Treatment Response Prediction in Major Depressive Disorder Using Multimodal MRI and Clinical Data: Secondary Analysis of a Randomized Clinical Trial.

OBJECTIVE: Response to antidepressant treatment in major depressive disorder varies substantially between individuals, which lengthens the process of finding effective treatment. The authors sought to determine whether a multimodal machine learning approach could predict early sertraline response in patients with major depressive disorder. They assessed the predictive contribution of MR neuroimaging and clinical assessments at baseline and after 1 week of treatment. METHODS: This was a preregistered secondary analysis of data from the Establishing Moderators and Biosignatures of Antidepressant Response in Clinical Care (EMBARC) study, a multisite double-blind, placebo-controlled randomized clinical trial that included 296 adult outpatients with unmedicated recurrent or chronic major depressive disorder. MR neuroimaging and clinical data were collected before and after 1 week of treatment. Performance in predicting response and remission, collected after 8 weeks, was quantified using balanced accuracy (bAcc) and area under the receiver operating characteristic curve (AUROC) scores. RESULTS: A total of 229 patients were included in the analyses (mean age, 38 years [SD=13]; 66% female). Internal cross-validation performance in predicting response to sertraline (bAcc=68% [SD=10], AUROC=0.73 [SD=0.03]) was significantly better than chance. External cross-validation on data from placebo nonresponders (bAcc=62%, AUROC=0.66) and placebo nonresponders who were switched to sertraline (bAcc=65%, AUROC=0.68) resulted in differences that suggest specificity for sertraline treatment compared with placebo treatment. Finally, multimodal models outperformed unimodal models. CONCLUSIONS: The study results confirm that early sertraline treatment response can be predicted; that the models are sertraline specific compared with placebo; that prediction benefits from integrating multimodal MRI data with clinical data; and that perfusion imaging contributes most to these predictions. Using this approach, a lean and effective protocol could individualize sertraline treatment planning to improve psychiatric care.

Multi-site benchmark classification of major depressive disorder using machine learning on cortical and subcortical measures.

Machine learning (ML) techniques have gained popularity in the neuroimaging field due to their potential for classifying neuropsychiatric disorders. However, the diagnostic predictive power of the existing algorithms has been limited by small sample sizes, lack of representativeness, data leakage, and/or overfitting. Here, we overcome these limitations with the largest multi-site sample size to date (N = 5365) to provide a generalizable ML classification benchmark of major depressive disorder (MDD) using shallow linear and non-linear models. Leveraging brain measures from standardized ENIGMA analysis pipelines in FreeSurfer, we were able to classify MDD versus healthy controls (HC) with a balanced accuracy of around 62%. But after harmonizing the data, e.g., using ComBat, the balanced accuracy dropped to approximately 52%. Accuracy results close to random chance levels were also observed in stratified groups according to age of onset, antidepressant use, number of episodes and sex. Future studies incorporating higher dimensional brain imaging/phenotype features, and/or using more advanced machine and deep learning methods may yield more encouraging prospects.

Modulation of functional networks related to the serotonin neurotransmitter system by citalopram: Evidence from a multimodal neuroimaging study.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) potentiate serotonergic neurotransmission by blocking the serotonin transporter (5-HTT), but the functional brain response to SSRIs involves neural circuits beyond regions with high 5-HTT expression. Currently, it is unclear whether and how changes in 5-HTT availability after SSRI administration modulate brain function of key serotoninergic circuits, including those characterized by high availability of the serotonin 1A receptor (5-HT1AR). AIM: We investigated the association between 5-HTT availability and 5-HTT- and 5-HT1AR-enriched functional connectivity (FC) after an acute citalopram challenge. METHODS: We analyzed multimodal data from a dose-response, placebo-controlled, double-blind study, in which 45 healthy women were randomized into three groups receiving placebo, a low (4 mg), or high (16 mg) oral dose of citalopram. Receptor-Enhanced Analysis of functional Connectivity by Targets was used to estimate 5-HTT- and 5-HT1AR-enriched FC from resting-state and task-based fMRI. 5-HTT availability was determined using [123I]FP-CIT single-photon emission computerized tomography. RESULTS: 5-HTT availability was negatively correlated with resting-state 5-HTT-enriched FC, and with task-dependent 5-HT1AR-enriched FC. Our exploratory analyses revealed lower 5-HT1AR-enriched FC in the low-dose group compared to the high-dose group at rest and the placebo group during the emotional face-matching task. CONCLUSIONS: Taken together, our findings provide evidence for differential links between 5-HTT availability and brain function within 5-HTT and 5-HT1AR pathways and in context- and dose-dependent manner. As such, they support a potential pivotal role of the 5-HT1AR in the effects of citalopram on the brain and add to its potential as a therapeutic avenue for mood and anxiety disturbances.

