Biology subjects

Kirsch, J.

Publications and source records attributed to Kirsch, J..

6 recordsLinked to original sources

bioRxiv2026

Monosynaptic connections link functionally similar regions in human cortex

The functional organization of human cortex has been mapped in considerable detail1-5, yet the axonal connections linking these areas remain largely unknown. This gap precludes inferring either the computational pathways through cortical networks or the principles governing why each area connects to its particular target regions. Here, in patients undergoing intracranial monitoring for epilepsy, we used concurrent electrical stimulation and functional magnetic resonance imaging (es-fMRI), validated previously against tracer studies in nonhuman primates6, to map anatomical connectivity of cortical sites across the whole brain, and combined these maps with task and resting-state fMRI in the same individuals. Es-fMRI revealed four main findings. First, connectivity followed an asymmetric functional-similarity principle: connected sites tended to share similar functional profiles, but, because connectivity is sparse, most pairs of functionally similar sites were not connected. Second, although connectivity also declines with distance7, the functional profile explained three times as much variance in connectivity as distance did, and long-range connections were the most functionally specific. Third, es-fMRI revealed direct monosynaptic links between established functional regions, including between the fusiform face area (FFA)2 and the temporoparietal junction (TPJ)3 for social cognition. Fourth, resting-state functional connectivity (rsFC) of a stimulation site was only weakly correlated with that sites es-fMRI connectivity. Together, these results provide a first principled link between anatomical connectivity and functional organization in the human cortex, and establish es-fMRI as a scalable approach to building a tracer-grade connectome of the human brain.

neuroscience↗

bioRxiv2025

Relaxin-2 drives regenerative healing and suppresses scar formation

Fibrotic scarring is a pervasive and unresolved challenge in medicine, leading to permanent disfigurement, impaired mobility, and severe disruption of basic skin functions including elasticity, barrier protection, and thermoregulation. Despite its far-reaching personal, clinical, and economic impact, affecting hundreds of millions worldwide after surgery, trauma, and burns, no effective treatments exist to halt or reverse pathological scar formation. Scarring results from uncontrolled TGF-b1 signaling, which drives excessive deposition of extracellular matrix (ECM) proteins such as collagen-I/III and accumulation of alpha-smooth muscle actin (alpha-SMA), producing rigid, dysfunctional tissue. Here, we present a mechanistically guided approach targeting this unmet clinical need, leveraging the natural antifibrotic peptide hormone relaxin-2 (RLX-2) to actively remodel dermal architecture. RLX-2 signals via its G-protein coupled receptor RXFP1, upregulating matrix metalloproteinases (MMPs) and inhibiting aberrant ECM production. In TGF-b1-activated dermal fibroblasts across 2D and 3D in vitro models, ex vivo healthy and scarred human skin samples - cultured under physiological and pathological tension - and in an in vivo murine burn wound model, RLX-2 robustly suppresses fibrosis, restores regenerative tissue features, and rescues dermal architecture. Importantly, RLX-2 achieves this result without compromising the normal wound healing process, highlighting its potential as a transformative therapy for both prevention and reversal of pathological scarring.

bioengineering↗

bioRxiv2021

Nucleolar stress controls mutant Huntingtin toxicity and monitors Huntington disease progression

Transcriptional and cellular stress surveillance deficits are hallmarks of Huntingtons disease (HD), a fatal autosomal dominant neurodegenerative disorder, caused by a pathological expansion of CAG repeats in the Huntingtin (HTT) gene. The nucleolus, a dynamic nuclear biomolecular condensate and the site of ribosomal RNA (rRNA) transcription, is implicated in the cellular stress response and in protein quality control. While the exact pathomechanisms of HD remain unclear, the impact of nucleolar dysfunction on HD pathophysiology in vivo is elusive. Here we identified aberrant maturation of rRNA and decreased translational rate in association with human mutant Huntingtin (mHTT) expression. Genetic disruption of nucleolar integrity in vulnerable striatal neurons of the R6/2 HD mouse model decreases mHTT disperse state in the nucleus, exacerbating the motor deficits. The protein nucleophosmin 1 (NPM1), important for nucleolar integrity and rRNA maturation, loses its nucleolar localization. NPM1 de-localization occurs in the striatum and in the skeletal muscle of the progressive zQ175 knock-in HD mouse model, mimicking the phenotype of HD patients in skeletal muscle biopsies. Taken together, we showed that nucleolar integrity regulates the formation of mHTT inclusions in vivo, and identified NPM1 as a novel, readily detectable peripheral histopathological marker of HD progression.

