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Human brain morphology undergoes complex changes over the lifespan. Despite recent progress in tracking brain development via normative models, current knowledge of underlying biological mechanisms is highly limited. We demonstrate that human cortical thickness development and aging trajectories unfold along patterns of molecular and cellular brain organization, traceable from population-level to individual developmental trajectories. During childhood and adolescence, cortex-wide spatial distributions of dopaminergic receptors, inhibitory neurons, glial cell populations, and brain-metabolic features explain up to 50% of the variance associated with a lifespan model of regional cortical thickness trajectories. In contrast, modeled cortical thickness change patterns during adulthood are best explained by cholinergic and glutamatergic neurotransmitter receptor and transporter distributions. These relationships are supported by developmental gene expression trajectories and translate to individual longitudinal data from over 8000 adolescents, explaining up to 59% of developmental change at cohort- and 18% at single-subject level. Integrating neurobiological brain atlases with normative modeling and population neuroimaging provides a biologically meaningful path to understand brain development and aging in living humans., (© 2024. The Author(s).)

While the analysis of gait and balance can be an important indicator of age- or disease-related changes, it remains unclear if repeated performance of gait and balance tests in healthy adults leads to habituation effects, if short-term gait and balance training can improve gait and balance performance, and whether the placement of wearable sensors influences the measurement accuracy. Healthy adults were assessed before and after performing weekly gait and balance tests over three weeks by using a force plate, motion capturing system and smartphone. The intervention group (n = 25) additionally received a home-based gait and balance training plan. Another sample of healthy adults (n = 32) was assessed once to analyze the impact of sensor placement (lower back vs. lower abdomen) on gait and balance analysis. Both the control and intervention group exhibited improvements in gait/stance. However, the trends over time were similar for both groups, suggesting that targeted training and repeated task performance equally contributed to the improvement of the measured variables. Since no significant differences were found in sensor placement, we suggest that a smartphone used as a wearable sensor could be worn both on the lower abdomen and the lower back in gait and balance analyses.

Robot-assisted imaging-guided sentinel lymph node biopsy is a novel technique that has not been widely investigated in testicular germ cell tumor (GCT). Current staging strategies have poor accuracy for prediction of occult metastatic disease in clinical stage I GCT. Feasibility studies have used 99m Tc-nanocolloid staining during laparoscopic procedures. The RAISN trial is investigating robot-assisted lymph node resection guided by indocyanine green fluorescence imaging. This new diagnostic approach is potentially more precise and easier to apply, and is widely available. Confirmation of its utility could change the management of newly diagnosed GCT by reducing overtreatment and treatment-related toxicity., (© 2024 The Author(s).)

In this study, we aimed to compare imaging-based features of brain function, measured by resting-state fMRI (rsfMRI), with individual characteristics such as age, gender, and total intracranial volume to predict behavioral measures. We developed a machine learning framework based on rsfMRI features in a dataset of 20,000 healthy individuals from the UK Biobank, focusing on temporal complexity and functional connectivity measures. Our analysis across four behavioral phenotypes revealed that both temporal complexity and functional connectivity measures provide comparable predictive performance. However, individual characteristics consistently outperformed rsfMRI features in predictive accuracy, particularly in analyses involving smaller sample sizes. Integrating rsfMRI features with demographic data sometimes enhanced predictive outcomes. The efficacy of different predictive modeling techniques and the choice of brain parcellation atlas were also examined, showing no significant influence on the results. To summarize, while individual characteristics are superior to rsfMRI in predicting behavioral phenotypes, rsfMRI still conveys additional predictive value in the context of machine learning, such as investigating the role of specific brain regions in behavioral phenotypes., (© 2024. The Author(s).)

The balance of excitation and inhibition is a key functional property of cortical microcircuits which changes through the lifespan. Adolescence is considered a crucial period for the maturation of excitation-inhibition balance. This has been primarily observed in animal studies, yet human in vivo evidence on adolescent maturation of the excitation-inhibition balance at the individual level is limited. Here, we developed an individualized in vivo marker of regional excitation-inhibition balance in human adolescents, estimated using large-scale simulations of biophysical network models fitted to resting-state functional magnetic resonance imaging data from two independent cross-sectional (N = 752) and longitudinal (N = 149) cohorts. We found a widespread relative increase of inhibition in association cortices paralleled by a relative age-related increase of excitation, or lack of change, in sensorimotor areas across both datasets. This developmental pattern co-aligned with multiscale markers of sensorimotor-association differentiation. The spatial pattern of excitation-inhibition development in adolescence was robust to inter-individual variability of structural connectomes and modeling configurations. Notably, we found that alternative simulation-based markers of excitation-inhibition balance show a variable sensitivity to maturational change. Taken together, our study highlights an increase of inhibition during adolescence in association areas using cross sectional and longitudinal data, and provides a robust computational framework to estimate microcircuit maturation in vivo at the individual level., Competing Interests: Disclosures Dr Banaschewski served in an advisory or consultancy role for eye level, Infectopharm, Medice, Neurim Pharmaceuticals, Oberberg GmbH and Takeda. He received conference support or speaker’s fee by Janssen, Medice and Takeda. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. Dr Barker has received honoraria from General Electric Healthcare for teaching on scanner programming courses. Dr Poustka served in an advisory or consultancy role for Roche and Viforpharm and received speaker’s fees from Shire. She received royalties from Hogrefe, Kohlhammer and Schattauer. The present work is unrelated to the above grants and relationships. The other authors report no biomedical financial interests or potential conflicts of interest.