Neurometabolite changes in response to antidepressant medication: A systematic review of 1H-MRS findings.

Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and (es)ketamine are used to treat major depressive disorder (MDD). These different types of medication may involve common neural pathways related to glutamatergic and GABAergic neurotransmitter systems, both of which have been implicated in MDD pathology. We conducted a systematic review of pharmacological proton Magnetic Resonance Spectroscopy (1H-MRS) studies in healthy volunteers and individuals with MDD to explore the potential impact of these medications on glutamatergic and GABAergic systems. We searched PubMed, Web of Science and Embase and included randomized controlled trials or cohort studies, which assessed the effects of SSRIs, SNRIs, or (es)ketamine on glutamate, glutamine, Glx or GABA using single-voxel 1H-MRS or Magnetic Resonance Spectroscopic Imaging (MRSI). Additionally, studies were included when they used a field strength > 1.5 T, and when a comparison of metabolite levels between antidepressant treatment and placebo or baseline with post-medication metabolite levels was done. We excluded animal studies, duplicate publications, or articles with 1H-MRS data already described in another included article. Twenty-nine studies were included in this review. Fifteen studies investigated the effect of administration or treatment with SSRIs or SNRIs, and fourteen studies investigated the effect of (es)ketamine on glutamatergic and GABAergic metabolite levels. Studies on SSRIs and SNRIs were highly variable, generally underpowered, and yielded no consistent findings across brain regions or specific populations. Although studies on (es)ketamine were also highly variable, some demonstrated an increase in glutamate levels in the anterior cingulate cortex in a time-dependent manner after administration. Our findings highlight the need for standardized study and acquisition protocols. Additionally, measuring metabolites dynamically over time or combining 1H-MRS with whole brain functional imaging techniques could provide valuable insights into the effects of these medications on glutamate and GABAergic neurometabolism.

Multimodal multilayer network centrality relates to executive functioning.

Executive functioning (EF) is a higher order cognitive process that is thought to depend on a network organization facilitating integration across subnetworks, in the context of which the central role of the fronto-parietal network (FPN) has been described across imaging and neurophysiological modalities. However, the potentially complementary unimodal information on the relevance of the FPN for EF has not yet been integrated. We employ a multilayer framework to allow for integration of different modalities into one 'network of networks.' We used diffusion MRI, resting-state functional MRI, MEG, and neuropsychological data obtained from 33 healthy adults to construct modality-specific single-layer networks as well as a single multilayer network per participant. We computed single-layer and multilayer eigenvector centrality of the FPN as a measure of integration in this network and examined their associations with EF. We found that higher multilayer FPN centrality, but not single-layer FPN centrality, was related to better EF. We did not find a statistically significant change in explained variance in EF when using the multilayer approach as compared to the single-layer measures. Overall, our results show the importance of FPN integration for EF and underline the promise of the multilayer framework toward better understanding cognitive functioning.

A comparison of how deep brain stimulation in two targets with anti-compulsive efficacy modulates brain activity using fMRI in awake rats.

