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Neural Engineering

Neural Engineering - Poster Session D

Poster K3 - Prolonged hippocampal deep brain stimulation leads to heterogeneous cellular responses in individual CA1 neurons

Friday, October 25, 2024
3:30 PM - 4:30 PM EST
Location: Exhibit Hall E, F & G

Introduction:  Deep brain stimulation (DBS) is effective for managing various neurological and psychiatric disorders. However, the therapeutic mechanisms of DBS are unknown. Studies suggest that electrical stimulation can directly influence the activity of local neurons, antidromically activate neurons projecting to the stimulation site, or orthodromically activate postsynaptic neurons via direct axonal neurotransmitter release. We recently demonstrated that DBS-evoked cellular membrane voltage changes around the stimulation site interfere with neuronal processing of inputs, leading to an informational lesion. Intriguingly, the clinical outcome of DBS in epilepsy and movement disorders is consistent with tissue resection and pharmacological lesion, suggesting that therapeutic DBS may lead to an overall inhibition of local neural activity. However, few studies have sampled large neuron populations to directly examine the cellular and network effect of prolonged DBS to complement clinical observations. To explore the population neuronal effect of DBS with single-cell resolution, we performed electrical artifact free cellular calcium imaging from >16,000 CA1 neurons while delivering DBS for 39 minutes.

Materials and

Methods:  We placed a custom imaging window coupled with a stimulating electrode and an infusion cannula above the CA1 region in six C57BL/6 mice. AAV9-Syn-jGCaMP7f was delivered through the cannula to express the genetically encoded calcium indicator jGCaMP7f in neurons. DBS amplitude was predetermined through systematic testing of a range of currents and set at the amplitude that produced an obvious population effect (Fig. 1). Across recording sessions, the current amplitude ranged from 40 - 180 µA (118.2 ± 39.7 µA, mean ± standard deviation, n = 32 sessions in 6 mice, corresponding to ~3.8–17.0 μC/cm2 charge density per stimulation phase).

Results, Conclusions, and Discussions: Results
The recording design is shown in Fig. 2. We have analyzed a total of 7299 neurons across 5 mice with 40 Hz DBS, and 9466 neurons with 140 Hz DBS. Our analysis thus far suggests that many neurons exhibit a prominent and transient change within a few seconds of DBS onset delivered at either 40 Hz or 140 Hz, with the majority showing a reduction in activity and some exhibiting an increase (Fig. 3). This initial change dissipates shortly after onset; most neurons settle into activity patterns similar to baseline (Fig. 3 A and B). However, a sizable fraction of neurons remain suppressed throughout the entire DBS period and recover at DBS offset (Fig. 3 E). Interestingly, while somatic calcium shows heterogeneous responses to DBS, dendritic dominated calcium activity is homogeneous across the imaged population (Fig. 4).

Discussion
DBS at both 40 Hz and 140 Hz lead to robust and transient suppression across a large fraction of neurons. While the suppression in many neurons is transient, a significant fraction of neurons exhibit sustained suppression throughout the entire DBS period, highlighting a prominent overall inhibitory effect. Our previous study demonstrated that both 40 Hz DBS and 140 Hz DBS produced a transient increase in spike rate within a couple hundred milliseconds of DBS onset. These results extend our previous analysis to a large number of >16,000 neurons, allowing us to probe the heterogeneity of DBS across neuronal populations. Our results reveal that the DBS-mediated effect quickly settles within seconds of DBS onset, and the neural activity remains diverse across the population, suggesting that DBS-evoked cellular changes stabilize shortly after DBS onset, and DBS does not produce detrimental uniform changes across neurons in the network.

Conclusion
Our results demonstrate that DBS evokes transient population suppression in the CA1 but with individual neurons showing heterogeneous responses. This transient suppression recovers within a few minutes, with the overall CA1 network appearing to exhibit few prolonged changes during chronic DBS. This suggests that DBS does not produce uniform changes across neurons in the network and produces a general inhibitory effect around the stimulation site.

Acknowledgements (Optional):