Biology subjects

Germann, J.

Publications and source records attributed to Germann, J..

9 recordsLinked to original sources

bioRxiv2026

Inhibitory Evoked Potentials as a Spatially Dependent Intraoperative Marker of Clinical Tremor Reduction

Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus may be used to treat medication refractory essential tremor. Using recordings from in vivo human Vim neurons, our previous work has suggested that evoked potentials (that we termed quasi-evoked inhibition) ~2 ms following high frequency microstimulation pulses may be related to inhibitory synapses onto the Vim. Here, we investigate whether (i) quasi-evoked inhibition is related to clinical tremor reduction, and (ii) if quasi-evoked inhibition is dependent on the stimulation location within the Vim. By developing an objective determination of the presence or absence of quasi-evoked inhibition and utilizing accelerometer recordings, we showed that recordings with quasi-evoked inhibition at 100 Hz microstimulation exhibit greater tremor reduction than those without (P < 0.05, BF > 30). The number of stimulation pulses with quasi-evoked inhibition is also correlated with tremor reduction (rho = 0.18, P < 0.05) at all stimulation frequencies >=100 Hz. Furthermore, by analyzing microelectrode trajectories reconstructed from structural MRIs, we found that proximity to the ventral caudal border (P < 0.005) and to a previously established sweet spot (P < 0.05) are anti-correlated with the number of stimulation pulses with quasi-evoked inhibition. Our findings suggest that quasi-evoked inhibition is a potential biomarker of tremor reduction by means of network inhibition, and the more posterior regions of the Vim may allow for better recruitment of inhibition. This may be useful for closed-loop stimulation design.

neuroscience↗

bioRxiv2026

Focal brain stimulation sites that modify autonomic arousal map to a convergent brain circuit and potential therapeutic target

Causal modulation of autonomic outflow could yield new therapeutic targets for autonomic hyperactivation. We employed three natural experiments in which different brain regions were targeted using transcranial magnetic stimulation (TMS) (n=139 sites, n=14 individuals), deep brain stimulation (n=392 sites, n=58 individuals), or low-intensity focused ultrasound (n=46 sites, n=23 individuals) with subsequent autonomic measurements. Using a human connectome database (n=1000) as a wiring diagram, we identified a convergent brain circuit that, when focally modulated, transiently reduces autonomic arousal. This circuit significantly resembled previously reported causal circuits for posttraumatic stress disorder (PTSD) and anxiety. In independent datasets, TMS to the autonomic arousal circuit reduced laboratory startle in healthy volunteers (n=28), lesions to this circuit reduced exaggerated startle in PTSD (n=193), and TMS to this circuit reduced anxiety-related autonomic symptoms in patients with clinically significant anxiety (n=30). Thus, the convergent circuit may serve as a potential neuromodulation target for autonomic hyperactivation.

neuroscience↗

bioRxiv2025

HypoAD: volumetric and single-cell analysis reveals changes in the human hypothalamus in aging and Alzheimer's disease

Alterations in metabolism, stress response, sleep, circadian rhythms, and neuroendocrine processes are key features of aging and neurodegeneration. These fundamental processes are regulated by the hypothalamus, yet how its functionally distinct subregions and cell types change during human aging and Alzheimers Disease (AD) remains largely unexplored. Here, we present HypoAD, a comprehensive atlas of the human hypothalamus in aging and AD, integrating high-resolution MRI from 202 individuals with single-nucleus RNA-seq (snRNA-seq) of 614,403 nuclei from young, AD, and age-matched non-dementia controls. Our analysis reveals that hypothalamic subregions governing metabolism, stress, and circadian rhythms are particularly vulnerable, exhibiting significant changes in both volumes and gene expression during aging and AD. At the molecular level, machine learning models identified the inflammatory response and regulators of circadian rhythms as key cellular predictors of AD. These signatures were reflected in specific cell types: microglia transitioned to a pro-inflammatory state, while inhibitory neurons within sleep-and circadian-regulating hypothalamic subregions showed the most profound transcriptional alterations, including disruptions in ligand-receptor interactions and G-protein-coupled receptor signaling. Together, HypoAD provides a high-resolution volumetric map and a comprehensive transcriptomic atlas of the human hypothalamus in aging and AD, linking lifestyle and behavioral changes to their underlying volumetric and molecular pathways. Additionally, HypoAD provides a framework to investigate hypothalamic dysfunction and establishes a roadmap for targeted interventions aimed at mitigating physiological disruptions to potentially slow disease progression.

neuroscience↗

bioRxiv2025

Evaluating the quality of brainstem ROI registration using structural and diffusion MRI