Deep brain stimulation (DBS) is an established neuromodulatory intervention against otherwise treatment-refractory obsessive-compulsive disorder (OCD). Several DBS targets, all of which are part of brain networks connecting basal ganglia and prefrontal cortex, alleviate OCD symptoms. Stimulation of these targets is thought to unfold its therapeutic effect by modulation of network activity through internal capsule (IC) connections. Research into DBS-induced network changes and the nature of IC-related effects of DBS in OCD is needed to further improve DBS. Here, we studied the effects of DBS at the ventral medial striatum (VMS) and IC on blood-oxygen level dependent (BOLD) responses in awake rats using functional magnetic resonance imaging (fMRI). BOLD-signal intensity was measured in five regions of interest (ROIs): medial and orbital prefrontal cortex, nucleus accumbens (NAc), IC area, and mediodorsal thalamus. In previous rodent studies, stimulation at both target locations resulted in a reduction of OCD-like behavior and activation of prefrontal cortical areas. Therefore, we hypothesized that stimulation at both targets would result in partially overlapping BOLD responses. Both differential and overlapping activity between VMS and IC stimulation was found. Stimulating the caudal part of the IC resulted in activation around the electrode, while stimulating the rostral part of the IC resulted in increased cross-correlations between the IC area, orbitofrontal cortex, and NAc. Stimulation of the dorsal part of the VMS resulted in increased activity in the IC area, suggesting this area is activated during both VMS and IC stimulation. This activation is also indicative of VMS-DBS impacting corticofugal fibers running through the medial caudate into the anterior IC, and both VMS and IC DBS might act on these fibers to induce OCD-reducing effects. These results show that rodent fMRI with simultaneous electrode stimulation is a promising approach to study the neural mechanisms of DBS. Comparing the effects of DBS in different target areas has the potential to improve our understanding of the neuromodulatory changes that take place across various networks and connections in the brain. Performing this research in animal disease models will lead to translational insights in the mechanisms underlying DBS, and can aid improvement and optimization of DBS in patient populations.

Brain Differences in Adolescents Living With Perinatally Acquired HIV Compared to Adoption Status Match Controls: A Cross-Sectional Study.

BACKGROUND AND OBJECTIVES: Despite effective combination antiretroviral therapy (cART), adolescents with perinatally acquired HIV (PHIV) exhibit cognitive impairment, of which structural changes could be the underlying pathophysiological mechanism. Prior MRI studies found lower brain volumes, more white matter (WM) hyperintensities (WMH) volume, lower WM integrity, and differences in cerebral blood flow (CBF). However, these findings may be confounded by adoption status, as the large portion PHIV adolescents have been adopted. Adoption has been associated with malnutrition and neglect which in turn may have affected brain development. We investigated the long-term effects of PHIV on the brain, while minimizing the confounding effect of adoption status. METHODS: We determined whole brain gray matter (GM) and WM volume with 3D T1-weighted scans; total WMH volume with fluid-attenuated inversion recovery (FLAIR); CBF in the following regions of interest (ROIs): WM, GM and subcortical GM with arterial spin labeling (ASL); and whole brain WM microstructural markers: fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), radial diffusivity (RD) with diffusion tensor imaging (DTI) in cART treated PHIV adolescents visiting our outpatient clinic in Amsterdam and controls matched for age, sex, ethnic origin, socio-economic status, and adoption status. We assessed differences in neuroimaging parameters between PHIV adolescents and controls using linear regression models adjusted for age and sex and applied multiple comparisons correction. RESULTS: 35 PHIV adolescents and 38 controls were included with a median age (years) of 14.9 (IQR: 10.7-18.5) and 15.6 (IQR:11.1-17.6), respectively with a similar rate of adoption. We found a lower overall FA (beta = -0.012; p<0.014, -2.4%), higher MD (beta = 0.014, p = 0.014, 1.3%) and higher RD (beta = 0.02, p = 0.014, 3.3%) in PHIV adolescents vs. adoption-matched controls, but no differences in AD. We found comparable GM, WM and WMH volume, and CBF in ROIs between PHIV adolescents and controls. We did not find an association between cognitive profiles and WM microstructural markers in PHIV adolescents. DISCUSSION: Irrespective of adoption status, PHIV adolescents exhibited subtle lower WM integrity. Our findings may point towards early-acquired WM microstructural alterations associated with HIV.