Introduction: Dopaminergic, opiod and endocannabinoid neurotransmission are thought to play an important role in the neurobiology of acute exercise and, in particular, in mediating positive affective responses and reward processes. Recent evidence indicates that changes in fractional amplitude of low-frequency fluctuations (zfALFF) in resting-state functional MRI (rs-fMRI) may reflect changes in specific neurotransmitter systems as tested by means of spatial correlation analyses., Methods: Here, we investigated this relationship at different exercise intensities in twenty young healthy trained athletes performing low-intensity (LIIE), high-intensity (HIIE) interval exercises, and a control condition on three separate days. Positive And Negative Affect Schedule (PANAS) scores and rs-fMRI were acquired before and after each of the three experimental conditions. Respective zfALFF changes were analyzed using repeated measures ANOVAs. We examined the spatial correspondence of changes in zfALFF before and after training with the available neurotransmitter maps across all voxels and additionally, hypothesis-driven, for neurotransmitter maps implicated in the neurobiology of exercise (dopaminergic, opiodic and endocannabinoid) in specific brain networks associated with "reward" and "emotion.", Results: Elevated PANAS Positive Affect was observed after LIIE and HIIE but not after the control condition. HIIE compared to the control condition resulted in differential zfALFF decreases in precuneus, temporo-occipital, midcingulate and frontal regions, thalamus, and cerebellum, whereas differential zfALFF increases were identified in hypothalamus, pituitary, and periaqueductal gray. The spatial alteration patterns in zfALFF during HIIE were positively associated with dopaminergic and μ-opioidergic receptor distributions within the 'reward' network., Discussion: These findings provide new insight into the neurobiology of exercise supporting the importance of reward-related neurotransmission at least during high-intensity physical activity., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Boecker, Daamen, Maurer, Bodensohn, Werkhausen, Lohaus, Manunzio, Manunzio, Radbruch, Attenberger, Dukart and Upadhyay.)

Importance: Despite decades of neuroimaging studies reporting brain structural and functional alterations in depression, discrepancies in findings across studies and limited convergence across meta-analyses have raised questions about the consistency and robustness of the observed brain phenotypes., Objective: To investigate the associations between 6 operational criteria of lifetime exposure to depression and functional and structural neuroimaging measures., Design, Setting, and Participants: This cross-sectional study analyzed data from a UK Biobank cohort of individuals aged 45 to 80 years who were enrolled between January 1, 2014, and December 31, 2018. Participants included individuals with a lifetime exposure to depression and matched healthy controls without indications of psychosis, mental illness, behavior disorder, and disease of the nervous system. Six operational criteria of lifetime exposure to depression were evaluated: help seeking for depression; self-reported depression; antidepressant use; depression definition by Smith et al; hospital International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnosis codes F32 and F33; and Composite International Diagnostic Interview Short Form score. Six increasingly restrictive depression definitions and groups were defined based on the 6 depression criteria, ranging from meeting only 1 criterion to meeting all 6 criteria. Data were analyzed between January and October 2022., Main Outcomes and Measures: Functional measures were calculated using voxel-wise fractional amplitude of low-frequency fluctuation (fALFF), global correlation (GCOR), and local correlation (LCOR). Structural measures were calculated using gray matter volume (GMV)., Results: The study included 20 484 individuals with lifetime depression (12 645 females [61.7%]; mean [SD] age, 63.91 [7.60] years) and 25 462 healthy controls (14 078 males [55.3%]; mean [SD] age, 65.05 [7.8] years). Across all depression criteria, individuals with lifetime depression displayed regionally consistent decreases in fALFF, LCOR, and GCOR (Cohen d range, -0.53 [95% CI, -0.88 to -0.15] to -0.04 [95% CI, -0.07 to -0.01]) but not in GMV (Cohen d range, -0.47 [95 % CI, -0.75 to -0.12] to 0.26 [95% CI, 0.15-0.37]). Hospital ICD-10 diagnosis codes F32 and F33 (median [IQR] difference in effect sizes, -0.14 [-0.17 to -0.11]) and antidepressant use (median [IQR] difference in effect sizes, -0.12 [-0.16 to -0.10]) were criteria associated with the most pronounced alterations., Conclusions and Relevance: Results of this cross-sectional study indicate that lifetime exposure to depression was associated with robust functional changes, with a more restrictive depression definition revealing more pronounced alterations. Different inclusion criteria for depression may be associated with the substantial variation in imaging findings reported in the literature.

Introduction: Duchenne muscular dystrophy (DMD) is a genetic muscle disorder that manifests during early childhood and is ultimately fatal. Recently approved treatments targeting the genetic cause of DMD are limited to specific subpopulations of patients, highlighting the need for therapies with wider applications. Pharmacologic inhibition of myostatin, an endogenous inhibitor of muscle growth produced almost exclusively in skeletal muscle, has been shown to increase muscle mass in several species, including humans. Taldefgrobep alfa is an anti-myostatin recombinant protein engineered to bind to and block myostatin signaling. Preclinical studies of taldefgrobep alfa demonstrated significant decreases in myostatin and increased lower limb volume in three animal species, including dystrophic mice., Methods: This manuscript reports the cumulative data from three separate clinical trials of taldefgrobep alfa in DMD: a phase 1 study in healthy adult volunteers (NCT02145234), and two randomized, double-blind, placebo-controlled studies in ambulatory boys with DMD-a phase 1b/2 trial assessing safety (NCT02515669) and a phase 2/3 trial including the North Star Ambulatory Assessment (NSAA) as the primary endpoint (NCT03039686)., Results: In healthy adult volunteers, taldefgrobep alfa was generally well tolerated and resulted in a significant increase in thigh muscle volume. Treatment with taldefgrobep alfa was associated with robust dose-dependent suppression of free myostatin. In the phase 1b/2 trial, myostatin suppression was associated with a positive effect on lean body mass, though effects on muscle mass were modest. The phase 2/3 trial found that the effects of treatment did not meet the primary endpoint pre-specified futility analysis threshold (change from baseline of ≥ 1.5 points on the NSAA total score)., Conclusions: The futility analysis demonstrated that taldefgrobep alfa did not result in functional change for boys with DMD. The program was subsequently terminated in 2019. Overall, there were no safety concerns, and no patients were withdrawn from treatment as a result of treatment-related adverse events or serious adverse events., Trial Registration: NCT02145234, NCT02515669, NCT03039686., (© 2024. The Author(s).)