Accurate registration of regions of interest (ROIs) from standard atlases to participants native spaces is a critical step in fMRI studies, as it directly affects the reliability of sampled BOLD signals. While T1-weighted (T1w) image-based ROI registration is well validated and widely adopted in cortical fMRI, its performance degrades in brainstem studies due to the small size, dense packing, and poor visibility of brainstem nuclei on T1w contrast. We hypothesized that incorporating diffusion MR images, containing more information about internal brainstem architecture, should improve ROI registration accuracy. To test this, we developed four registration pipelines that either included or excluded diffusion-based alignment components and evaluated their performance using data from n=20 healthy participants. Registration accuracy was assessed using Dice coefficient for the red nucleus (RN) and the substantia nigra (SN), and mis-registration fraction--a metric developed for nuclei that cannot be manually delineated--for the dorsal raphe nucleus (DRN). The results showed that diffusion-based pipelines, using fractional anisotropy (FA) images, non-diffusion-weighted (b0) images, and multivariate combination, outperformed the T1w-only baseline. Probabilistic maps derived from inverse-transformed native ROIs further supported improved sensitivity to inter-individual anatomical variability in the diffusion-augmented pipelines. In addition, analysis of gradient magnitude maps from the Jacobian determinants revealed associations between localized deformation and image modality-specific landmarks. These findings demonstrate the potential of diffusion-augmented pipelines for improving brainstem ROI registration, which could enhance the robustness of fMRI studies on brainstem disorders characterized by functional dysregulation.

neuroscience↗

bioRxiv2024

Longitudinal deformation based morphometry pipeline to study neuroanatomical differences in structural MRI based on SyN unbiased templates

Morphometric measures in humans derived from magnetic resonance imaging (MRI) have provided important insights into brain differences and changes associated with development and disease in vivo. Deformation-based morphometry (DBM) is a registration-based technique that has been shown to be useful in detecting local volume differences and longitudinal brain changes while not requiring a priori segmentation or tissue classification. Typically, DBM measures are derived from registration to common template brain space (one-level DBM). Here, we present a two-level DBM technique: first, the Jacobian determinants are calculated for each individual input MRI at the subject level to capture longitudinal individual brain changes; then, in a second step, an unbiased common group space is created, and the Jacobians co-registered to enable the comparison of individual morphological changes across subjects or groups. This two-level DBM is particularly suitable for capturing longitudinal intra-individual changes in vivo, as calculating the Jacobians within-subject space leads to superior accuracy. Using artificially induced volume differences, we demonstrate that this two-level DBM pipeline is 4.5x more sensitive in detecting longitudinal within-subject volume changes compared to a typical one-level DBM approach. It also captures the magnitude of the induced volume change much more accurately. Using 150 subjects from the OASIS-2 dataset, we demonstrate that the two-level DBM is superior in capturing cortical volume changes associated with cognitive decline across patients with dementia and cognitively healthy individuals. This pipeline provides researchers with a powerful tool to study longitudinal brain changes with superior accuracy and sensitivity. It is publicly available and has already been used successfully, proving its utility.

neuroscience↗

bioRxiv2022

Dissociable default-mode subnetworks subserve childhood attention and cognitive flexibility: evidence from deep learning and stereotaxic electroencephalography

BackgroundCognitive flexibility encompasses the ability to efficiently shift focus and forms a critical component of goal-directed attention. The neural substrates of this process are incompletely understood in part due to difficulties in sampling the involved circuitry. MethodsStereotactic intracranial recordings that permit direct resolution of local-field potentials from otherwise inaccessible structures were employed to study moment-to-moment attentional activity in children with epilepsy during the performance of an attentional set-shifting task. A combined deep learning and model-agnostic feature explanation approach was used to analyze these data and decode attentionally-relevant neural features. Connectomic profiling of highly predictive attentional nodes was further employed to examine task-related engagement of large-scale functional networks. ResultsThrough this approach, we show that beta/gamma power within executive control, salience, and default mode networks accurately predicts single-trial attentional performance. Connectomic profiling reveals that key attentional nodes exclusively recruit dorsal default mode subsystems during attentional shifts. ConclusionsThe identification of distinct substreams within the default mode system supports a key role for this network in cognitive flexibility and attention in children. Furthermore, convergence of our results onto consistent functional networks despite significant inter-subject variability in electrode implantations supports a broader role for deep learning applied to intracranial electrodes in the study of human attention. FundingNo funds supported this specific investigation. Awards and grants supporting authors include: Canadian Institutes of Health Research (CIHR) Vanier Scholarship (NMW, HY); CIHR Frederick Banting and Charles Best Canada Graduate Scholarship Doctoral Award (SMW); CIHR Canada Graduate Scholarship Masters Award (ONA); and a CIHR project grant (GMI).