Effects of a single-dose methylphenidate challenge on resting-state functional connectivity in stimulant-treatment naive children and adults with ADHD.

Prior studies suggest that methylphenidate, the primary pharmacological treatment for attention-deficit/hyperactivity disorder (ADHD), alters functional brain connectivity. As the neurotransmitter systems targeted by methylphenidate undergo significant alterations throughout development, the effects of methylphenidate on functional connectivity may also be modulated by age. Therefore, we assessed the effects of a single methylphenidate challenge on brain network connectivity in stimulant-treatment naïve children and adults with ADHD. We obtained resting-state functional MRI from 50 boys (10-12 years of age) and 49 men (23-40 years of age) with ADHD (DSM IV, all subtypes), before and after an oral challenge with 0.5 mg/kg methylphenidate; and from 11 boys and 12 men as typically developing controls. Connectivity strength (CS), eigenvector centrality (EC), and betweenness centrality (BC) were calculated for the striatum, thalamus, dorsal anterior cingulate cortex (dACC), and prefrontal cortex (PFC). In line with our hypotheses, we found that methylphenidate decreased measures of connectivity and centrality in the striatum and thalamus in children with ADHD, but increased the same metrics in adults with ADHD. Surprisingly, we found no major effects of methylphenidate in the dACC and PFC in either children or adults. Interestingly, pre-methylphenidate, participants with ADHD showed aberrant connectivity and centrality compared to controls predominantly in frontal regions. Our findings demonstrate that methylphenidate's effects on connectivity of subcortical regions are age-dependent in stimulant-treatment naïve participants with ADHD, likely due to ongoing maturation of dopamine and noradrenaline systems. These findings highlight the importance for future studies to take a developmental perspective when studying the effects of methylphenidate treatment.

Targeting working memory to modify emotional reactivity in adult attention deficit hyperactivity disorder: a functional magnetic resonance imaging study.

Understanding the neural mechanisms of emotional reactivity in Attention-Deficit/Hyperactivity Disorder (ADHD) may help develop more effective treatments that target emotion dysregulation. In adult ADHD, emotion regulation problems cover a range of dimensions, including emotional reactivity (ER). One important process that could underlie an impaired ER in ADHD might be impaired working memory (WM) processing. We recently demonstrated that taxing WM prior to the exposure of emotionally salient stimuli reduced physiological and subjective reactivity to such cues in heavy drinkers, suggesting lasting effects of WM activation on ER. Here, we investigated neural mechanisms that could underlie the interaction between WM and ER in adult ADHD participants. We included 30 male ADHD participants and 30 matched controls. Participants performed a novel functional magnetic resonance imaging paradigm in which active WM-blocks were alternated with passive blocks of negative and neutral images. We demonstrated group-independent significant main effects of negative emotional images on amygdala activation, and WM-load on paracingulate gyrus and dorsolateral prefrontal cortex activation. Contrary to earlier reports in adolescent ADHD, no impairments were found in neural correlates of WM or ER. Moreover, taxing WM did not alter the neural correlates of ER in either ADHD or control participants. While we did find effects on the amygdala, paCG, and dlPFC activation, we did not find interactions between WM and ER, possibly due to the relatively unimpaired ADHD population and a well-matched control group. Whether targeting WM might be effective in participants with ADHD with severe ER impairments remains to be investigated.

Brain White Matter Microstructure as a Risk Factor for Cognitive Decline After Chemotherapy for Breast Cancer.