Background: Aside to clinical changes, behavioral variant frontotemporal dementia (bvFTD) is characterized by progressive structural and functional alterations in frontal and temporal regions. We examined if there is a selective vulnerability of specific neurotransmitter systems in bvFTD by evaluating the link between disease-related functional alterations and the spatial distribution of specific neurotransmitter systems and their underlying gene expression levels., Methods: Maps of fractional amplitude of low-frequency fluctuations (fALFF) were derived as a measure of local activity from resting-state functional magnetic resonance imaging for 52 bvFTD patients (mean age = 61.5 ± 10.0 years; 14 females) and 22 healthy controls (HC) (mean age = 63.6 ± 11.9 years; 13 females). We tested if alterations of fALFF in patients co-localize with the non-pathological distribution of specific neurotransmitter systems and their coding mRNA gene expression. Furthermore, we evaluated if the strength of co-localization is associated with the observed clinical symptoms., Results: Patients displayed significantly reduced fALFF in frontotemporal and frontoparietal regions. These alterations co-localized with the distribution of serotonin (5-HT1b and 5-HT2a) and γ-aminobutyric acid type A (GABAa) receptors, the norepinephrine transporter (NET), and their encoding mRNA gene expression. The strength of co-localization with NET was associated with cognitive symptoms and disease severity of bvFTD., Conclusions: Local brain functional activity reductions in bvFTD followed the distribution of specific neurotransmitter systems indicating a selective vulnerability. These findings provide novel insight into the disease mechanisms underlying functional alterations. Our data-driven method opens the road to generate new hypotheses for pharmacological interventions in neurodegenerative diseases even beyond bvFTD., Funding: This study has been supported by the German Consortium for Frontotemporal Lobar Degeneration, funded by the German Federal Ministry of Education and Research (BMBF; grant no. FKZ01GI1007A)., Competing Interests: LH, SE, KM, LS, KF, KF, JK, JP, MS No competing interests declared, HB received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Life Molecular Imaging and Novartis/AAA. The author has no other competing interests to declare, MS has received consulting fees from, and currently act as a consultant for Aviado Bio, Prevail, Servier, Reata and Orphazyme. They have received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from GenOrph. The author has no other competing interests to declare, JW has received consulting fees from Boehringer-Ingelheim, F. Hoffmann-La Roche, Biogen, Immungenetics, Roboscreen and Abbott. They currently act as a consultant for Boehringer-Ingelheim, F. Hoffmann-La Roche, Biogen and Immungenetics, and hold a Leadership or fiduciary role at CSF Society, AGNP and DGLN. The author has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Janssen, MSD SHARP & DOHME, Amgen, Roche Pharma, Actelion Pharmaceutical, Guangzhou Glorylen Medicial Technology Co. (China), Bejing Yibai Science and Technology Ltd. The author has been issued the following patents; EP2095128B1 and EP3105589A1. The author has no other competing interests to declare, JD has received a speaker fee from Jansen and Roche. The author has no other competing interests to declare, MO has received grants from BMBF - FTLD consortium, moodmarker, ALS association and EU - MIRIADE. The author has received consulting fees from, and currently acts as a consultant for, BIOGEN, Axon and Roche. The author has been issued a patent for Foundation state Baden-Wuerttemberg, Beta Syn as Biomarker for neurodegenerative diseases. The author holds an unpaid leadership or fiduciary role at the German Society for CSF diagnostics and neurochemistry and the Society for CSF diagnostics and neurochemistry, and as a speaker at the FTLD consortium. The author is co-inventor of a patent application (PCT/EP2020/072559) for using beta-synuclein measurement in blood.The author has no other competing interests to declare, JD former employee of and current consultant for F.Hoffmann-La Roche, (© 2024, Hahn et al.)

While animal models indicate altered brain dopaminergic neurotransmission after premature birth, corresponding evidence in humans is scarce due to missing molecular imaging studies. To overcome this limitation, we studied dopaminergic neurotransmission changes in human prematurity indirectly by evaluating the spatial co-localization of regional alterations in blood oxygenation fluctuations with the distribution of adult dopaminergic neurotransmission. The study cohort comprised 99 very premature-born (<32 weeks of gestation and/or birth weight below 1500 g) and 107 full-term born young adults, being assessed by resting-state functional MRI (rs-fMRI) and IQ testing. Normative molecular imaging dopamine neurotransmission maps were derived from independent healthy control groups. We computed the co-localization of local (rs-fMRI) activity alterations in premature-born adults with respect to term-born individuals to different measures of dopaminergic neurotransmission. We performed selectivity analyses regarding other neuromodulatory systems and MRI measures. In addition, we tested if the strength of the co-localization is related to perinatal measures and IQ. We found selectively altered co-localization of rs-fMRI activity in the premature-born cohort with dopamine-2/3-receptor availability in premature-born adults. Alterations were specific for the dopaminergic system but not for the used MRI measure. The strength of the co-localization was negatively correlated with IQ. In line with animal studies, our findings support the notion of altered dopaminergic neurotransmission in prematurity which is associated with cognitive performance., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R 2 varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants.

