Electrical stimulation of the endopiriform nucleus attenuates epilepsy in rats by network modulation

Li, Donghong; Luo, Deng; Wang, Junling; Wang, Wei; Yuan, Zhangyi; Xing, Yue; Yan, Jiaqing; Sha, Zhiyi; Loh, Horace H.; Zhang, Milin; Henry, Thomas R.; Yang, Xiaofeng

doi:10.1002/acn3.51214

Cited by 10 publications

(9 citation statements)

References 68 publications

(115 reference statements)

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“…As inhibition in APC is particularly susceptible to kindling-induced long-term deficits 40 and that the APC is extensively connected with the “easiest ignition point”, endopiriform nucleus, this could be a main reason for the epileptogenicity of APC. Consistent with this notion, repeated, low-frequency stimulation (1 Hz) of the endopiriform nucleus suppresses the incidence of severe seizures 41 . It is also reported that low-frequency stimulation of APC can reduce seizures in the KA model 42 .…”

Section: Discussionmentioning

confidence: 75%

Suppression of piriform cortex alters brain-wide dynamics and alleviates seizures in temporal lobe epilepsy

Zhang,

Chiu,

Jiang

et al. 2023

Preprint

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Temporal lobe epilepsy (TLE) is a pathological state that involves altered excitation-inhibition (E-I) in the brain and exhibits recurrent seizures. Many circuit studies of TLE have focused on the hippocampus. Anterior piriform cortex (APC) is also a limbic area closely associated with TLE, but is understudied. In the APC, parvalbumin-expressing (PV+) interneurons provide strong inhibition and help maintain E-I balance. However, whether APCPVneurons play a causal role in TLE is unclear.We used the systemic pilocarpine and intrahippocampal kainic acid (KA) mouse models, which showed pathological changes and spontaneous recurrent seizures (SRSs) akin to those observed in patients with TLE. Whole-cell patch clamp recording and immunohistochemistry were used to examine inhibitory synaptic transmission in the pilocarpine model. Then, using chemogenetics and multi-site local field potential (LFP) recording, we manipulated APCPVneurons at different periods, before applying convulsant, during status epilepticus (SE) and in chronic epileptic phase, and examined the efficacy of APCPVneuronal activation on seizures. For chronic period experiments, KA-injected mice underwent four-site longitudinal LFP recordings. We quantified SRSs based on the frequency and duration of epileptic discharges (> 2 Hz, 10 seconds). For the underlying functional network dynamics, we analyzed the power of each recording site and functional connectivity of each pair of regions in four epileptic states, preictal, ictal, postictal and interictal.In the pilocarpine model, we found impaired synaptic inhibition and loss of PV synapses in the APC. APCPVneuronal pre-activation decreased seizure susceptibility and mortality, but could not stop an ongoing SE. In the chronic KA model, activation of APCPVneurons reduced the frequency and duration of SRSs in the hippocampus. Interestingly, APCPVneuronal activation altered the brain-wide dynamics of seizure network and afforded differential modulation based on epileptic states, brain regions and frequency bands.Our work demonstrates the causal role of APCPVin TLE and provides detailed functional characterization of mechanisms underlying the effectiveness of APCPVactivation. We reveal how a cortical microcircuit can alter neural activity in multiple brain regions and exert antiepileptic benefits. These findings strengthen the idea that large-scale connections from APC play a key role in maintaining the E-I balance of the entire seizure network and thus provide the basis for future circuit-based therapies.

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Section: Discussionmentioning

confidence: 75%

Suppression of piriform cortex alters brain-wide dynamics and alleviates seizures in temporal lobe epilepsy

Zhang,

Chiu,

Jiang

et al. 2023

Preprint

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“…This consistency across models indicates that pulse modulation strategies can be applied to suppress or amplify neural activity in distinct brain circuits and conditions, whenever spontaneous and stimulation-evoked responses of comparable magnitude are generated in the targeted neuronal population. For example, underdamped neural responses in the hippocampus CA1 area evoked by stimulation of the endopiriform nucleus (23) could be employed, together with our pulse modulation strategies, to control hippocampal, frequency-specific neural activity.…”

Section: Discussionmentioning

confidence: 99%

Deep brain stimulation pulse sequences to optimally modulate frequency-specific neural activity

