Biology subjects

Kozak, G.

Publications and source records attributed to Kozak, G..

4 recordsLinked to original sources

bioRxiv2025

Plasticity of interhemispheric motor cortex connectivity induced by brain state-dependent cortico-cortical paired-associative stimulation

Transcallosal connectivity between the hand areas of the two primary motor cortices (M1) is important for coordination of unimanual and bimanual hand motor function. Effective connectivity of this M1-M1 pathway can be tested in the form of short-interval interhemispheric inhibition (SIHI) using dual-coil transcranial magnetic stimulation (TMS). Recently, we and others have demonstrated that the phase of the ongoing sensorimotor {micro}-rhythm has significant impact on corticospinal excitability as measured by motor evoked potential (MEP) amplitude, and repetitive TMS of the high-excitability state (trough of the {micro}-rhythm) but not other states resulted in long-term potentiation-like MEP increase. Here, we tested to what extent the phase of the ongoing {micro}-rhythm in the two M1 cortices affects long-term change in SIHI. In healthy subjects we applied cortico-cortical paired associative stimulation (ccPAS) in four different {micro}-phase conditions in the left conditioning M1 and right test M1 (trough-trough, trough-positive peak, positive peak-trough, random phase). We found long-term strengthening of SIHI but no differential effect of phase conditions. Findings point to a distinct regulation of plasticity of corticospinal vs. M1-M1 connectivity. The observed ccPAS-induced strengthening of effective M1-M1 connectivity (SIHI) may be utilized for therapeutic applications that potentially benefit from modification of interhemispheric excitation/inhibition balance.

neuroscience↗

bioRxiv2025

A High-Precision Timing Method and Digital Interface for Closed-Loop TMS

ObjectiveCurrent transcranial magnetic stimulation (TMS) protocols exhibit high inter-subject variability in treatment outcomes, highlighting the need for personalized, brain-state-dependent closed-loop stimulation protocols. To enable such protocols, we aim to provide robust, precisely timed external control of TMS, with stimulation timed relative to feedback signals such as the electroencephalogram (EEG). ApproachCommercial TMS devices typically rely on trigger signals for precise external pulse timing, while adjusting stimulation parameters, such as intensity, is better handled via serial digital communication, which supports robust error detection and feedback. However, combining these communication methods is inherently complex and prone to timing issues, such as race conditions. Furthermore, trigger signals lack capabilities essential for real-time systems, such as preventing late pulse delivery. We present a method for precise and accurate pulse timing, implemented through a digital interface that uses exclusively serial digital messaging, eliminating the need for trigger signals. This interface enables external control of pulse timing, intensity, and other parameters. The TMS device maintains its own internal clock and delivers pulses at pre-scheduled times, decoupling timing precision from the control device. Additionally, we propose a method for synchronizing such time-tracking TMS devices with commercial EEG systems, enabling precisely timed EEG-TMS. Main resultsUsing these methods, our custom TMS device delivered pulses precisely aligned to the EEG signal, with timing errors consistently below 0.3 ms. These errors were constrained by the experimental setup, including the sampling rate of our EEG device and the signal-to-noise ratio affecting pulse detection. SignificanceOur timing method achieves sub-millisecond precision in brain-state-dependent closed-loop EEG-TMS, providing a foundation for robust TMS timing that supports adaptive, personalized stimulation protocols. The digital control interface, co-designed with our TMS device, integrates pulse timing and parameters, setting a precedent for future advancements in computer-controlled TMS.

bioengineering↗

bioRxiv2025

Non-vectorial Integration of Intersectional Short-Pulse Stimulation Enables Enhanced Deep Brain Modulation and Effective Seizure Control

Transcranial electrical stimulation (TES) holds promise to treat neurological disorders, but its efficacy is limited by poor spatial focality and depth of penetration. Here, we examined the potential utility of Intersectional Short-Pulse (ISP) stimulation of deeper brain penetration. Using computational modeling and in vivo patch-clamp recordings in rats, we demonstrate that neurons integrate ISP-induced electric fields in a non-vectorial manner. This mechanism allows ISP to overcome some limits of conventional TES, achieving spatially limited stimulation across cortical and subcortical structures. In a rat model of temporal lobe epilepsy, closed-loop ISP stimulation significantly outperformed conventional TES in reducing seizure duration and severity. ISP reduced hippocampal seizure duration by 49% and 41% compared to sham stimulation and conventional TES and significantly reduced motor seizure severity. Our findings demonstrate that ISP stimulation can rapidly terminate hippocampal seizures, offering a potential new approach for non-invasive neuromodulation with applications across diverse neurologic and psychiatric disorders.

neuroscience↗

bioRxiv2022

Closed-loop brain stimulation to reduce pathologic fear

Maladaptive processing of trauma related memory engrams leads to dysregulated fear reactions. In post-traumatic stress disorder (PTSD), dysfunctional extinction learning prevents discretization of trauma-related memory engrams and leads to generalized fear responses. PTSD is postulated as a mnemonic-based disorder, but we lack markers or treatments targeting pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. We demonstrate that closed-loop SWRs triggered neuromodulation of the medial forebrain bundle (MFB) can enhance the consolidation of fear extinction. It modified fear memories that became resistant to induced recall (i.e., renewal and reinstatement) and did not reemerge spontaneously as a PTSD-like phenotype. The effects are mediated by D2 receptor signaling induced synaptic remodeling in the basolateral amygdala. These results suggest that SWRs help consolidating fear extinction memories. Furthermore, enhancing the consolidation of extinction engrams by SWR-triggered induction of reward signals can alleviate pathologic fear reactions in a rodent model of PSTD. No adverse effects were seen, suggesting this potential therapy for PTSD and anxiety disorders.

neuroscience↗