Structural grey and white matter changes precede the manifestation of clinical signs of Huntington's disease by many years. Conversion to clinically manifest disease therefore likely reflects not merely atrophy but a more widespread breakdown of brain function. Here, we investigated the structure-function relationship close to and after clinical onset, in important regional brain hubs, particularly caudate nucleus and putamen, which are central to maintaining normal motor behaviour. In two independent cohorts of patients with premanifest Huntington's disease close to onset and very early manifest Huntington's disease (total n = 84; n = 88 matched controls), we used structural and resting state functional MRI. We show that measures of functional activity and local synchronicity within cortical and subcortical regions remain normal in the premanifest Huntington's disease phase despite clear evidence of brain atrophy. In manifest Huntington's disease, homeostasis of synchronicity was disrupted in subcortical hub regions such as caudate nucleus and putamen, but also in cortical hub regions, for instance the parietal lobe. Cross-modal spatial correlations of functional MRI data with receptor/neurotransmitter distribution maps showed that Huntington's disease-specific alterations co-localize with dopamine receptors D1 and D2, as well as dopamine and serotonin transporters. Caudate nucleus synchronicity significantly improved models predicting the severity of the motor phenotype or predicting the classification into premanifest Huntington's disease or motor manifest Huntington's disease. Our data suggest that the functional integrity of the dopamine receptor-rich caudate nucleus is key to maintaining network function. The loss of caudate nucleus functional integrity affects network function to a degree that causes a clinical phenotype. These insights into what happens in Huntington's disease could serve as a model for what might be a more general relationship between brain structure and function in neurodegenerative diseases in which other brain regions are vulnerable., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Chemoarchitecture, the heterogeneous distribution of neurotransmitter transporter and receptor molecules, is a relevant component of structure-function relationships in the human brain. Here, we studied the organization of the receptome, a measure of interareal chemoarchitectural similarity, derived from positron-emission tomography imaging studies of 19 different neurotransmitter transporters and receptors. Nonlinear dimensionality reduction revealed three main spatial gradients of cortical chemoarchitectural similarity - a centro-temporal gradient, an occipito-frontal gradient, and a temporo-occipital gradient. In subcortical nuclei, chemoarchitectural similarity distinguished functional communities and delineated a striato-thalamic axis. Overall, the cortical receptome shared key organizational traits with functional and structural brain anatomy, with node-level correspondence to functional, microstructural, and diffusion MRI-based measures decreasing along a primary-to-transmodal axis. Relative to primary and paralimbic regions, unimodal and heteromodal regions showed higher receptomic diversification, possibly supporting functional flexibility., Competing Interests: BH, JH, BB, SE, JD, BM, SV No competing interests declared, (© 2023, Hänisch et al.)

Primary progressive aphasias (PPAs) are a group of neurodegenerative diseases mainly characterized by language impairment, and with variably presence of dysexecutive syndrome, behavioural disturbances and parkinsonism. Detailed knowledge of neurotransmitters impairment and its association with clinical features hold the potential to develop new tailored therapeutic approaches. In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of magnetic resonance imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 103 PPA patients and 80 age-matched healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in PPA patients (relative to HC) are correlated with specific neurotransmitter systems. As compared to HC, voxel-based brain changes in PPA were significantly associated with spatial distribution of serotonin, dopamine, and glutamatergic pathways (p < .05, False Discovery Rate corrected-corrected). Disease severity was negatively correlated with the strength of GMV colocalization of D1 receptors (p = .035) and serotonin transporter (p = .020). Moreover, we observed a significant negative correlation between positive behavioural symptoms, as measured with Frontal Behavioural Inventory, and GMV colocalization of D1 receptors (p = .007) and serotonin transporter (p < .001). This pilot study suggests that JuSpace is a helpful tool to indirectly assess neurotransmitter deficits in neurodegenerative dementias and may provide novel insight into disease mechanisms and associated clinical features., (© 2023 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Neurotransmitters deficits in Frontotemporal Dementia (FTD) are still poorly understood. Better knowledge of neurotransmitters impairment, especially in prodromal disease stages, might tailor symptomatic treatment approaches., Methods: In the present study, we applied JuSpace toolbox, which allowed for cross-modal correlation of Magnetic Resonance Imaging (MRI)-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, GABAergic and glutamatergic neurotransmission. We included 392 mutation carriers (157 GRN, 164 C9orf72, 71 MAPT), together with 276 non-carrier cognitively healthy controls (HC). We tested if the spatial patterns of grey matter volume (GMV) alterations in mutation carriers (relative to HC) are correlated with specific neurotransmitter systems in prodromal (CDR® plus NACC FTLD = 0.5) and in symptomatic (CDR® plus NACC FTLD≥1) FTD., Results: In prodromal stages of C9orf72 disease, voxel-based brain changes were significantly associated with spatial distribution of dopamine and acetylcholine pathways; in prodromal MAPT disease with dopamine and serotonin pathways, while in prodromal GRN disease no significant findings were reported (p < 0.05, Family Wise Error corrected). In symptomatic FTD, a widespread involvement of dopamine, serotonin, glutamate and acetylcholine pathways across all genetic subtypes was found. Social cognition scores, loss of empathy and poor response to emotional cues were found to correlate with the strength of GMV colocalization of dopamine and serotonin pathways (all p < 0.01)., Conclusions: This study, indirectly assessing neurotransmitter deficits in monogenic FTD, provides novel insight into disease mechanisms and might suggest potential therapeutic targets to counteract disease-related symptoms., (Crown Copyright © 2023. Published by Elsevier Inc. All rights reserved.)

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry., (© 2023. The Author(s).)