PURPOSE: Cognitive decline is frequently observed after chemotherapy. As chemotherapy is associated with changes in brain white matter microstructure, we investigated whether white matter microstructure before chemotherapy is a risk factor for cognitive decline after chemotherapy. METHODS: Neuropsychologic tests were administered before and 6 months (n = 49), 2 years (n = 32), and 3 years (n = 32) after chemotherapy in patients with breast cancer receiving anthracycline-based chemotherapy (BC + CT group), at matched intervals to patients with BC who did not receive systemic therapy (BC - CT group: n = 39, 23, and 19, respectively) and to no-cancer controls (NC group: n = 37, 29, and 28, respectively). Using multivariate normative comparison, we evaluated to what extent the cognitive profiles of patients deviated from those of controls. Fractional anisotropy (FA), derived from magnetic resonance diffusion tensor imaging, was used to measure white matter microstructure before treatment. FA was evaluated as a risk factor for cognitive decline, in addition to baseline age, fatigue, cognitive complaints, and premorbid intelligence quotient. We subsequently ran voxel-wise diffusion tensor imaging analyses to investigate white matter microstructure in specific nerve tracts. RESULTS: Low FA independently predicted cognitive decline early (6 months, P = .013) and late (3 years, P < .001) after chemotherapy. FA did not predict cognitive decline in the BC - CT and NC groups. Voxel-wise analysis indicated involvement of white matter tracts essential for cognitive functioning. CONCLUSION: Low FA may reflect low white matter reserve. This may be a risk factor for cognitive decline after chemotherapy for BC. If validated in future trials, identification of patients with low white matter reserve could improve patient care, for example, by facilitating targeted, early interventions or even by influencing choices of patients and doctors for receiving chemotherapy.

Animal studies in clinical MRI scanners: A custom setup for combined fMRI and deep-brain stimulation in awake rats.

BACKGROUND: In humans, functional magnetic resonance imaging (fMRI) cannot be used to its full potential to study the effects of deep-brain stimulation (DBS) on the brain due to safety reasons. Application of DBS in small animals is an alternative, but was hampered by technical limitations thus far. NEW METHOD: We present a novel setup that extends the range of available applications by studying animals in a clinical scanner. We used a 3 T-MRI scanner with a custom-designed receiver coil and a restrainer to measure brain activity in awake rats. DBS electrodes made of silver were used to minimize electromagnetic artifacts. Before scanning, rats were habituated to the restrainer. RESULTS: Using our novel setup, we observed minor DBS-electrode artifacts, which did not interfere with brain-activity measurements significantly. Movement artifacts were also minimal and were not further reduced by restrainer habituation. Bilateral DBS in the dorsal part of the ventral striatum (dVS) resulted in detectable increases in brain activity around the electrodes tips. COMPARISON WITH EXISTING METHODS: This novel setup offers a low-cost alternative to dedicated small-animal scanners. Moreover, it can be implemented in widely available clinical 3 T scanners. Although spatial and temporal resolution was lower than what is achieved in anesthetized rats in high-field small-animal scanners, we obtained scans in awake animals, thus, testing the effects of bilateral DBS of the dVS in a more physiological state. CONCLUSIONS: With this new technical setup, the neurobiological mechanism of action of DBS can be explored in awake, restrained rats in a clinical 3 T-MRI scanner.

Brain Correlates of Suicide Attempt in 18,925 Participants Across 18 International Cohorts.

BACKGROUND: Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior. METHODS: Here, we pooled data from 18 international cohorts with neuroimaging and clinical measurements in 18,925 participants (12,477 healthy control subjects and 6448 people with depression, of whom 694 had attempted suicide). We compared regional cortical thickness and surface area and measures of subcortical, lateral ventricular, and intracranial volumes between suicide attempters, clinical control subjects (nonattempters with depression), and healthy control subjects. RESULTS: We identified 25 regions of interest with statistically significant (false discovery rate < .05) differences between groups. Post hoc examinations identified neuroimaging markers associated with suicide attempt including smaller volumes of the left and right thalamus and the right pallidum and lower surface area of the left inferior parietal lobe. CONCLUSIONS: This study addresses the lack of replicability and consistency in several previously published neuroimaging studies of suicide attempt and further demonstrates the need for well-powered samples and collaborative efforts. Our results highlight the potential involvement of the thalamus, a structure viewed historically as a passive gateway in the brain, and the pallidum, a region linked to reward response and positive affect. Future functional and connectivity studies of suicidal behaviors may focus on understanding how these regions relate to the neurobiological mechanisms of suicide attempt risk.

