Differences in electric field strength between clinical and non-clinical populations induced by prefrontal tDCS: a cross-diagnostic, individual MRI-based modeling study

Introduction: Prefrontal cortex (PFC) regions are promising targets for therapeutic applications of non-invasive brain stimulation, e.g. transcranial direct current stimulation (tDCS), which has been proposed as a novel intervention for major depressive disorder (MDD) and negative symptoms of schizophrenia (SCZ). However, the effects of tDCS vary inter-individually, and dose-response relationships have not been established. Stimulation parameters are often tested in healthy subjects and transferred to clinical populations. The current study investigates the variability of individual MRI-based electric fields (e-fields) of standard bifrontal tDCS across individual subjects and diagnoses.Method: The study included 74 subjects, i.e. 25 patients with MDD, 24 patients with SCZ, and 25 healthy controls (HC). Individual e-fields of a common tDCS protocol (i.e. 2 mA stimulation intensity, bifrontal anode-F3/ cathode-F4 montage) were modeled by two investigators using SimNIBS (2.0.1) based on structural MRI scans.Result: On a whole-brain level, the average e-field strength was significantly reduced in MDD and SCZ compared to HC, but MDD and SCZ did not differ significantly. Regions of interest (ROI) analysis for PFC subregions showed reduced e-fields in Sallet areas 8B and 9 for MDD and SCZ compared to HC, whereas there was again no difference between MDD and SCZ. Within groups, we generally observed high inter-individual variability of e-field intensities at a higher percentile of voxels.Conclusion: MRI-based e-field modeling revealed significant differences in e-field strengths between clinical and non-clinical populations in addition to a general inter-individual variability. These findings support the notion that dose-response relationships for tDCS cannot be simply transferred from healthy to clinical cohorts and need to be individually established for clinical groups. In this respect, MRI-based e-field modeling may serve as a proxy for individualized dosing

Fitness is positively associated with hippocampal formation subfield volumes in schizophrenia: a multiparametric magnetic resonance imaging study

Hippocampal formation (HF) volume loss is a well-established finding in schizophrenia, with select subfields, such as the cornu ammonis and dentate gyrus, being particularly vulnerable. These morphologic alterations are related to functional abnormalities and cognitive deficits, which are at the core of the insufficient recovery frequently seen in this illness. To counteract HF volume decline, exercise to improve aerobic fitness is considered as a promising intervention. However, the effects of aerobic fitness levels on HF subfields are not yet established in individuals with schizophrenia. Therefore, our study investigated potential associations between aerobic fitness and HF subfield structure, functional connectivity, and related cognitive impact in a multiparametric research design. In this cross-sectional study, 53 participants diagnosed with schizophrenia (33 men, 20 women; mean [SD] age, 37.4 [11.8] years) underwent brain structural and functional magnetic resonance imaging and assessments of aerobic fitness and verbal memory. Multivariate multiple linear regressions were performed to determine whether aerobic fitness was associated with HF subfield volumes and functional connections. In addition, we explored whether identified associations mediated verbal memory functioning. Significant positive associations between aerobic fitness levels and volumes were demonstrated for most HF subfields, with the strongest associations for the cornu ammonis, dentate gyrus, and subiculum. No significant associations were found for HF functional connectivity or mediation effects on verbal memory. Aerobic fitness may mitigate HF volume loss, especially in the subfields most affected in schizophrenia. This finding should be further investigated in longitudinal studies

Machine-learning based exploration of determinants of gray matter volume in the KORA-MRI study

To identify the most important factors that impact brain volume, while accounting for potential collinearity, we used a data-driven machine-learning approach. Gray Matter Volume (GMV) was derived from magnetic resonance imaging (3T, FLAIR) and adjusted for intracranial volume (ICV). 93 potential determinants of GMV from the categories sociodemographics, anthropometric measurements, cardio-metabolic variables, lifestyle factors, medication, sleep, and nutrition were obtained from 293 participants from a population-based cohort from Southern Germany. Elastic net regression was used to identify the most important determinants of ICV-adjusted GMV. The four variables age (selected in each of the 1000 splits), glomerular filtration rate (794 splits), diabetes (323 splits) and diabetes duration (122 splits) were identified to be most relevant predictors of GMV adjusted for intracranial volume. The elastic net model showed better performance compared to a constant linear regression (mean squared error = 1.10 vs. 1.59, p<0.001). These findings are relevant for preventive and therapeutic considerations and for neuroimaging studies, as they suggest to take information on metabolic status and renal function into account as potential confounders