Regional homogeneity (ReHo) is a measure of local functional brain connectivity that has been reported to be altered in a wide range of neuropsychiatric disorders. Computed from brain resting-state functional MRI time series, ReHo is also sensitive to fluctuations in cerebral blood flow (CBF) that in turn may be influenced by cerebrovascular health. We accessed cerebrovascular health with Framingham cardiovascular risk score (FCVRS). We hypothesize that ReHo signal may be influenced by regional CBF; and that these associations can be summarized as FCVRS→CBF→ReHo. We used three independent samples to test this hypothesis. A test-retest sample of N = 30 healthy volunteers was used for test-retest evaluation of CBF effects on ReHo. Amish Connectome Project (ACP) sample (N = 204, healthy individuals) was used to evaluate association between FCVRS and ReHo and testing if the association diminishes given CBF. The UKBB sample (N = 6,285, healthy participants) was used to replicate the effects of FCVRS on ReHo. We observed strong CBF→ReHo links (p<2.5 × 10 -3 ) using a three-point longitudinal sample. In ACP sample, marginal and partial correlations analyses demonstrated that both CBF and FCVRS were significantly correlated with the whole-brain average (p<10 -6 ) and regional ReHo values, with the strongest correlations observed in frontal, parietal, and temporal areas. Yet, the association between ReHo and FCVRS became insignificant once the effect of CBF was accounted for. In contrast, CBF→ReHo remained significantly linked after adjusting for FCVRS and demographic covariates (p<10 -6 ). Analysis in N = 6,285 replicated the FCVRS→ReHo effect (p = 2.7 × 10 -27 ). In summary, ReHo alterations in health and neuropsychiatric illnesses may be partially driven by region-specific variability in CBF, which is, in turn, influenced by cardiovascular factors., Competing Interests: Competing Interests LEH has received or plans to receive research funding or consulting fees on research projects from Mitsubishi, Your Energy Systems LLC, Neuralstem, Taisho, Heptares, Pfizer, Luye Pharma, Sound Pharma, Takeda, and Regeneron. None was involved in the design, analysis or outcomes of the study. NJ and PT received a research grant from Biogen, Inc., for research unrelated to this project. All other authors declare no conflicts of interest., (Published by Elsevier Inc.)

There is growing evidence that pregnancy may have a significant impact on the maternal brain, causing changes in its structure. To investigate the patterns of these changes, we compared nulliparous women (n = 40) with a group of primiparous women (n = 40) and multiparous mothers (n = 37) within 1-4 days postpartum, using voxel-based and surface-based morphometry (SBM). Compared with the nulliparous women, the young mothers showed decreases in gray matter volume in the bilateral hippocampus/amygdala, the orbitofrontal/subgenual prefrontal area, the right superior temporal gyrus and insula, and the cerebellum. These pregnancy-related changes in brain structure did not predict the quality of mother-infant attachment at either 3 or 12 weeks postpartum nor were they more pronounced among the multiparous women. SBM analyses showed significant cortical thinning especially in the frontal and parietal cortices, with the parietal cortical thinning likely potentiated by multiple pregnancies. We conclude that, compared with the brain of nulliparous women, the maternal brain shows widespread morphological changes shortly after childbirth. Also, the experience of pregnancy alone may not be the underlying cause of the adaptations for mothering. As regards the exact biological function of the changes in brain morphology, longitudinal research will be needed to draw any definitive conclusions., (© The Author(s) 2021. Published by Oxford University Press.)

Patients with schizophrenia frequently suffer from motor abnormalities, but underlying alterations in neuroarchitecture remain unclear. Here, we aimed to disentangle dyskinesia from parkinsonism in motor structures of patients with schizophrenia and to assess associated molecular architecture. We measured grey matter of motor regions and correlated volumetric estimates with dyskinesia and parkinsonism severity. Associations with molecular architecture were identified by cross-modal spatial correlations between ensuing maps of abnormality-related volume alterations and neurotransmitter maps from healthy populations. Both phenomena were linked to (specific) striatal and basal forebrain reductions as well as to D 1 receptor density. Dyskinesia also manifested in cerebellar decrease, while parkinsonism was associated with less motor cortex volume. The parkinsonism-related brain pattern was additionally associated with 5-HT 1A/2A and µ-opioid receptors distribution. Findings suggest the need to develop psychopharmacological compounds that display not only selectivity for receptor subtypes but also anatomical selectivity for alleviating dyskinesia without worsening parkinsonism and vice versa., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

There are currently no standard methods for evaluating gait and balance performance at home. Smartphones include acceleration sensors and may represent a promising and easily accessible tool for this purpose. We performed an interventional feasibility study and compared a smartphone-based approach with two standard gait analysis systems (force plate and motion capturing systems). Healthy adults ( n = 25, 44.1 ± 18.4 years) completed two laboratory evaluations before and after a three-week gait and balance training at home. There was an excellent agreement between all systems for stride time and cadence during normal, tandem and backward gait, whereas correlations for gait velocity were lower. Balance variables of both standard systems were moderately intercorrelated across all stance tasks, but only few correlated with the corresponding smartphone measures. Significant differences over time were found for several force plate and mocap system-obtained gait variables of normal, backward and tandem gait. Changes in balance variables over time were more heterogeneous and not significant for any system. The smartphone seems to be a suitable method to measure cadence and stride time of different gait, but not balance, tasks in healthy adults. Additional optimizations in data evaluation and processing may further improve the agreement between the analysis systems.

