons between the volumetric methods against the 2D-MRCDI showed that relatively long acquisition times of 3D-DENSE using a single slab with six slices hindered the expected sensitivity improvement in the current-induced field measurements but improved sensitivity by 61% in the Laplacian of the field, on which some MRCDI reconstruction methods rely. Also, SMS-SPARSE acquisition of three slices, with a factor 2 CAIPIRINHA (controlled aliasing in parallel imaging results in higher acceleration) acceleration, performed best against the 2D-MRCDI with sensitivity improvements for the ∆ B z , c $$ \Delta {B}_{z,c} $$ and Laplacian noise floors of 56% and 78% (baseline without current flow) as well as 43% and 55% (current injection into head). SMS-SPARSE reached a sensitivity of 67 pT for three distant slices at 2 × 2 × 3 mm3 resolution in 10 min of total scan time, and consistently improved image quality. CONCLUSION: Volumetric MRCDI measurements with high sensitivity and image quality are well suited to characterize the TES field distribution in the human brain.

Is it all in the baseline? Trajectories of chair stand performance over 4 years and their association with grey matter structure in older adults.

Understanding individual variability in response to physical activity is key to developing more effective and personalised interventions for healthy ageing. Here, we aimed to unpack individual differences by using longitudinal data from a randomised-controlled trial of a 12-month muscle strengthening intervention in older adults. Physical function of the lower extremities was collected from 247 participants (66.3 ± 2.5 years) at four time-points. At baseline and at year 4, participants underwent 3 T MRI brain scans. K-means longitudinal clustering was used to identify patterns of change in chair stand performance over 4 years, and voxel-based morphometry was applied to map structural grey matter volume at baseline and year 4. Results identified three groups showing trajectories of poor (33.6%), mid (40.1%), and high (26.3%) performance. Baseline physical function, sex, and depressive symptoms significantly differed between trajectory groups. High performers showed greater grey matter volume in the motor cerebellum compared to the poor performers. After accounting for baseline chair stand performance, participants were re-assigned to one of four trajectory-based groups: moderate improvers (38.9%), maintainers (38.5%), improvers (13%), and decliners (9.7%). Clusters of significant grey matter differences were observed between improvers and decliners in the right supplementary motor area. Trajectory-based group assignments were unrelated to the intervention arms of the study. In conclusion, patterns of change in chair stand performance were associated with greater grey matter volumes in cerebellar and cortical motor regions. Our findings emphasise that how you start matters, as baseline chair stand performance was associated with cerebellar volume 4 years later.

Hippocampal anterior- posterior shift in childhood and adolescence.

Hippocampal-cortical networks play an important role in neurocognitive development. Applying the method of Connectivity-Based Parcellation (CBP) on hippocampal-cortical structural covariance (SC) networks computed from T1-weighted magnetic resonance images, we examined how the hippocampus differentiates into subregions during childhood and adolescence (N = 1105, 6-18 years). In late childhood, the hippocampus mainly differentiated along the anterior-posterior axis similar to previous reported functional differentiation patterns of the hippocampus. In contrast, in adolescence a differentiation along the medial-lateral axis was evident, reminiscent of the cytoarchitectonic division into cornu ammonis and subiculum. Further meta-analytical characterization of hippocampal subregions in terms of related structural co-maturation networks, behavioural and gene profiling suggested that the hippocampal head is related to higher order functions (e.g. language, theory of mind, autobiographical memory) in late childhood morphologically co-varying with almost the whole brain. In early adolescence but not in childhood, posterior subicular SC networks were associated with action-oriented and reward systems. The findings point to late childhood as an important developmental period for hippocampal head morphology and to early adolescence as a crucial period for hippocampal integration into action- and reward-oriented cognition. The latter may constitute a developmental feature that conveys increased propensity for addictive disorders.

An open-source tool for longitudinal whole-brain and white matter lesion segmentation.