Association between aerobic fitness and the functional connectome in patients with schizophrenia

BACKGROUND: Schizophrenia is accompanied by widespread alterations in static functional connectivity associated with symptom severity and cognitive deficits. Improvements in aerobic fitness have been demonstrated to ameliorate symptomatology and cognition in people with schizophrenia, but the intermediary role of macroscale connectivity patterns remains unknown. OBJECTIVE: Therefore, we aim to explore the relation between aerobic fitness and the functional connectome in individuals with schizophrenia. Further, we investigate clinical and cognitive relevance of the identified fitness-connectivity links. METHODS: Patients diagnosed with schizophrenia were included in this cross-sectional resting-state fMRI analysis. Multilevel Bayesian partial correlations between aerobic fitness and functional connections across the whole brain as well as between static functional connectivity patterns and clinical and cognitive outcome were performed. Preliminary causal inferences were enabled based on mediation analyses. RESULTS: Static functional connectivity between the subcortical nuclei and the cerebellum as well as between temporal seeds mediated the attenuating relation between aerobic fitness and total symptom severity. Functional connections between cerebellar seeds affected the positive link between aerobic fitness and global cognition, while the functional interplay between central and limbic seeds drove the beneficial association between aerobic fitness and emotion recognition. CONCLUSION: The current study provides first insights into the interactions between aerobic fitness, the functional connectome and clinical and cognitive outcome in people with schizophrenia, but causal interpretations are preliminary. Further interventional aerobic exercise studies are needed to replicate the current findings and to enable conclusive causal inferences. TRIAL REGISTRATION: The study which the manuscript is based on is registered in the International Clinical Trials Database (ClinicalTrials.gov identifier [NCT number]: NCT03466112) and in the German Clinical Trials Register (DRKS-ID: DRKS00009804). SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00406-022-01411-x

Microglial activation and connectivity in Alzheimer disease and aging

OBJECTIVE Alzheimer disease (AD) is characterized by amyloid β (Aβ) plaques and neurofibrillary tau tangles, but increasing evidence suggests that neuroinflammation also plays a key role, driven by the activation of microglia. Aβ and tau pathology appear to spread along pathways of highly connected brain regions, but it remains elusive whether microglial activation follows a similar distribution pattern. Here, we assess whether connectivity is associated with microglia activation patterns. METHODS We included 32 Aβ-positive early AD subjects (18 women, 14 men) and 18 Aβ-negative age-matched healthy controls (10 women, 8 men) from the prospective ActiGliA (Activity of Cerebral Networks, Amyloid and Microglia in Aging and Alzheimer's Disease) study. All participants underwent microglial activation positron emission tomography (PET) with the third-generation mitochondrial 18 kDa translocator protein (TSPO) ligand [18 F]GE-180 and magnetic resonance imaging (MRI) to measure resting-state functional and structural connectivity. RESULTS We found that inter-regional covariance in TSPO-PET and standardized uptake value ratio was preferentially distributed along functionally highly connected brain regions, with MRI structural connectivity showing a weaker association with microglial activation. AD patients showed increased TSPO-PET tracer uptake bilaterally in the anterior medial temporal lobe compared to controls, and higher TSPO-PET uptake was associated with cognitive impairment and dementia severity in a disease stage-dependent manner. INTERPRETATION Microglial activation distributes preferentially along highly connected brain regions, similar to tau pathology. These findings support the important role of microglia in neurodegeneration, and we speculate that pathology spreads throughout the brain along vulnerable connectivity pathways. ANN NEUROL 2022

Individual regional associations between Aβ-, tau- and neurodegeneration (ATN) with microglial activation in patients with primary and secondary tauopathies.