Background: Understanding the development of the neuronal circuitry underlying autism spectrum disorder (ASD) is critical to shed light into its etiology and for the development of treatment options. Resting state EEG provides a window into spontaneous local and long-range neuronal synchronization and has been investigated in many ASD studies, but results are inconsistent. Unbiased investigation in large and comprehensive samples focusing on replicability is needed., Methods: We quantified resting state EEG alpha peak metrics, power spectrum (PS, 2-32 Hz) and functional connectivity (FC) in 411 children, adolescents and adults (n = 212 ASD, n = 199 neurotypicals [NT], all with IQ > 75). We performed analyses in source-space using individual head models derived from the participants' MRIs. We tested for differences in mean and variance between the ASD and NT groups for both PS and FC using linear mixed effects models accounting for age, sex, IQ and site effects. Then, we used machine learning to assess whether a multivariate combination of EEG features could better separate ASD and NT participants. All analyses were embedded within a train-validation approach (70%-30% split)., Results: In the training dataset, we found an interaction between age and group for the reactivity to eye opening (p = .042 uncorrected), and a significant but weak multivariate ASD vs. NT classification performance for PS and FC (sensitivity 0.52-0.62, specificity 0.59-0.73). None of these findings replicated significantly in the validation dataset, although the effect size in the validation dataset overlapped with the prediction interval from the training dataset., Limitations: The statistical power to detect weak effects-of the magnitude of those found in the training dataset-in the validation dataset is small, and we cannot fully conclude on the reproducibility of the training dataset's effects., Conclusions: This suggests that PS and FC values in ASD and NT have a strong overlap, and that differences between both groups (in both mean and variance) have, at best, a small effect size. Larger studies would be needed to investigate and replicate such potential effects., (© 2022. The Author(s).)

Health-related data being collected by smartphones offer a promising complementary approach to in-clinic assessments. Despite recent contributions, the trade-off between privacy, optimization, stability and research-grade data quality is not well met by existing platforms. Here we introduce the JTrack platform as a secure, reliable and extendable open-source solution for remote monitoring in daily-life and digital-phenotyping. JTrack is an open-source (released under open-source Apache 2.0 licenses) platform for remote assessment of digital biomarkers (DB) in neurological, psychiatric and other indications. JTrack is developed and maintained to comply with security, privacy and the General Data Protection Regulation (GDPR) requirements. A wide range of anonymized measurements from motion-sensors, social and physical activities and geolocation information can be collected in either active or passive modes by using JTrack Android-based smartphone application. JTrack also provides an online study management dashboard to monitor data collection across studies. To facilitate scaling, reproducibility, data management and sharing we integrated DataLad as a data management infrastructure. Smartphone-based Digital Biomarker data may provide valuable insight into daily-life behaviour in health and disease. As illustrated using sample data, JTrack provides as an easy and reliable open-source solution for collection of such information., Competing Interests: JD is a former employee and received consultancy fees on another topic from F. Hoffmann-La Roche AG. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sahandi Far, Stolz, Fischer, Eickhoff and Dukart.)

Background: Digital biomarkers (DB), as captured using sensors embedded in modern smart devices, are a promising technology for home-based sign and symptom monitoring in Parkinson disease (PD)., Objective: Despite extensive application in recent studies, test-retest reliability and longitudinal stability of DB have not been well addressed in this context. We utilized the large-scale m-Power data set to establish the test-retest reliability and longitudinal stability of gait, balance, voice, and tapping tasks in an unsupervised and self-administered daily life setting in patients with PD and healthy controls (HC)., Methods: Intraclass correlation coefficients were computed to estimate the test-retest reliability of features that also differentiate between patients with PD and healthy volunteers. In addition, we tested for longitudinal stability of DB measures in PD and HC, as well as for their sensitivity to PD medication effects., Results: Among the features differing between PD and HC, only a few tapping and voice features had good to excellent test-retest reliabilities and medium to large effect sizes. All other features performed poorly in this respect. Only a few features were sensitive to medication effects. The longitudinal analyses revealed significant alterations over time across a variety of features and in particular for the tapping task., Conclusions: These results indicate the need for further development of more standardized, sensitive, and reliable DB for application in self-administered remote studies in patients with PD. Motivational, learning, and other confounders may cause variations in performance that need to be considered in DB longitudinal applications., (©Mehran Sahandi Far, Simon B Eickhoff, Maria Goni, Juergen Dukart. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 13.09.2021.)

Postpartum depression (PPD) affects approximately 1 in 10 women after childbirth. A thorough understanding of a preexisting vulnerability to PPD will likely aid the early detection and treatment of PPD. Using a within-sample association, the study examined whether the brain's structural and functional alterations predict the onset of depression. 157 euthymic postpartum women were subjected to a multimodal MRI scan within the first 6 days of childbirth and were followed up for 12 weeks. Based on a clinical interview 12 weeks postpartum, participants were classified as mentally healthy or having either PPD or adjustment disorder (AD). Voxel-based morphometry and resting-state functional connectivity comparisons were performed between the three groups. 13.4% of women in our study developed PPD (n = 21) and 12.1% (n = 19) adjustment disorder (AD). The risk factors for PPD were a psychiatric history and the experience and severity of baby blues and the history of premenstrual syndrome. Despite the different risk profiles, no differences between the PPD, AD and control group were apparent based on structural and functional neuroimaging data immediately after childbirth. At 12 weeks postpartum, a significant association was observed between Integrated Local Correlation (LCor) and the Edinburgh Postnatal Depression Score (EPDS). Our findings do not support the notion that the brain's structural and resting-state functional alterations, if present, can be used as an early biomarker of PPD or AD. However, effects may become apparent if continuous measures of symptom severity are chosen.

