Authors :
Presenting Author: James Niemeyer, PhD – Weill Cornell Medicine
Fengrui Zhan, BS – Weill Cornell Medicine
Carmen Pons, MD – University of Chicaco
Theodore Schwartz, MD – Weill Cornell Medicine
Rationale:
Focal epilepsy exhibits drug-resistance in over a quarter of patients, and surgical interventions like neurostimulation rarely provide seizure freedom. A major hindrance to improving surgical treatment is our lack of understanding of how distant brain regions are recruited to form a “seizure network” of sites that produce reciprocal and reverberating activity that drives propagating seizures. To better understand this process, we have developed methods to study excitatory and inhibitory activity across a bilateral brain network in mice that is also amenable to neurostimulation testing.
Methods:
We performed widefield calcium imaging of Thy1+ excitatory and PV+ inhibitory neurons in focal onset seizures induced by the chemoconvulsant 4-Aminopyridine (4-AP) in awake mice. Seizures were initiated in primary somatosensory cortex (S1), to create a seizure network encompassing contralateral S1 and ipsi- and contralateral secondary motor cortex (iM2, cM2). Across mice (N=12) and seizures (n=41), we measured the seizure propagation patterns in both cell types. We next applied electrical microstimulation of S1 and M2 to determine how pathological activity spreads through this network (N=6 mice). We focused on high frequency 50 Hz stimulation and low frequency 3 Hz stimulation. In preliminary tests, we examined how microstimulation of sites outside of the seizure onset zone can affect ongoing seizures.
Results:
Focal onset seizures in S1 frequently propagate to become focal to bilateral tonic clonic events, with a significant preference ( >92%) for contralateral propagation at frontal M2 sites. We observed no significant difference in timing of Thy1+ or PV+ cell activity in seizures. However, microstimulation of S1 revealed a significantly higher excitatory/inhibitory imbalance at cM2 versus cS1 (p< .01, p< .001 for 100 ms- and 10-sec stimulations), which aligns with the frontal propagation in this seizure network. We also found that 50 Hz microstimulation results in significantly adapting Thy1+ excitatory responses over a 10-second period, but not PV+ inhibitory responses (p< .001 PV vs Thy1 calcium responses). Meanwhile, low 3 Hz stimulation results in facilitating activity in both cell types. We observed a similar effect even at connected network sites. In preliminary tests, we find that indeed low 3 Hz stimulation, in the presence of 4-AP, can induce seizures while high frequency 50 Hz stimulation at an extra-focal site can halt an ongoing seizure.