Imaging of the dopamine system with focus on pharmacological MRI and neuromelanin imaging.

The dopamine system in the brain is involved in a variety of neurologic and psychiatric disorders, such as Parkinson's disease, attention-deficit/hyperactivity disorder and psychosis. Different aspects of the dopamine system can be visualized and measured with positron emission tomography (PET) and single photon emission computed tomography (SPECT), including dopamine receptors, dopamine transporters, and dopamine release. New developments in MR imaging also provide proxy measures of the dopamine system in the brain, offering alternatives with the advantages MR imaging, i.e. no radiation, lower costs, usually less invasive and time consuming. This review will give an overview of these developments with a focus on the most developed techniques: pharmacological MRI (phMRI) and neuromelanin sensitive MRI (NM-MRI). PhMRI is a collective term for functional MRI techniques that administer a pharmacological challenge to assess its effects on brain hemodynamics. By doing so, it indirectly assesses brain neurotransmitter function such as dopamine function. NM-MRI is an upcoming MRI technique that enables in vivo visualization and semi-quantification of neuromelanin in the substantia nigra. Neuromelanin is located in the cell bodies of dopaminergic neurons of the nigrostriatal pathway and can be used as a proxy measure for long term dopamine function or degeneration of dopaminergic neurons. Both techniques are still primarily used in clinical research, but there is promise for clinical application, in particular for NM-MRI in dopaminergic neurodegenerative diseases like Parkinson's disease.

ENIGMA-Sleep: Challenges, opportunities, and the road map.

Neuroimaging and genetics studies have advanced our understanding of the neurobiology of sleep and its disorders. However, individual studies usually have limitations to identifying consistent and reproducible effects, including modest sample sizes, heterogeneous clinical characteristics and varied methodologies. These issues call for a large-scale multi-centre effort in sleep research, in order to increase the number of samples, and harmonize the methods of data collection, preprocessing and analysis using pre-registered well-established protocols. The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium provides a powerful collaborative framework for combining datasets across individual sites. Recently, we have launched the ENIGMA-Sleep working group with the collaboration of several institutes from 15 countries to perform large-scale worldwide neuroimaging and genetics studies for better understanding the neurobiology of impaired sleep quality in population-based healthy individuals, the neural consequences of sleep deprivation, pathophysiology of sleep disorders, as well as neural correlates of sleep disturbances across various neuropsychiatric disorders. In this introductory review, we describe the details of our currently available datasets and our ongoing projects in the ENIGMA-Sleep group, and discuss both the potential challenges and opportunities of a collaborative initiative in sleep medicine.

Do effects of methylphenidate on cognitive performance last beyond treatment? A randomized placebo-controlled trial in boys and men with ADHD.

Methylphenidate (MPH) is the first-choice pharmacological treatment for treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) across the lifespan. However, it is unclear whether MPH affects cognitive development, while recent (pre-) clinical studies suggest effects on the developing brain. The present randomized, placebo-controlled trial aims to determine whether MPH has short-term, age-dependent effects on cognitive performance in ADHD after a 1-week washout. Effects of 16 weeks MPH treatment were assessed after a one-week washout on cognitive functioning. Boys (age=10-12) and men (age=23-40) with ADHD were assigned to MPH treatment (boys n=25, men n=24) or placebo (boys n=25, men n=24). Outcome measures were working memory, response inhibition, response speed, episodic memory, and delay aversion. Differences in task performances over time (pre-, mid-, and post-treatment, following a 1-week wash-out) were compared between age and treatment conditions with mixed ANOVAs. MPH improved working memory and response speed, but only during treatment. No lasting age*treatment effects were observed post intervention. Overall, the results from the present randomized, placebo-controlled trial show that the effects of MPH on cognition do not extend past treatment in children or adults. While treatment with MPH improves cognition during treatment, these effects appear transient after 16-weeks of treatment. (Title trial: "Effects of methylphenidate on the developing brain"; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=3103).

