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J Neurophysiol. 2018 Apr 1;119(4):1497-1505. doi: 10.1152/jn.00832.2017. Epub 2017 Dec 27.

Phase-amplitude coupling within the anterior thalamic nuclei during seizures.

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Division of Neurosurgery, Department of Surgery, University of Toronto , Toronto, Ontario , Canada.
Department of Diagnostic Imaging, The Hospital for Sick Children , Toronto, Ontario , Canada.
Department of Neurosurgery, Mattel Children's Hospital, David Geffen School of Medicine at University of California Los Angeles , Los Angeles, California.
Division of Pediatric Neurosurgery, Department of Surgery, Sainte Justine Hospital, University of Montreal , Montreal, Quebec , Canada.
The Ohio State University, Center for Neuromodulation, Department of Neurosurgery , Columbus, Ohio.
The Ohio State University, Department of Neuroscience , Columbus, Ohio.
Division of Neurology, Krembil Neuroscience Centre, Toronto Western Hospital, University of Toronto , Toronto, Ontario , Canada.


Cross-frequency phase-amplitude coupling (cfPAC) subserves an integral role in the hierarchical organization of interregional neuronal communication and is also expressed by epileptogenic cortex during seizures. Here, we sought to characterize patterns of cfPAC expression in the anterior thalamic nuclei during seizures by studying extra-operative recordings in patients implanted with deep brain stimulation electrodes for intractable epilepsy. Nine seizures from two patients were analyzed in the peri-ictal period. CfPAC was calculated using the modulation index and interregional functional connectivity was indexed using the phase-locking value. Statistical analysis was performed within subjects on the basis of nonparametric permutation and corrected with Gaussian field theory. Five of the nine analyzed seizures demonstrated significant cfPAC. Significant cfPAC occurred during the pre-ictal and ictal periods in three seizures, as well as the postictal windows in four seizures. The preferred phase at which cfPAC occurred differed 1) in space, between the thalami of the epileptogenic and nonepileptogenic hemispheres; and 2) in time, at seizure termination. The anterior thalamic nucleus of the epileptogenic hemisphere also exhibited altered interregional phase-locking synchrony concurrent with the expression of cfPAC. By analyzing extraoperative recordings from the anterior thalamic nuclei, we show that cfPAC associated with altered interregional phase synchrony is lateralized to the thalamus of the epileptogenic hemisphere during seizures. Electrophysiological differences in cfPAC, including preferred phase of oscillatory interactions may be further investigated as putative targets for individualized neuromodulation paradigms in patients with drug-resistant epilepsy. NEW & NOTEWORTHY The association between fast brain activity and slower oscillations is an integral mechanism for hierarchical neuronal communication, which is also manifested in epileptogenic cortex. Our data suggest that the same phenomenon occurs in the anterior thalamic nuclei during seizures. Further, the preferred phase of modulation shows differences in space, between the epileptogenic and nonepileptogenic hemispheres and time, as seizures terminate. Our data encourage the study of cross-frequency coupling for targeted, individualized closed-loop stimulation paradigms.


cross-frequency coupling; deep brain stimulation; epilepsy; functional connectivity; neural networks; oscillations; thalamocortical dysrhythmia


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