Dissecting the biophysical mechanisms of deep brain stimulation using voltage fluorescence microscopy

Projektinformationen

OptoDBS

ID Finanzhilfevereinbarung: 101116609

DOI

10.3030/101116609

EK-Unterschriftsdatum 12 Dezember 2023

Startdatum 1 Januar 2024

Enddatum 31 Dezember 2028

Finanziert unter

• European Research Council (ERC)

Gesamtkosten

€ 1 498 729,75

EU-Beitrag

€ 1 498 729,75

Koordiniert durch

ERASMUS UNIVERSITAIR MEDISCH CENTRUM ROTTERDAM
Netherlands

Periodic Reporting for period 1 - OptoDBS (Dissecting the biophysical mechanisms of deep brain stimulation using voltage fluorescence microscopy)

Berichtszeitraum: 2024-01-01 bis 2026-06-30

Zusammenfassung vom Kontext und den Gesamtzielen des Projekts

The clinical application of Deep Brain Stimulation (DBS) represents one of the most significant leaps in neuromodulation, yet the field remains constrained by a fundamental paradox: we are successfully deploying an intervention whose primary biophysical mechanisms remain a matter of intense academic debate. While it is clear that implanted electrodes can alleviate symptoms of psychiatric and neurological diseases, the black box nature of the interaction between electrical fields and neural tissue persists, For decades, the search for a definitive mechanistic framework has been stalled by electrical interference—where the stimulation pulse creates an artifact that drowns out the very neuronal signals we need to measure—and a persistent inability to record high-resolution membrane voltage in vivo during DBS. This project aims to break this technical impasse by shifting the paradigm from electrical to optical recording, utilizing cellular voltage fluorescence microscopy to bypass the artifact problem entirely. By integrating this advanced imaging with computational modeling in a mouse model of temporal lobe epilepsy, the research will provide an unprecedented view of how temporal lobe circuits react to DBS and provide the first direct in vivo evidence of how DBS modulates information transfer and network synchronization to enable therapeutic effects. This innovative and comprehensive approach will likely provide fundamental insights into the membrane voltage changes occurring with DBS, which will provide an unprecedented opportunity to build a data-driven mechanistic framework of DBS action with the ultimate goal of identifying more effective and targeted DBS protocols for human patients.

Arbeit, die ab Beginn des Projekts bis zum Ende des durch den Bericht erfassten Berichtszeitraums geleistet wurde, und die wichtigsten bis dahin erzielten Ergebnisse

WP1: Cellular Activation Mechanisms
Objective: Distinguish between direct axonal and indirect synaptic recruitment using high-speed voltage imaging (>1kHz).
Implementation: Implementation of high-speed voltage microscopy. Comparative analysis of voltage deflection latency following discrete stimulation pulses to map activation kinetics.
Current Focus: Parametric modulation of pulse width and amplitude to characterize entrainment; implementing pharmacological blockade to isolate specific biophysical contributions.

WP2: Information Transfer Dynamics
Objective: Investigate how high-frequency stimulation modulates the propagation of subthreshold oscillations and population-level activity.
Implementation: Integrated voltage imaging with behavioral tracking (ventral mirror imaging) to synchronize neural dynamics with motor parameters.
Current focus: Evaluating the "information lesion" model by analyzing how stimulation impacts task-related vs. pathological signaling across different circuit states.

WP3: Cell-Type Specific Circuit Dynamics
Objective: Define the differential responses of excitatory and inhibitory (E-I) subpopulations using transgenic targeting (e.g. PV/SST Cre-lines).
Implementation: Development of effective dual-color imaging using a single sCMOS camera to observe real-time interactions between distinct cell types in the same animal.
Current focus: Assessing whether observed signal changes represent global network suppression or a redistribution of firing patterns across cell-type-specific ensembles.

WP4: Therapeutic Parameters & Disease Models
Objective: Identify optimal stimulation parameters for seizure control and characterize their impact on epileptogenesis.
Implementation: Utilizing a rapid kindling model to map membrane voltage changes from focal initiation through to secondary generalization.
Implementation of multi-site voltage fiber photometry to track seizure focal and generalized activity across brain structures without and with DBS protocols.
Current focus: Validating biophysical mechanisms (e.g. entrainment/depolarization) across disease states to determine if therapeutic mechanisms are conserved or circuit-specific.

Fortschritte, die über den aktuellen Stand der Technik hinausgehen und voraussichtliche potenzielle Auswirkungen (einschließlich der bis dato erzielten sozioökonomischen Auswirkungen und weiter gefassten gesellschaftlichen Auswirkungen des Projekts)

OptoDBS has successfully bypassed the "artifact barrier" that has stalled DBS research for decades. By further developing voltage fluorescence imaging technology, we have achieved high-temporal resolution recording of specific cell-type activities in awake, behaving mice—a feat previously impossible with electrical sensors during active stimulation.

Expected Outcomes of OptoDBS:
1) Mapping pulse-by-pulse membrane voltage dynamics and thereby establishing the first empirical framework for DBS action in vivo.
2) Direct testing of the 'informational lesion' hypothesis by characterizing its unknown mechanisms and dependence on DBS parameters
3) Dissecting how DBS modulates excitatory and inhibitory dynamics and network states that underlie pathological processing.
4) Mechanistic insights into the therapeutic effects of DBS for epilepsy and a scientific foundation for DBS parameter selection

Technological innovation:
An important advancement for OptoDBS has been the successful implementation of cellular-resolution voltage microscopy and multi-site voltage fiber photometry. While calcium imaging is well-established, it lacks the temporal resolution to capture the high-frequency dynamics (e.g. 130Hz) of DBS.By adapting this technology for voltage indicators, we have gained unprecedented access to electrical activity in specific cell types across multiple brain regions in awake, behaving mice. This allows us to characterize seizure dynamics across the temporal lobe network and directly observe how DBS modulates these pathological states in real-time—an achievement that signifies a major leap for both systems and clinical neuroscience.