In this paper we describe and validate a longitudinal method for whole-brain segmentation of longitudinal MRI scans. It builds upon an existing whole-brain segmentation method that can handle multi-contrast data and robustly analyze images with white matter lesions. This method is here extended with subject-specific latent variables that encourage temporal consistency between its segmentation results, enabling it to better track subtle morphological changes in dozens of neuroanatomical structures and white matter lesions. We validate the proposed method on multiple datasets of control subjects and patients suffering from Alzheimer's disease and multiple sclerosis, and compare its results against those obtained with its original cross-sectional formulation and two benchmark longitudinal methods. The results indicate that the method attains a higher test-retest reliability, while being more sensitive to longitudinal disease effect differences between patient groups. An implementation is publicly available as part of the open-source neuroimaging package FreeSurfer.

TMS combined with EEG: Recommendations and open issues for data collection and analysis.

Transcranial magnetic stimulation (TMS) evokes neuronal activity in the targeted cortex and connected brain regions. The evoked brain response can be measured with electroencephalography (EEG). TMS combined with simultaneous EEG (TMS-EEG) is widely used for studying cortical reactivity and connectivity at high spatiotemporal resolution. Methodologically, the combination of TMS with EEG is challenging, and there are many open questions in the field. Different TMS-EEG equipment and approaches for data collection and analysis are used. The lack of standardization may affect reproducibility and limit the comparability of results produced in different research laboratories. In addition, there is controversy about the extent to which auditory and somatosensory inputs contribute to transcranially evoked EEG. This review provides a guide for researchers who wish to use TMS-EEG to study the reactivity of the human cortex. A worldwide panel of experts working on TMS-EEG covered all aspects that should be considered in TMS-EEG experiments, providing methodological recommendations (when possible) for effective TMS-EEG recordings and analysis. The panel identified and discussed the challenges of the technique, particularly regarding recording procedures, artifact correction, analysis, and interpretation of the transcranial evoked potentials (TEPs). Therefore, this work offers an extensive overview of TMS-EEG methodology and thus may promote standardization of experimental and computational procedures across groups.

Linking Impulsivity to Activity Levels in Pre-Supplementary Motor Area during Sequential Gambling.

Impulsivity refers to the tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Since the pre-supplementary motor area (pre-SMA) has been implicated in inhibitory control, this region may also contribute to impulsivity. Here, we examined whether functional recruitment of pre-SMA may contribute to risky choice behavior (state impulsivity) during sequential gambling and its relation to self-reported trait impulsivity. To this end, we performed task-based functional MRI (fMRI) after low-frequency (1 Hz) repetitive transcranial magnetic stimulation (rTMS) of the pre-SMA. We expected low-frequency rTMS to modulate task-related engagement of the pre-SMA and, hereby, tune the tendency to make risky choices. Twenty-four healthy volunteers (12 females; age range, 19-52 years) received real or sham-rTMS on separate days in counterbalanced order. Thereafter, participants performed a sequential gambling task with concurrently increasing stakes and risk during whole-brain fMRI. In the sham-rTMS session, self-reported trait impulsivity scaled positively with state impulsivity (riskier choice behavior) during gambling. The higher the trait impulsivity, the lower was the task-related increase in pre-SMA activity with increasingly risky choices. Following real-rTMS, low-impulsivity participants increased their preference for risky choices, while the opposite was true for high-impulsivity participants, resulting in an overall decoupling of trait impulsivity and state impulsivity during gambling. This rTMS-induced behavioral shift was mirrored in the rTMS-induced change in pre-SMA activation. These results provide converging evidence for a causal link between the level of task-related pre-SMA activity and the propensity for impulsive risk-taking behavior in the context of sequential gambling.SIGNIFICANCE STATEMENT Impulsivity is a personal trait characterized by a tendency to act prematurely or without forethought, and excessive impulsivity is a key problem in many neuropsychiatric disorders. Here we provide evidence that the pre-supplementary motor area (pre-SMA) is causally involved in implementing general impulsive tendencies (trait impulsivity) into actual behavior (state impulsivity). Participants' self-reported impulsivity levels (trait impulsivity) were reflected in their choice behavior (state impulsivity) when involved in a sequential gambling task. This relationship was uncoupled after perturbing the pre-SMA with repetitive transcranial stimulation (rTMS). This effect was contingent on trait impulsivity and was echoed in rTMS-induced changes in pre-SMA activity. Pre-SMA is key in translating trait impulsivity into behavior, possibly by integrating prefrontal goals with corticostriatal motor control.

