Transient Cognitive Dysfunction Associated with Hypothalamic Hamartoma Syndrome Is Caused by Epileptic Discharges Propagating to the Thalamic Mediodorsal Nucleus in a Time-specific Manner
Abstract number :
2.052
Submission category :
3. Neurophysiology / 3F. Animal Studies
Year :
2022
Submission ID :
2204466
Source :
www.aesnet.org
Presentation date :
12/4/2022 12:00:00 PM
Published date :
Nov 22, 2022, 05:25 AM
Authors :
Masaki Sonoda, MD, PhD – Yokohama City University; Hisao Aimi, MD – Department of Physiology – Niigata University School of Medicine; Keisuke Kawasaki, PhD – Department of Physiology – Niigata University School of Medicine; Haruo Toda, MD, PhD – Department of Orthoptics and Visual Science – Niigata University of Health and Welfare; Shinobu Hirai, PhD – Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences – Tokyo Metropolitan Institute of Medical Science; Masao Horie, PhD – Department of Nursing – Niigata College of Nursing, Niigata; Reiko Meguro, MD, PhD – Graduate School ofHealth Sciences; Haruo Okado, PhD – Sleep Disorders Project, Department of Psychiatry and Behavioral Sciences – Tokyo Metropolitan Institute of Medical Science; Shigeki Kameyama, MD, PhD – Department of Neurosurgery – Niigata Seiro Hospital; Tetsuya Yamamoto, MD, PhD – Department of Neurosurgery – Yokohama City University; Isao Hasegawa, MD, PhD – Department of Physiology – Niigata University School of Medicine
Rationale: Cognitive dysfunction is a common symptom in patients with gelastic seizures-hypothalamic hamartoma syndrome (GH-HH). And the cognitive decline is suggested to be partially improved by surgical disconnection of hypothalamic hamartoma from the healthy brain (Figure 1A). We believe that interictal epileptic discharges (IEDs) from hypothalamic hamartoma contribute to transient cognitive impairment. However, it is unclear whether IEDs propagated to the thalamic mediodorsal nucleus (MD) directly interfere with the neural activity related to cognition in a time-specific manner, resulting in the transient cognitive decline (Figure 1B). The purpose of this study is to demonstrate in an animal model of GH-HH whether pathway-specific IED-like discharges directly inhibit task-related neural activity tasks and reduce task performance.
Methods: To test our hypothesis (Figure 1C), we induced pathway-specific abnormal neural excitation mimicking interictal epileptic discharges in GH-HH using an optogenetic approach with channelrhodpsin2 (ChR2) in adult Long-Evans rats. We injected pCAG-ChR2-GFP incorporating adeno-associated virus serotype 9 (AAV9) into the lateral hypothalamus area (LHA). We histologically and functionally observed ChR2-GFP expression in the injected area and the ipsilateral MD and prelimbic cortex (PrL, Figure 2A-B). To clarify the neural activity underlying the performance of the working memory (WM) tasks in the MD and iPrL sites (Figure 2C-E), we recorded local field potentials in MD and PrL and conducted machine learning analysis to calculate the absolute beta of the time-frequency component that can predict whether a given trial in the WM task will be successful. Mixed model analysis was also used to test whether the induced abnormal neural activity during specific periods during the WM task would decline task performance. Finally, mixed logistic regression analysis was employed to examine whether the specific time-frequency change related to photostimulation during the given period increased the probability of task failure.
Results: We analyzed ten rats' behavior that successfully performed operant conditioning behavior using the spout lever system after 70.7 ± 20.1 training days (135.2 ± 20.1 trials per day, mean ± SD). The predictive model identified statistically significant time-frequency clusters in MD and iPrL (Figure 2F-G). Performance of the WM task with photostimulation during the period including the instruction (IST) period was significantly reduced (Figure 2H-I). The higher degree of induced initial neural augmentation and subsequent attenuation in MD during the IST period significantly increased the probability of WM-task failure (Figure 2J-K).
Conclusions: Abnormal neural excitation propagated to the MD during the encoding period of a WM task, resulting in altered task-related neural activity and a transient decrease in task performance. This spatiotemporally direct interference of abnormal neuronal excitation with cognitive neural processes may suggest a pathophysiological mechanism underlying the transient cognitive dysfunction of epileptic encephalopathy associated with GS-HH.
Funding: This research was supported by AMED under Grant Number 22he2202018h0001 (to M. Sonoda).
Neurophysiology