neuroscience↗

bioRxiv2019

RF heating of deep brain stimulation implants in open-bore vertical MRI systems

PurposePatients with deep brain stimulation (DBS) implants highly benefit from MRI, however access to MRI is restricted for these patients due to safety hazards associated with RF heating of the implant. To date, all MRI studies on RF heating of medical implants have been performed in horizontal closed-bore systems. Vertical MRI scanners have a fundamentally different distribution of electric and magnetic fields and are now available at 1.2T, capable of high-resolution structural and functional MRI. This work presents the first simulation study of RF heating of DBS implants in high-field vertical scanners.\n\nMethodsWe performed finite element electromagnetic simulations to calculate SAR at tips of DBS leads during MRI in a commercially available 1.2 T vertical coil compared to a 1.5 T horizontal scanner. Both isolated leads and fully implanted systems were included.\n\nResultsWe found 10-30-fold reduction in SAR implication at tips of isolated DBS leads, and up to 19-fold SAR reduction at tips of leads in fully implanted systems in vertical coils compared to horizontal birdcage coils.\n\nConclusionsIf confirmed in larger patient cohorts and verified experimentally, this result can open the door to plethora of structural and functional MRI applications to guide, interpret, and advance DBS therapy.

biophysics↗

bioRxiv2018

Reconfigurable MRI coil technology can substantially reduce RF heating at the tips of bilateral deep brain stimulation implants

Patients with deep brain stimulation (DBS) implants can significantly benefit from magnetic resonance imaging (MRI) examination, however, access to MRI is restricted in this patients because of safety concerns due to RF heating of the leads. Recently we introduced a patient-adjustable reconfigurable MRI coil system to reduce the SAR at the tip of deep brain stimulation implants during MRI at 1.5T. A simulation study with realistic models of single (unilateral) DBS leads demonstrated a substantial reduction in the local SAR up to 500-fold could be achieved using the coil system compared to quadrature birdcage coils. Many patients however, have bilateral DBS implants and the question arises whether the rotating coil system can be used in for them. This work reports the results of phantom experiments measuring the temperature rise at the tips of bilateral DBS implants with realistic trajectories extracted from postoperative CT images of 10 patients (20 leads in total). A total of 200 measurements were performed to record temperature rise at the tips of the leads during 2 minutes of scanning with the coil rotated to cover all accessible rotation angles. In all patients, we were able to find an optimum coil rotation angle and reduced the heating of both left and right leads to a level below the heating produced by the body coil. An average heat reduction of 65% was achieved for bilateral leads. Reconfigurable coil technology introduces a promising approach for imaging of patients with DBS implants.

biophysics↗

bioRxiv2018

Reducing RF-Induced Heating Near Implanted Leads Through High-Dielectric Capacitive Bleeding of Current (CBLOC)

Patients with implanted medical devices such as deep brain stimulation or spinal cord stimulation are often unable to receive magnetic resonance imaging (MRI). This is because once the device is within the radiofrequency (RF) field of the MRI scanner, electrically conductive leads act as antenna, amplifying the RF energy deposition in the tissue and causing possible excessive tissue heating. Here we propose a novel concept in lead design in which 40cm lead wires are coated with a ~1.2mm layer of high dielectric constant material (155 <{varepsilon} r < 250) embedded in a weakly conductive insulation ({sigma} = 20 S/m). The technique called High-Dielectric Capacitive Bleeding of Current, or CBLOC, works by forming a distributed capacitance along the lengths of the lead, efficiently dissipating RF energy before it reaches the exposed tip. Measurements during RF exposure at 64 MHz and 123 MHz demonstrated that CBLOC leads generated 20-fold less heating at 1.5 T, and 40-fold less heating at 3 T compared to control leads. Numerical simulations of RF exposure at 297 MHz (7T) predicted a 15-fold reduction in specific absorption rate (SAR) of RF energy around the tip of CBLOC leads compared to control leads.

biophysics↗