Stability of associations between neuroticism and microstructural asymmetry of the cingulum during late childhood and adolescence: Insights from a longitudinal study with up to 11 waves.

Adolescence is characterized by significant brain development and marks a period of the life span with an increased incidence of mood disorders, especially in females. The risk of developing mood disorders is also higher in individuals scoring high on neuroticism, a personality trait characterized by a tendency to experience negative and anxious emotions. We previously found in a cross-sectional study that neuroticism is associated with microstructural left-right asymmetry of the fronto-limbic white matter involved in emotional processing, with opposite effects in female and male adolescents. We now have extended this work collecting longitudinal data in 76 typically developing children and adolescents aged 7-18 years, including repeated MRI sampling up to 11 times. This enabled us, for the first time, to address the critical question, whether the association between neuroticism and frontal-limbic white matter asymmetry changes or remains stable across late childhood and adolescence. Neuroticism was assessed up to four times and showed good intraindividual stability and did not significantly change with age. Conforming our cross-sectional results, females scoring high on neuroticism displayed increased left-right cingulum fractional anisotropy (FA), while males showed decreased left-right cingulum FA asymmetry. Despite ongoing age-related increases in FA in cingulum, the association between neuroticism and cingulum FA asymmetry was already expressed in females in late childhood and remained stable across adolescence. In males, the association appeared to become more prominent during adolescence. Future longitudinal studies need to cover an earlier age span to elucidate the time point at which the relationship between neuroticism and cingulum FA asymmetry arises.

Linking lesions in sensorimotor cortex to contralateral hand function in multiple sclerosis: a 7†T MRI study.

Cortical lesions constitute a key manifestation of multiple sclerosis and contribute to clinical disability and cognitive impairment. Yet it is unknown whether local cortical lesions and cortical lesion subtypes contribute to domain-specific impairments attributable to the function of the lesioned cortex. In this cross-sectional study, we assessed how cortical lesions in the primary sensorimotor hand area relate to corticomotor physiology and sensorimotor function of the contralateral hand. Fifty relapse-free patients with relapsing-remitting or secondary-progressive multiple sclerosis and 28 healthy age- and sex-matched participants underwent whole-brain 7 T MRI to map cortical lesions. Brain scans were also used to estimate normalized brain volume, pericentral cortical thickness, white matter lesion fraction of the corticospinal tract, infratentorial lesion volume and the cross-sectional area of the upper cervical spinal cord. We tested sensorimotor hand function and calculated a motor and sensory composite score for each hand. In 37 patients and 20 healthy controls, we measured maximal motor-evoked potential amplitude, resting motor threshold and corticomotor conduction time with transcranial magnetic stimulation and the N20 latency from somatosensory-evoked potentials. Patients showed at least one cortical lesion in the primary sensorimotor hand area in 47 of 100 hemispheres. The presence of a lesion was associated with worse contralateral sensory (P = 0.014) and motor (P = 0.009) composite scores. Transcranial magnetic stimulation of a lesion-positive primary sensorimotor hand area revealed a decreased maximal motor-evoked potential amplitude (P < 0.001) and delayed corticomotor conduction (P = 0.002) relative to a lesion-negative primary sensorimotor hand area. Stepwise mixed linear regressions showed that the presence of a primary sensorimotor hand area lesion, higher white-matter lesion fraction of the corticospinal tract, reduced spinal cord cross-sectional area and higher infratentorial lesion volume were associated with reduced contralateral motor hand function. Cortical lesions in the primary sensorimotor hand area, spinal cord cross-sectional area and normalized brain volume were also associated with smaller maximal motor-evoked potential amplitude and longer corticomotor conduction times. The effect of cortical lesions on sensory function was no longer significant when controlling for MRI-based covariates. Lastly, we found that intracortical and subpial lesions had the largest effect on reduced motor hand function, intracortical lesions on reduced motor-evoked potential amplitude and leucocortical lesions on delayed corticomotor conduction. Together, this comprehensive multilevel assessment of sensorimotor brain damage shows that the presence of a cortical lesion in the primary sensorimotor hand area is associated with impaired corticomotor function of the hand, after accounting for damage at the subcortical level. The results also provide preliminary evidence that cortical lesion types may affect the various facets of corticomotor function differentially.