Anxiety, Mental Stress, and Sudden Cardiac Arrest: Epidemiology, Possible Mechanisms and Future Research.

Sudden cardiac arrest (SCA) is a leading cause of mortality and morbidity in affluent societies, which underscores the need to identify persons at risk. The etiology of SCA is however complex, with predisposing and precipitating factors interacting. Although anxiety and mental stress have been linked to SCA for decades, their precise role and impact remain unclear and the biological underpinnings are insufficiently understood. In this paper, we systematically reviewed various types of observational studies (total n = 20) examining the association between anxiety or mental stress and SCA. Multiple methodological considerations challenged the summarizing and interpretation of the findings. For anxiety, the overall picture suggests that it predisposes for SCA in physically healthy populations (unadjusted OR = 2.44; 95% CI: 1.06-5.59; n = 3). However, in populations at risk for SCA (n = 4), associations were heterogeneous but not significant. Anxiety may partly predispose to SCA by contributing to other risk factors such as cardiovascular disease and diabetes mellitus via mechanisms such as unhealthy lifestyle and metabolic abnormalities. Mental stress appears to precipitate SCA, presumably by more directly impacting on the cardiac ion channels that control the heart's electrical properties. This may lead to ventricular fibrillation, the arrhythmia that underlies SCA. To advance this field of research, experimental studies that unravel the underlying biological mechanisms are deemed important, and most easily designed for mental stress as a precipitating factor because of the short timeframe. These proof-of-concept studies should examine the whole pathway from the brain to the autonomic nervous system, and eventually to cardiac ion channels. Ultimately, such studies may facilitate the identification of persons at risk and the development of novel preventive strategies.

A Randomized Controlled Trial on the Effects of a 12-Week High- vs. Low-Intensity Exercise Intervention on Hippocampal Structure and Function in Healthy, Young Adults.

Physical exercise affects hippocampal structure and function, but the underlying neural mechanisms and the effects of exercise intensity remain incompletely understood. Therefore, we undertook a comprehensive, multi-modal 3T and 7T MRI randomized controlled trial (Netherlands Trial Register - NL5847) in which we randomized 52 young, non-athletic volunteers to a 12-week low- or high-intensity exercise program. Using state-of-the-art methods, we investigated changes in hippocampal volume, as well as changes in vasculature, neuro-metabolites, and peripheral growth factors as potential underpinnings. Cardiorespiratory fitness improved over time (p < 0.001), but no interaction with exercise intensity was found (p = 0.48). Accordingly, we did not observe significant interactions between exercise condition and time on MRI measures (all p > 0.06). However, we found a significant decrease in right hippocampal volume (p < 0.01), an increase in left hippocampal glutathione (p < 0.01), and a decrease of left hippocampal cerebral blood volume (p = 0.01) over time, regardless of exercise condition. Additional exploratory analyses showed that changes in brain-derived neurotrophic factor (p = 0.01), insulin-like growth-factor (p = 0.03), and dorsal anterior cingulate cortex N-acetyl-aspartate levels (p = 0.01) were positively associated with cardiorespiratory fitness changes. Furthermore, a trend toward a positive association of fitness and gray-matter cerebral blood flow (p = 0.06) was found. Our results do not provide evidence for differential effects between high-intensity (aerobic) and low-intensity (toning) exercise on hippocampal structure and function in young adults. However, we show small but significant effects of exercise on hippocampal volume, neurometabolism and vasculature across exercise conditions. Moreover, our exploratory results suggest that exercise might not specifically only benefit hippocampal structure and function, but rather has a more widespread effect. These findings suggest that, in agreement with previous MRI studies demonstrating moderate to strong effects in elderly and diseased populations, but none to only mild effects in young healthy cohorts, the benefits of exercise on the studied brain measures may be age-dependent and restorative rather than stimulatory. Our study highlights the importance of a multi-modal, whole-brain approach to assess macroscopic and microscopic changes underlying exercise-induced brain changes, to better understand the role of exercise as a potential non-pharmacological intervention.

