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Interictal epileptiform discharges induce hippocampal–cortical coupling in temporal lobe epilepsy


Interactions between the hippocampus and the cortex are critical for memory. Interictal epileptiform discharges (IEDs) identify epileptic brain regions and can impair memory, but the mechanisms by which they interact with physiological patterns of network activity are mostly undefined. We show in a rat model of temporal lobe epilepsy that spontaneous hippocampal IEDs correlate with impaired memory consolidation, and that they are precisely coordinated with spindle oscillations in the prefrontal cortex during nonrapid-eye-movement (NREM) sleep. This coordination surpasses the normal physiological ripple–spindle coupling and is accompanied by decreased ripple occurrence. IEDs also induce spindles during rapid-eye movement (REM) sleep and wakefulness—behavioral states that do not naturally express these oscillations—by generating a cortical 'down' state. In a pilot clinical examination of four subjects with focal epilepsy, we confirm a similar correlation of temporofrontal IEDs with spindles over anatomically restricted cortical regions. These findings imply that IEDs may impair memory via the misappropriation of physiological mechanisms for hippocampal–cortical coupling, which suggests a target for the treatment of memory impairment in epilepsy.

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Figure 1: The occurrence, detection and coupling of hippocampal and mPFC oscillations during kindling.
Figure 2: Hippocampal IEDs impair memory.
Figure 3: Correlation of hippocampal IEDs and ripples with mPFC spindles.
Figure 4: Hippocampal IEDs trigger mPFC spindles in all behavioral states.
Figure 5: Hippocampal IEDs trigger cortical down states in the mPFC.
Figure 6: IEDs in subjects with epilepsy-trigger cortical spindles.


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This work was supported by US National Institute of Health grants (NS90583, MH54671, MH107396, MH102840; G.B.), the US National Science Foundation PIRE (G.B.), and the Mathers Foundation (G.B.). J.N.G. is a fellow of the Pediatric Scientist Development Program, and this project was supported through the March of Dimes Foundation. D.K. is supported through the Simons Foundation (junior fellow). We thank A. Peyrache for fruitful discussion; J. Long for use of the cheeseboard maze and advice on behavioral protocol; and Z. Zhao for technical support. We thank K. Berry, A. Boomhaur and P. del Prato for providing access to the sleep electrocorticography epilepsy data. Thanks also to H.X. Wang for providing the MRI-based electrode localizations for this data.

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J.N.G. and G.B. conceived the project. J.N.G. and D.K. did the in vivo rat experiments. J.N.G. and D.K. analyzed rat and human neural data. T.T. and O.D. supervised the human epilepsy recordings and processes related to the institutional review board. J.N.G., D.K. and G.B. wrote the paper, with input from the other authors.

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Correspondence to György Buzsáki.

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The authors declare no competing financial interests.

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Supplementary Figures 1–7 and Supplementary Tables 1 and 2 (PDF 3617 kb)


Rat performs cheeseboard-maze trial Caption: Left, rat navigates to and consumes three hidden water rewards during the last trial of a training session. Right, offline analysis of rat's location during same trial, with navigation periods in red and consummatory periods in blue. (MP4 11283 kb)

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Gelinas, J., Khodagholy, D., Thesen, T. et al. Interictal epileptiform discharges induce hippocampal–cortical coupling in temporal lobe epilepsy. Nat Med 22, 641–648 (2016).

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