Add-On MEmaNtine to Dopamine Antagonism to Improve Negative Symptoms at First Psychosis- the AMEND Trial Protocol.

Background: Antipsychotic drugs are primarily efficacious in treating positive symptoms by blocking the dopamine D2 receptor, but they fail to substantially improve negative symptoms and cognitive deficits. The limited efficacy may be attributed to the fact that the pathophysiology of psychosis involves multiple neurotransmitter systems. In patients with chronic schizophrenia, memantine, a non-competitive glutamatergic NMDA receptor antagonist, shows promise for ameliorating negative symptoms and improving cognition. Yet, it is unknown how memantine modulates glutamate levels, and memantine has not been investigated in patients with first-episode psychosis. Aims: This investigator-initiated double-blinded randomized controlled trial is designed to (1) test the clinical effects on negative symptoms of add-on memantine to antipsychotic medication, and (2) neurobiologically characterize the responders to add-on memantine. Materials and Equipment: Antipsychotic-naïve patients with first-episode psychosis will be randomized to 12 weeks treatment with [amisulpride + memantine] or [amisulpride + placebo]. We aim for a minimum of 18 patients in each treatment arm to complete the trial. Brain mapping will be performed before and after 12 weeks focusing on glutamate and neuromelanin in predefined regions. Regional glutamate levels will be probed with proton magnetic resonance spectroscopy (MRS), while neuromelanin signal will be mapped with neuromelanin-sensitive magnetic resonance imaging (MRI). We will also perform structural and diffusion weighted, whole-brain MRI. MRS and MRI will be performed at an ultra-high field strength (7 Tesla). Alongside, participants undergo clinical and neuropsychological assessments. Twenty matched healthy controls will undergo similar baseline- and 12-week examinations, but without receiving treatment. Outcome Measures: The primary endpoint is negative symptom severity. Secondary outcomes comprise: (i) clinical endpoints related to cognition, psychotic symptoms, side effects, and (ii) neurobiological endpoints related to regional glutamate- and neuromelanin levels, and structural brain changes. Anticipated Results: We hypothesize that add-on memantine to amisulpride will be superior to amisulpride monotherapy in reducing negative symptoms, and that this effect will correlate with thalamic glutamate levels. Moreover, we anticipate that add-on memantine will restore regional white matter integrity and improve cognitive functioning. Perspectives: By combining two licensed, off-patent drugs, AMEND aims to optimize treatment of psychosis while investigating the memantine response. Alongside, AMEND will provide neurobiological insights to effects of dual receptor modulation, which may enable future stratification of patients with first-episode psychosis before initial antipsychotic treatment. Clinical Trial Registration: [ClinicalTrials.gov], identifier [NCT04789915].

Transcranial magnetic stimulation of the brain: What is stimulated? - A consensus and critical position paper.