Dopamine (DA) mediated brain activity is intimately linked to reward-driven cerebral responses, while aberrant reward processing has been implicated in several psychiatric disorders. fMRI has been a valuable tool in understanding the mechanism by which DA modulators alter reward-driven responses and how they may exert their therapeutic effect. However, the potential effects of a pharmacological compound on aspects of neurovascular coupling may cloud the interpretability of the BOLD contrast. Here, we assess the effects of risperidone on reward driven BOLD signals produced by reward anticipation and outcome, while attempting to control for potential drug effects on regional cerebral blood flow (CBF) and cerebrovascular reactivity (CVR). Healthy male volunteers (n = 21) each received a single oral dose of either 0.5 mg, 2 mg of risperidone or placebo in a double-blind, placebo-controlled, randomised, three-period cross-over study design. Participants underwent fMRI scanning while performing the widely used Monetary Incentive Delay (MID) task to assess drug impact on reward function. Measures of CBF (Arterial Spin Labelling) and breath-hold challenge induced BOLD signal changes (as a proxy for CVR) were also acquired and included as covariates. Risperidone produced divergent, dose-dependent effects on separate phases of reward processing, even after controlling for potential nonneuronal influences on the BOLD signal. These data suggest the D2 antagonist risperidone has a wide-ranging influence on DA-mediated reward function independent of nonneuronal factors. We also illustrate that assessment of potential vascular confounds on the BOLD signal may be advantageous when investigating CNS drug action and advocate for the inclusion of these additional measures into future study designs., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Reduced activation of dopamine D 1 receptor signaling may be implicated in reward functioning as a potential driver of negative symptoms in schizophrenia. Phosphodiesterase 10A (PDE10A), an enzyme that is highly expressed in the striatum, modulates both dopamine D 2 - and D 1 -dependent signaling., Methods: We assessed whether augmentation of D 1 signaling by the PDE10 inhibitor RG7203 enhances imaging and behavioral markers of reward functions in patients with schizophrenia and negative symptoms. In a 3-period, double-blind, crossover study, we investigated the effects of RG7203 (5 mg and 15 mg doses) and placebo as adjunctive treatment to stable background antipsychotic treatment in patients with chronic schizophrenia with moderate levels of negative symptoms. Effects on reward functioning and reward-based effortful behavior were evaluated using the monetary incentive delay task during functional magnetic resonance imaging and the effort-cost-benefit and working memory reinforcement learning tasks., Results: Patients ( N  = 33; 30 male, mean age ± SD 36.6 ± 7.0 years; Positive and Negative Syndrome Scale negative symptom factor score 23.0 ± 3.5 at screening) were assessed at three study centers in the United States; 24 patients completed the study. RG7203 at 5 mg significantly increased reward expectation-related activity in the monetary incentive delay task, but in the context of significantly decreased overall activity across all task conditions., Conclusions: In contrast to our expectations, RG7203 significantly worsened reward-based effortful behavior and indices of reward learning. The results do not support the utility of RG7203 as adjunctive treatment for negative symptoms in patients with schizophrenia., (© 2021 The Authors.)

Recent studies have shown that drug-induced spatial alteration patterns in resting state functional activity as measured using magnetic resonance imaging (rsfMRI) are associated with the distribution of specific receptor systems targeted by respective compounds. Based on this approach, we introduce a toolbox (JuSpace) allowing for cross-modal correlation of MRI-based measures with nuclear imaging derived estimates covering various neurotransmitter systems including dopaminergic, serotonergic, noradrenergic, and GABAergic (gamma-aminobutric acid) neurotransmission. We apply JuSpace to two datasets covering Parkinson's disease patients (PD) and risperidone-induced changes in rsfMRI and cerebral blood flow (CBF). Consistently with the predominant neurodegeneration of dopaminergic and serotonergic system in PD, we find significant spatial associations between rsfMRI activity alterations in PD and dopaminergic (D2) and serotonergic systems (5-HT1b). Risperidone induced CBF alterations were correlated with its main targets in serotonergic and dopaminergic systems. JuSpace provides a biologically meaningful framework for linking neuroimaging to underlying neurotransmitter information., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Postpartum depression (PPD) and adjustment disorder (AD) affect up to 25% of women after childbirth. However, there are no accurate screening tools for either disorder to identify at-risk mothers and enable them to benefit from early intervention. Combinations of anamnestic, clinical, and remote assessments were evaluated for an early and accurate identification of PPD and AD. Two cohorts of mothers giving birth were included in the study (N = 308 and N = 193). At baseline, participants underwent a detailed sociodemographic-anamnestic and clinical interview. Remote assessments were collected over 12 weeks comprising mood and stress levels as well as depression and attachment scores. At 12 weeks postpartum, an experienced clinician assigned the participants to three distinct groups: women with PPD, women with AD, and healthy controls (HC). Combinations of these assessments were assessed for an early an accurate detection of PPD and AD in the first cohort and, after pre-registration, validated in a prospective second cohort. Combinations of postnatal depression, attachment (for AD) and mood scores at week 3 achieved balanced accuracies of 93 and 79% for differentiation of PPD and AD from HC in the validation cohort and balanced accuracies of 87 and 91% in the first cohort. Differentiation between AD and PPD, with a balanced accuracy of 73% was possible at week 6 based on mood levels only with a balanced accuracy of 73% in the validation cohort and a balanced accuracy of 76% in the first cohort. Combinations of in clinic and remote self-assessments allow for early and accurate detection of PPD and AD as early as three weeks postpartum, enabling early intervention to the benefit of both mothers and children.

Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses 1 . The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset 2-5 . Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.