β-amyloid (Aβ) and tau aggregation as well as neuronal injury and atrophy (ATN) are the major hallmarks of Alzheimer's disease (AD), and biomarkers for these hallmarks have been linked to neuroinflammation. However, the detailed regional associations of these biomarkers with microglial activation in individual patients remain to be elucidated. We investigated a cohort of 55 patients with AD and primary tauopathies and 10 healthy controls that underwent TSPO-, Aβ-, tau-, and perfusion-surrogate-PET, as well as structural MRI. Z-score deviations for 246 brain regions were calculated and biomarker contributions of Aβ (A), tau (T), perfusion (N1), and gray matter atrophy (N2) to microglial activation (TSPO, I) were calculated for each individual subject. Individual ATN-related microglial activation was correlated with clinical performance and CSF soluble TREM2 (sTREM2) concentrations. In typical and atypical AD, regional tau was stronger and more frequently associated with microglial activation when compared to regional Aβ (AD: βT = 0.412 ± 0.196 vs. βA = 0.142 ± 0.123, p < 0.001; AD-CBS: βT = 0.385 ± 0.176 vs. βA = 0.131 ± 0.186, p = 0.031). The strong association between regional tau and microglia reproduced well in primary tauopathies (βT = 0.418 ± 0.154). Stronger individual associations between tau and microglial activation were associated with poorer clinical performance. In patients with 4RT, sTREM2 levels showed a positive association with tau-related microglial activation. Tau pathology has strong regional associations with microglial activation in primary and secondary tauopathies. Tau and Aβ related microglial response indices may serve as a two-dimensional in vivo assessment of neuroinflammation in neurodegenerative diseases

Flow sculpting enabled anaerobic digester for energy recovery from low-solid content waste

Traditionally, energy recovery from low-solid-content wastes occurs in Continuously Stirred Tank Reactors, whereas Plug Flow Reactors (PFR) are used to treat high-solid-content wastes. In comparison, this study uses a special configuration of anaerobic PFR (AnPFR), consisting of a coiled tubular structure, for energy recovery from a mixture of Food Waste and Wastewater, fed at a loading rate of 3 gVS.L−1.d−1 and a solids content of 2.5%. The AnPFR was upgraded into a Flow Sculpting enabled Anaerobic Digester (FSAD), an innovative plug flow design relying on flow sculpting via a sequence of pillars to provide passive mixing. The purpose of the FSAD design is to optimize operational performance while maintaining minimum mixing energy requirements. Computational fluid dynamics simulations revealed that pillars induce local vorticity in the fluid and contribute to the inertial deformation of the flow to enhance mixing. Coherently, experimental results proved that upgrading the AnPFR to FSAD resulted in a better stability (VFA dropped from 4433 to 2034 mg L−1) and a higher efficiency (removal efficiencies of COD and volatile solids increased from 75% to 77%–88% and 91%, respectively). Equally important, the methane yield, indicative of energy generation potential, increased from 181 L kg VSfed−1 to 291 L kg VSfed−1.This is a manuscript of an article published as Ghanimeh, Sophia, Charbel Abou Khalil, Daniel Stoecklein, Aditya Kommasojula, and Baskar Ganapathysubramanian. "Flow sculpting enabled anaerobic digester for energy recovery from low-solid content waste." Renewable Energy (2020). DOI: 10.1016/j.renene.2020.02.071. Posted with permission.</p

White matter hyperintensity volume in pre-diabetes, diabetes and normoglycemia

INTRODUCTION: As white matter hyperintensities (WMHs) of the brain are associated with an increased risk of stroke, cognitive decline, and depression, elucidating the associated risk factors is important. In addition to age and hypertension, pre-diabetes and diabetes may play important roles in the development of WMHs. Previous studies have, however, shown conflicting results. We aimed to investigate the effect of diabetes status and quantitative markers of glucose metabolism on WMH volume in a population-based cohort without prior cardiovascular disease. RESEARCH DESIGN AND METHODS: 400 participants underwent 3 T MRI. WMHs were manually segmented on 3D fluid-attenuated inversion recovery images. An oral glucose tolerance test (OGTT) was administered to all participants not previously diagnosed with diabetes to assess 2-hour serum glucose concentrations. Fasting glucose concentrations and glycated hemoglobin (HbA1c) levels were measured. Zero-inflated negative binomial regression analyses of WMH volume and measures of glycemic status were performed while controlling for cardiovascular risk factors and multiple testing. RESULTS: The final study population comprised 388 participants (57% male; age 56.3±9.2 years; n=98 with pre-diabetes, n=51 with diabetes). Higher WMH volume was associated with pre-diabetes (p=0.001) and diabetes (p=0.026) compared with normoglycemic control participants after adjustment for cardiovascular risk factors. 2-hour serum glucose (p<0.001), but not fasting glucose (p=0.389) or HbA1c (p=0.050), showed a significant positive association with WMH volume after adjustment for cardiovascular risk factors. CONCLUSION: Our results indicate that high 2-hour serum glucose concentration in OGTT, but not fasting glucose levels, may be an independent risk factor for the development of WMHs, with the potential to inform intensified prevention strategies in individuals at risk of WMH-associated morbidity