Measuring decline in white matter integrity after systemic treatment for breast cancer: omitting skeletonization enhances sensitivity.

Chemotherapy for non-central nervous system cancers is associated with abnormalities in brain structure and function. Diffusion tensor imaging (DTI) allows for studying in vivo microstructural changes in brain white matter. Tract-based spatial statistics (TBSS) is a widely used processing pipeline in which DTI data are typically normalized to a generic DTI template and then 'skeletonized' to compensate for misregistration effects. However, this approach greatly reduces the overall white matter volume that is subjected to statistical analysis, leading to information loss. Here, we present a re-analysis of longitudinal data previously analyzed with standard TBSS (Menning et al., BIB 2018, 324-334). For our current approach, we constructed a pipeline with an optimized registration method in Advanced Normalization Tools (ANTs) where DTI data are registered to a study-specific, high-resolution T1 template and the skeletonization step is omitted. In a head to head comparison, we show that with our novel approach breast cancer survivors who had received chemotherapy plus or minus endocrine therapy (BC + SYST, n = 26) showed a global decline in overall FA that was not present in breast cancer survivors who did not receive systemic therapy (BC-SYST, n = 23) or women without a cancer diagnosis (no cancer controls, NC, n = 30). With the standard TBSS approach we did not find any group differences. Moreover, voxel-based analysis for our novel pipeline showed a widespread decline in FA in the BC + SYST compared to the NC group. Interestingly, the BC-SYST group also showed a decline in FA compared to the NC group, although in much less voxels. These results were not found with the standard TBSS approach. We demonstrate that a modified processing pipeline makes DTI data more sensitive to detecting changes in white matter integrity in non-CNS cancer patients after treatment, particularly chemotherapy.

Postnatal Brain Growth Patterns in Pontocerebellar Hypoplasia.

BACKGROUND: Pontocerebellar hypoplasia (PCH) is a rare group of disorders mainly affecting the cerebellum and pons. Supratentorial structures are variably involved. We assessed brain growth patterns in patients with the most frequent forms of PCH, namely PCH1B (OMIM#614678) and PCH2A (OMIM#277470), since in these types of PCH, pre- and postnatal neurodegeneration is established by neuropathological profiling. To assess the influence of the different pathomechanisms on postnatal growth patterns, we included CASK-associated microcephaly and PCH (MICPCH, OMIM#300749) patients in our analyses, as MICPH mimics PCH on magnetic resonance imaging (MRI) but represents a developmental disorder including abnormal neuronal migration. METHODS: A total of 66 patients were included: 9 patients with PCH1B, 18 patients with PCH2A, 6 patients with MICPCH, and 33 age- and gender-matched hospital-based controls. Segmentation of the vermis and cerebellum was performed manually, as were measurements of the thickness of the head of the caudate nucleus, the width of the anterior horn, and lateral ventricle size. RESULTS: The cerebellum was severely hypoplastic at birth in all patients, and postnatal growth was nearly absent. In patients with PCH1B/2A, we found relative sparing of the vermis compared with the cerebellar hemispheres. In addition, PCH1B and PCH2A cases demonstrated thinning of the head of the caudate nucleus, an associated increase in anterior horn width, and an increase in lateral ventricle size. None of these features were seen in the MICPCH group. CONCLUSIONS: Our findings confirm the progressive nature including caudate nucleus atrophy in PCH1B and PCH2A. In MICPCH, the relative sparing of supratentorial structures confirms its different pathomechanism.