The pharmacological modulation of functional connectivity in the brain may underlie therapeutic efficacy for several neurological and psychiatric disorders. Functional magnetic resonance imaging (fMRI) provides a noninvasive method of assessing this modulation, however, the indirect nature of the blood-oxygen level dependent signal restricts the discrimination of neural from physiological contributions. Here we followed two approaches to assess the validity of fMRI functional connectivity in developing drug biomarkers, using simultaneous electroencephalography (EEG)/fMRI in a placebo-controlled, three-way crossover design with ketamine and midazolam. First, we compared seven different preprocessing pipelines to determine their impact on the connectivity of common resting-state networks. Independent components analysis (ICA)-denoising resulted in stronger reductions in connectivity after ketamine, and weaker increases after midazolam, than pipelines employing physiological noise modelling or averaged signals from cerebrospinal fluid or white matter. This suggests that pipeline decisions should reflect a drug's unique noise structure, and if this is unknown then accepting possible signal loss when choosing extensive ICA denoising pipelines could engender more confidence in the remaining results. We then compared the temporal correlation structure of fMRI to that derived from two connectivity metrics of EEG, which provides a direct measure of neural activity. While electrophysiological estimates based on the power envelope were more closely aligned to BOLD signal connectivity than those based on phase consistency, no significant relationship between the change in electrophysiological and hemodynamic correlation structures was found, implying caution should be used when making cross-modal comparisons of pharmacologically-modulated functional connectivity., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Subanesthetic administration of ketamine is a pharmacological model to elicit positive and negative symptoms of psychosis in healthy volunteers. We used resting-state pharmacological functional MRI (rsPhfMRI) to identify cerebral networks affected by ketamine and compared them to the functional connectivity (FC) in schizophrenia. Ketamine can produce sedation and we contrasted its effects with the effects of the anxiolytic drug midazolam. Thirty healthy male volunteers (age = 19-37 years) underwent a randomized, three-way, cross-over study consisting of three imaging sessions, with 48 hr between sessions. A session consisted of a control period followed by infusion of placebo or ketamine or midazolam. The ENIGMA rsfMRI pipeline was used to derive two long-distance (seed-based and dual-regression) and one local (regional homogeneity, ReHo) FC measures. Ketamine induced significant reductions in the connectivity of the salience network (Cohen's d: 1.13 ± 0.28, p = 4.0 × 10 -3 ), auditory network (d: 0.67 ± 0.26, p = .04) and default mode network (DMN, d: 0.63 ± 0.26, p = .05). Midazolam significantly reduced connectivity in the DMN (d: 0.77 ± 0.27, p = .03). The effect sizes for ketamine for resting networks showed a positive correlation (r = .59, p = .07) with the effect sizes for schizophrenia-related deficits derived from ENIGMA's study of 261 patients and 327 controls. Effect sizes for midazolam were not correlated with the schizophrenia pattern (r = -.17, p = .65). The subtraction of ketamine and midazolam patterns showed a significant positive correlation with the pattern of schizophrenia deficits (r = .68, p = .03). RsPhfMRI reliably detected the shared and divergent pharmacological actions of ketamine and midazolam on cerebral networks. The pattern of disconnectivity produced by ketamine was positively correlated with the pattern of connectivity deficits observed in schizophrenia, suggesting a brain functional basis for previously poorly understood effects of the drug., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

There is an increasing interest in identifying non-invasive biomarkers of disease severity and prognosis in idiopathic Parkinson's disease (PD). Dopamine-transporter SPECT (DAT-SPECT), diffusion tensor imaging (DTI), and structural magnetic resonance imaging (sMRI) provide unique information about the brain's neurotransmitter and microstructural properties. In this study, we evaluate the relative and combined capability of these imaging modalities to predict symptom severity and clinical progression in de novo PD patients. To this end, we used MRI, SPECT, and clinical data of de novo drug-naïve PD patients ( n = 205, mean age 61 ± 10) and age-, sex-matched healthy controls ( n = 105, mean age 58 ± 12) acquired at baseline. Moreover, we employed clinical data acquired at 1 year follow-up for PD patients with or without L-Dopa treatment in order to predict the progression symptoms severity. Voxel-based group comparisons and covariance analyses were applied to characterize baseline disease-related alterations for DAT-SPECT, DTI, and sMRI. Cortical and subcortical alterations in de novo PD patients were found in all evaluated imaging modalities, in line with previously reported midbrain-striato-cortical network alterations. The combination of these imaging alterations was reliably linked to clinical severity and disease progression at 1 year follow-up in this patient population, providing evidence for the potential use of these modalities as imaging biomarkers for disease severity and prognosis that can be integrated into clinical trials.

The outpatient sector represents a growing share of health care. This review examines how patients choose their physician for continuous outpatient care and why they are willing to bypass the nearest physician. It was conducted according to the PRISMA extension for scoping reviews (PRISMA-ScR). Three databases (PubMed/Medline, ScienceDirect, and Ovid Medline) were searched, focusing on articles in which distance influenced the choice of physician. In all, 1,308 articles were accessed, and 17 selected for final review. First, we extracted methods for assessing distance traveled and bypassing. Second, we identified determinants that directly influence the traveled distance and transferred all into a conceptual framework. The center of this framework is the individual "willingness-to-go", which reflects the willingness of patients to accept additional distances. Our findings can support studies on patient mobility and physician choice, which are essential for examining both the distribution and use of medical services, as well as for adequate need related planning.

Despite their wide-spread use, only limited information is available on the comparative test-retest reliability of task-based functional and resting state magnetic resonance imaging measures of blood oxygen level dependence (tb-fMRI and rs-fMRI) and cerebral blood flow (CBF) using arterial spin labeling. This information is critical to designing properly powered longitudinal studies. Here we comprehensively quantified and compared the test-retest reliability and reproducibility performance of 8 commonly applied fMRI tasks, 6 rs-fMRI metrics and CBF in 30 healthy volunteers. We find large variability in test-retest reliability performance across the different tb-fMRI paradigms and rs-fMRI metrics, ranging from poor to excellent. A larger extent of activation in tb-fMRI is linked to higher between-subject reliability of the respective task suggesting that differences in the amount of activation may be used as a first reliability estimate of novel tb-fMRI paradigms. For rs-fMRI, a good reliability of local activity estimates is paralleled by poor performance of global connectivity metrics. Evaluated CBF measures provide in general a good to excellent test-reliability matching or surpassing the best performing tb-fMRI and rs-fMRI metrics. This comprehensive effort allows for direct comparisons of test-retest reliability between the evaluated MRI domains and measures to aid the design of future tb-fMRI, rs-fMRI and CBF studies., Competing Interests: SH, FS, CL, GG, NS SAS, AB and JD are current or former full-time employees of F. Hoffmann-La Roche, Basel, Switzerland. This does not alter our adherence to PLOS ONE policies on sharing data and materials.