Transcranial (electro)magnetic stimulation (TMS) is currently the method of choice to non-invasively induce neural activity in the human brain. A single transcranial stimulus induces a time-varying electric field in the brain that may evoke action potentials in cortical neurons. The spatial relationship between the locally induced electric field and the stimulated neurons determines axonal depolarization. The induced electric field is influenced by the conductive properties of the tissue compartments and is strongest in the superficial parts of the targeted cortical gyri and underlying white matter. TMS likely targets axons of both excitatory and inhibitory neurons. The propensity of individual axons to fire an action potential in response to TMS depends on their geometry, myelination and spatial relation to the imposed electric field and the physiological state of the neuron. The latter is determined by its transsynaptic dendritic and somatic inputs, intrinsic membrane potential and firing rate. Modeling work suggests that the primary target of TMS is axonal terminals in the crown top and lip regions of cortical gyri. The induced electric field may additionally excite bends of myelinated axons in the juxtacortical white matter below the gyral crown. Neuronal excitation spreads ortho- and antidromically along the stimulated axons and causes secondary excitation of connected neuronal populations within local intracortical microcircuits in the target area. Axonal and transsynaptic spread of excitation also occurs along cortico-cortical and cortico-subcortical connections, impacting on neuronal activity in the targeted network. Both local and remote neural excitation depend critically on the functional state of the stimulated target area and network. TMS also causes substantial direct co-stimulation of the peripheral nervous system. Peripheral co-excitation propagates centrally in auditory and somatosensory networks, but also produces brain responses in other networks subserving multisensory integration, orienting or arousal. The complexity of the response to TMS warrants cautious interpretation of its physiological and behavioural consequences, and a deeper understanding of the mechanistic underpinnings of TMS will be critical for advancing it as a scientific and therapeutic tool.

Database of 25 validated coil models for electric field simulations for TMS.

BACKGROUND: The effects of transcranial magnetic stimulation (TMS) on brain activity depend on the design of the stimulation coil. A wide range of coils from different vendors are currently used with different stimulation properties. This decreases the comparability of study results. OBJECTIVE: To systematically compare widely used commercial TMS coils concerning their focality, stimulation depth and efficacy. To provide validated models and data of these coils for accurate simulations of the induced electric fields. METHODS: We reconstructed the magnetic vector potential of 25 commercially available TMS coils of different vendors from measurements of their magnetic fields. Most coils had a figure-of-eight configuration. We employed the reconstructed magnetic vector potential in simulations of the electric field in a spherical head model. We estimated the motor thresholds of the coil-stimulator combinations using the calculated fields, the pulse waveforms and a leaky integrator model of the neural membrane. RESULTS: Our results confirm a previously reported systematic trade-off between focality and relative depth of stimulation. However, neither the peak field strength in the "cortex" of the sphere model nor the estimated motor thresholds were strongly related to the two former measures and need to be additionally determined. CONCLUSION: Our comprehensive coil characterization facilitates objective comparisons of coils of different sizes and from different vendors. The models and auxiliary data will be made available for electric field simulations in SimNIBS. Our work will support TMS users making an informed selection of a suited coil for a specific application and will help to reduce uncertainty regarding the TMS-induced electric field in the brain target region.

Uncovering Cortical Units of Processing From Multi-Layered Connectomes.

Modern diffusion and functional magnetic resonance imaging (dMRI/fMRI) provide non-invasive high-resolution images from which multi-layered networks of whole-brain structural and functional connectivity can be derived. Unfortunately, the lack of observed correspondence between the connectivity profiles of the two modalities challenges the understanding of the relationship between the functional and structural connectome. Rather than focusing on correspondence at the level of connections we presently investigate correspondence in terms of modular organization according to shared canonical processing units. We use a stochastic block-model (SBM) as a data-driven approach for clustering high-resolution multi-layer whole-brain connectivity networks and use prediction to quantify the extent to which a given clustering accounts for the connectome within a modality. The employed SBM assumes a single underlying parcellation exists across modalities whilst permitting each modality to possess an independent connectivity structure between parcels thereby imposing concurrent functional and structural units but different structural and functional connectivity profiles. We contrast the joint processing units to their modality specific counterparts and find that even though data-driven structural and functional parcellations exhibit substantial differences, attributed to modality specific biases, the joint model is able to achieve a consensus representation that well accounts for both the functional and structural connectome providing improved representations of functional connectivity compared to using functional data alone. This implies that a representation persists in the consensus model that is shared by the individual modalities. We find additional support for this viewpoint when the anatomical correspondence between modalities is removed from the joint modeling. The resultant drop in predictive performance is in general substantial, confirming that the anatomical correspondence of processing units is indeed present between the two modalities. Our findings illustrate how multi-modal integration admits consensus representations well-characterizing each individual modality despite their biases and points to the importance of multi-layered connectomes as providing supplementary information regarding the brain's canonical processing units.