neuroscience↗

bioRxiv2020

Early or late gestational exposure to maternal immune activation alters neurodevelopmental trajectories in mice: an integrated neuroimaging, behavioural, and transcriptional study

Prenatal maternal immune activation (MIA) is a risk factor for neurodevelopmental disorders. How gestational timing of MIA-exposure differentially impacts downstream development remains unclear. Here, we characterize neurodevelopmental trajectories of mice exposed to MIA induced by poly I:C either early (gestational day [GD]9) or late (GD17) in gestation using longitudinal structural magnetic resonance imaging from weaning to adulthood. Early MIA-exposure associated with accelerated brain volume increases in adolescence/early-adulthood that normalized in later adulthood, in regions including the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety, stereotypic, and sensorimotor gating behaviours observed in adolescence normalized in adulthood. In contrast, MIA-exposure in late gestation had less impact on anatomical and behavioural profiles. Using a multivariate technique to relate imaging and behavioural variables for the time of greatest alteration, i.e. adolescence/early adulthood, we demonstrate that variation in anxiety, social, and sensorimotor gating associates significantly with volume of regions including the dorsal and ventral hippocampus, and anterior cingulate cortex. Using RNA sequencing to explore the molecular underpinnings of region-specific alterations in early MIA-exposed mice in adolescence, we observed the most transcriptional changes in the dorsal hippocampus, with regulated genes enriched for fibroblast growth factor regulation, autistic behaviours, inflammatory pathways, and microRNA regulation. This indicates that MIA in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders. Our findings demonstrate the inherent strength of an integrated hypothesis- and data-driven approach in linking brain-behavioural alterations to the transcriptome to understand how MIA confers risk for major mental illness.

neuroscience↗

bioRxiv2019

An MRI-Derived Neuroanatomical Atlas of the Fischer 344 Rat Brain for Automated Anatomical Segmentation

This paper reports the development of a high-resolution 3-D MRI atlas of the Fischer 344 adult rat brain. The atlas is a 60 m isotropic image volume composed of 256 coronal slices with 71 manually delineated structures and substructures. The atlas was developed using Pydpiper image registration pipeline to create an average brain image of 41 four-month-old male and female Fischer 344 rats. Slices in the average brain image were then manually segmented, individually and bilaterally, on the basis of image contrast in conjunction with Paxinos and Watsons (2007) stereotaxic rat brain atlas. Summary statistics (mean and standard deviation of regional volumes) are reported for each brain region across the sample used to generate the atlas, and a statistical comparison of a chosen subset of regional brain volumes between male and female rats is presented. On average, the coefficient of variation of regional brain volumes across all rats in our sample was 4%, with no individual brain region having a coefficient of variation greater than 13%. A full description of methods used, as well as the atlas, the template that the atlas was derived from, and a masking file, can be found at Zenodo at https://doi.org/10.5281/zenodo.3555556. To our knowledge, this is the first MRI atlas created using Fischer 344 rats and will thus provide an appropriate neuroanatomical model for researchers working with this strain. HIGHLIGHTS Open-access high-resolution anatomical MRI template for Fischer 344 rat brain. Segmented atlas of 71 regions for use as a tool in Fischer 344 preclinical research paradigms. Analysis of population variability of regional brain volumes. Analysis of sex-differences in regional brain volumes KEYWORDS: Fischer 344; Structural MRI; Segmentation; Rat brain template; Digital brain atlas; Sex-differences;

neuroscience↗

bioRxiv2019

Clinical, imaging genetics and deformation based morphometry study of longitudinal changes after surgery for intractable aggressive behaviour

Intractable aggressive behaviour is a devastating behavioural disorder that reach 30% of psychiatric aggressive patients. Neuromodulatory surgeries may be treatment alternatives to reduce suffering. We investigated the outcomes of bilateral amygdala radiofrequency ablation in four patients with intractable aggressive behaviour (life-threatening-self-injury and social aggression) by studying whole brain magnetic resonance imaging and clinical data. Post-surgery assessments revealed decreases in aggression and agitation and improvements in quality of life. Aggressive behaviour was positively correlated with serum testosterone levels and the testosterone/cortisol ratio in males. No clinically significant side effects were observed. Imaging analyses revealed preoperative amygdala volumes within normal range and confirmed appropriate lesion locations. Reduction in aggressiveness were accompanied by volumetric reduction in brain areas associated with aggressive behaviour (express genes related to aggressive behaviour), and increases in regions related to somatosensation. These findings further elucidates the neurocircuitry of aggression and suggests novel neuromodulation targets.

clinical trials↗