Farooqi

Vitek

Sanabria

2022

Preprint

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Precise neuromodulation systems are needed to identify the role of neural oscillatory dynamics in brain function, and to advance the development of electrical stimulation therapies tailored to each patient's signature of brain dysfunction. Low-frequency, local field potentials (LFPs) are of increasing interest for the development of these systems because they reflect the synaptic inputs to a recorded neuronal population and can be chronically recorded in humans. Here, we identified stimulation pulse sequences to optimally minimize or maximize the 2-norm of frequency-specific LFP oscillations using a generalized mathematical model of spontaneous and stimulation-evoked LFP activity, and a subject-specific model of neural dynamics in the pallidum of a Parkinson's disease patient. We leveraged convex and mixed-integer optimization tools to identify the pulse patterns, and employed constraints on the pulse frequency and amplitude that are required to keep electrical stimulation within its safety envelope. Our analysis revealed that a combination of phase, amplitude, and frequency pulse modulation is needed to attain optimal suppression or amplification of the targeted oscillations. Phase modulation is sufficient to modulate oscillations with a constant amplitude envelope. To attain optimal modulation for oscillations with a time-varying envelope, a trade-off between frequency and amplitude pulse modulation is needed. The optimized pulse sequences identified here were invariant to changes in the dynamics of stimulation-evoked neural activity, including the damping and natural frequency or complexity (i.e., generalized vs. patient-specific model). Our results reveal the structure of pulse sequences that can be used in closed-loop brain stimulation devices to control neural activity in real-time.

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“…A study in rodents demonstrated that miniscule injections of cholinergic agents to piriform cortex generated bilateral clonic seizures, an effect that was not replicated in other MTL structures 38 . Conversely, a recent study showed that electrical stimulation of the endopiriform nucleus improved seizure outcomes in mice 39 . In humans, a multicenter 2019 study of 107 adults demonstrated that removal of at least half of the piriform cortex in ATL increased the odds of seizure freedom by 16‐fold, and that these odds were directly proportional to the extent of piriform resection 16 .…”

Section: Discussionmentioning

confidence: 99%

“…38 Conversely, a recent study showed that electrical stimulation of the endopiriform nucleus improved seizure outcomes in mice. 39 In humans, a multicenter 2019 study of 107 adults demonstrated that removal of at least half of the piriform cortex in ATL increased the odds of seizure freedom by 16-fold, and that these odds were directly proportional to the extent of piriform resection. 16 These studies suggest that increased ablation of piriform cortex would also be associated with improved outcomes.…”

Section: Improved Coverage Of Piriform Cortexmentioning

confidence: 99%

Two‐trajectory laser amygdalohippocampotomy: Anatomic modeling and initial seizure outcomes

et al. 2021

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Objective: Laser interstitial thermal therapy (LITT) for mesial temporal lobe epilepsy (mTLE) is typically performed with one trajectory to target the medial temporal lobe (MTL). MTL structures such as piriform and entorhinal cortex are epileptogenic, but due to their relative geometry, they are difficult to target with one trajectory while simultaneously maintaining adequate ablation of the amygdala and hippocampus. We hypothesized that a two-trajectory approach could improve ablation of all relevant MTL structures. First, we created large-scale computer simulations to compare idealized one-vs two-trajectory approaches. A two-trajectory approach was then validated in an initial cohort of patients. Methods:We used magnetic resonance imaging (MRI) from the Human Connectome Project (HCP) to create subject-specific target structures consisting of hippocampus, amygdala, and piriform/entorhinal/perirhinal cortex. An algorithm searched for safe potential trajectories along the hippocampal axis (catheter one) and along the amygdala-piriform axis (catheter two) and compared this to a single trajectory optimized over all structures. The proportion of each structure ablated at various burn radii was evaluated. A cohort of 11 consecutive patients with mTLE received two-trajectory LITT; demographic, operative, and outcome data were collected. Results:The two-trajectory approach was superior to the one-trajectory approach at nearly all burn radii for all hippocampal subfields and amygdala nuclei (p < .05). Two-laser trajectories achieved full ablation of MTL cortical structures at physiologically realistic burn radii, whereas one-laser trajectories could not. Five patients with at least 1 year of follow-up (mean = 21.8 months) experienced Engel class I outcomes; 6 patients with less than 1 year of follow-up (mean = 6.6 months) are on track for Engel class I outcomes.

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Electrical stimulation of the endopiriform nucleus attenuates epilepsy in rats by network modulation

Cited by 10 publications

References 68 publications

Suppression of piriform cortex alters brain-wide dynamics and alleviates seizures in temporal lobe epilepsy

Suppression of piriform cortex alters brain-wide dynamics and alleviates seizures in temporal lobe epilepsy

Deep brain stimulation pulse sequences to optimally modulate frequency-specific neural activity

Two‐trajectory laser amygdalohippocampotomy: Anatomic modeling and initial seizure outcomes

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