Locus Coeruleus Shows a Spatial Pattern of Structural Disintegration in Parkinson's Disease.

BACKGROUND: Parkinson's disease (PD) causes a loss of neuromelanin-positive, noradrenergic neurons in the locus coeruleus (LC), which has been implicated in nonmotor dysfunction. OBJECTIVES: We used "neuromelanin sensitive" magnetic resonance imaging (MRI) to localize structural disintegration in the LC and its association with nonmotor dysfunction in PD. METHODS: A total of 42 patients with PD and 24 age-matched healthy volunteers underwent magnetization transfer weighted (MTw) MRI of the LC. The contrast-to-noise ratio of the MTw signal (CNRMTw ) was used as an index of structural LC integrity. We performed slicewise and voxelwise analyses to map spatial patterns of structural disintegration, complemented by principal component analysis (PCA). We also tested for correlations between regional CNRMTw and severity of nonmotor symptoms. RESULTS: Mean CNRMTw of the right LC was reduced in patients relative to controls. Voxelwise and slicewise analyses showed that the attenuation of CNRMTw was confined to the right mid-caudal LC and linked regional CNRMTw to nonmotor symptoms. CNRMTw attenuation in the left mid-caudal LC was associated with the orthostatic drop in systolic blood pressure, whereas CNRMTw attenuation in the caudal most portion of right LC correlated with apathy ratings. PCA identified a bilateral component that was more weakly expressed in patients. This component was characterized by a gradient in CNRMTw along the rostro-caudal and dorso-ventral axes of the nucleus. The individual expression score of this component reflected the overall severity of nonmotor symptoms. CONCLUSION: A spatially heterogeneous disintegration of LC in PD may determine the individual expression of specific nonmotor symptoms such as orthostatic dysregulation or apathy. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.

A checklist for assessing the methodological quality of concurrent tES-fMRI studies (ContES checklist): a consensus study and statement.

Low-intensity transcranial electrical stimulation (tES), including alternating or direct current stimulation, applies weak electrical stimulation to modulate the activity of brain circuits. Integration of tES with concurrent functional MRI (fMRI) allows for the mapping of neural activity during neuromodulation, supporting causal studies of both brain function and tES effects. Methodological aspects of tES-fMRI studies underpin the results, and reporting them in appropriate detail is required for reproducibility and interpretability. Despite the growing number of published reports, there are no consensus-based checklists for disclosing methodological details of concurrent tES-fMRI studies. The objective of this work was to develop a consensus-based checklist of reporting standards for concurrent tES-fMRI studies to support methodological rigor, transparency and reproducibility (ContES checklist). A two-phase Delphi consensus process was conducted by a steering committee (SC) of 13 members and 49 expert panelists through the International Network of the tES-fMRI Consortium. The process began with a circulation of a preliminary checklist of essential items and additional recommendations, developed by the SC on the basis of a systematic review of 57 concurrent tES-fMRI studies. Contributors were then invited to suggest revisions or additions to the initial checklist. After the revision phase, contributors rated the importance of the 17 essential items and 42 additional recommendations in the final checklist. The state of methodological transparency within the 57 reviewed concurrent tES-fMRI studies was then assessed by using the checklist. Experts refined the checklist through the revision and rating phases, leading to a checklist with three categories of essential items and additional recommendations: (i) technological factors, (ii) safety and noise tests and (iii) methodological factors. The level of reporting of checklist items varied among the 57 concurrent tES-fMRI papers, ranging from 24% to 76%. On average, 53% of checklist items were reported in a given article. In conclusion, use of the ContES checklist is expected to enhance the methodological reporting quality of future concurrent tES-fMRI studies and increase methodological transparency and reproducibility.

Glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with differences in uncinate fasciculus microstructure.

BACKGROUND: Evidence suggests that fronto-limbic brain regions and connecting white matter fibre tracts in the left hemisphere are more sensitive to glucocorticoids than in the right hemisphere. It is unknown whether treatment with glucocorticoids in childhood is associated with microstructural differences of the uncinate fasciculus and cingulum bundle, which connect fronto-limbic brain regions. Here, we tested the hypothesis that prior glucocorticoid treatment would be associated with differences in fractional anisotropy (FA) of the left relative to right uncinate fasciculus and cingulum bundle. METHODS: We performed diffusion-weighted imaging in 28 children and adolescents aged 7-16 years previously treated with glucocorticoids for nephrotic syndrome or rheumatic disease and 28 healthy controls. RESULTS: Patients displayed significantly different asymmetry in the microstructure of uncinate fasciculus with higher left but similar right uncinate fasciculus FA and axial diffusivity compared to controls. No apparent differences were observed for the cingulum. Notably, higher cumulative glucocorticoid doses were significantly associated with higher uncinate fasciculus FA and axial diffusivity bilaterally. CONCLUSIONS: Our findings indicate that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in the microstructure of the uncinate fasciculi, and that higher cumulative glucocorticoid doses have a proportional impact on the microstructure. IMPACT: It is unknown if treatment with glucocorticoids in childhood have long-term effects on fronto-limbic white matter microstructure. The study examined if children and adolescents previously treated with glucocorticoids for nephrotic syndrome or rheumatic disorder differed in fronto-limbic white matter microstructure compared to healthy controls. The nephrotic and rheumatic patients had higher left but similar right uncinate fasciculus FA and axial diffusivity. Higher bilateral uncinate fasciculus FA and axial diffusivity was associated with higher cumulative glucocorticoid doses. We revealed new evidence suggesting that previous glucocorticoid treatment for non-cerebral diseases in children and adolescents is associated with long-term changes in uncinate fasciculi microstructure.

Mapping cortico-subcortical sensitivity to 4 Hz amplitude modulation depth in human auditory system with functional MRI.

Temporal modulations in the envelope of acoustic waveforms at rates around 4 Hz constitute a strong acoustic cue in speech and other natural sounds. It is often assumed that the ascending auditory pathway is increasingly sensitive to slow amplitude modulation (AM), but sensitivity to AM is typically considered separately for individual stages of the auditory system. Here, we used blood oxygen level dependent (BOLD) fMRI in twenty human subjects (10 male) to measure sensitivity of regional neural activity in the auditory system to 4 Hz temporal modulations. Participants were exposed to AM noise stimuli varying parametrically in modulation depth to characterize modulation-depth effects on BOLD responses. A Bayesian hierarchical modeling approach was used to model potentially nonlinear relations between AM depth and group-level BOLD responses in auditory regions of interest (ROIs). Sound stimulation activated the auditory brainstem and cortex structures in single subjects. BOLD responses to noise exposure in core and belt auditory cortices scaled positively with modulation depth. This finding was corroborated by whole-brain cluster-level inference. Sensitivity to AM depth variations was particularly pronounced in the Heschl's gyrus but also found in higher-order auditory cortical regions. None of the sound-responsive subcortical auditory structures showed a BOLD response profile that reflected the parametric variation in AM depth. The results are compatible with the notion that early auditory cortical regions play a key role in processing low-rate modulation content of sounds in the human auditory system.