Current Literature In Basic Science
Downsides and Downstream Effects of Interictal Epileptiform Discharges
Interictal Epileptiform Discharges Induce Hippocampal-Cortical Coupling in Temporal Lobe Epilepsy. Gelinas JN, Khodagholy D, Thesen T, Devinsky O, Buzsáki G. Nat Med 2016;22:641–648.
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.
Commentary Oscillations with superficially similar properties can have different underlying neuronal mechanisms as well as different consequences for downstream regions and cognition. Differences between physiological and pathological oscillations are of obvious importance in epilepsy. One important physiological oscillation in the hippocampus, termed ripples, appears during periods of rest and NREM sleep and is associated with replay of previously experienced neuronal firing sequences. Ripple replay is believed to play an important role in memory consolidation, as hippocampal ripples increase the likelihood of cortical spindles (also associated with sequential replay of neuronal firing), and disruption of ripples impairs performance on spatial memory tasks (1–3). Using a rat kindling model of temporal lobe epilepsy, Gelinas and colleagues found that kindling reduced the frequency of hippocampal ripples. Fitting with the importance of ripples, they also found a reduction in the rats’ spatial memory consolidation, as assessed using the cheeseboard maze. As ripple frequency decreased over the course of kindling, a different phenomenon, with likely different underlying neural mechanisms (4), increased in parallel: spontaneous interictal epileptiform discharges (IEDs). While the frequency of ripple occurrence was positively correlated with performance on the cheeseboard maze, the frequency of IED occurEpilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 325–326 © American Epilepsy Society
rence was negatively correlated. This provides further (albeit correlative) support to the growing recognition that IEDs can have a negative impact on cognition (5, 6). After the completion of kindling, animals were given a recovery period. During this time period, ripple frequency rebounded, IED frequency dropped, and performance on the cheeseboard task improved. This indicates that, at least to some extent, the system can recover from the plasticity induced by kindling, and provides further support for the correlations between IED frequency, decreased ripples, and impaired memory consolidation. However, as detailed below, despite these indications of “recovery,” changes in the system—and importantly in hippocampalcortical interaction—remained. As hippocampal ripples show a temporal correlation with cortical spindle events, Gelinas and colleagues looked beyond the hippocampus to examine the downstream effects of IEDs on the cortex, in particular, the medial prefrontal cortex. They found that, like hippocampal ripples, hippocampal IEDs also induced cortical spindles. In fact, IEDs induced cortical spindles more robustly than did physiological ripples. Like ripples, IEDs preferentially occurred during NREM sleep, a brain state during which cortical spindles appear; however, IEDs did occasionally occur outside of NREM sleep. Remarkably, even though these are states in which cortical spindles do not typically occur, IEDs during REM or awake states still produced cortical spindles. The average filtered waveforms of spindles occurring after IEDs in NREM, REM, and awake states were indistinguishable, indicating a remarkable ability of IEDs to induce spindle-like activity even in brain states not normally conducive to spindle activity.
325
Kindling and Spindling
Importantly, this finding may reflect not only the difference between IEDs and physiological ripple events but also a large network change in the epileptic animal. Evidence supporting this idea comes from experiments by the authors using artificial IEDs (aIEDs), induced by stimulating the hippocampal commissure. Low intensity stimulation of the hippocampal commissure has been used in previous studies to disrupt hippocampal ripples without inducing large changes in cortical activity (1). (When such low stimulation is applied outside of ripples, no negative impact on performance was noted, suggesting the critical aspect in these prior studies was disruption of ripple events.) Higher intensity stimulation, however, causes excitation followed by inhibition of firing in prefrontal cortex (1) and the induction of ripples. However, in non-kindled animals, Gelinas et al. found this to happen only during NREM sleep, a state during which spindles naturally occur. In kindled animals, aIEDs, just like spontaneous IEDs, were able to induce spindles even in REM and awake states. This indicates a kindling induced change in prefrontal circuits and that normal brain-state restrictions on oscillations can be altered in epilepsy. Alteration of cortical activity was not limited to the induction of ripples. During NREM sleep, spontaneous hippocampal IEDs, like aIEDs, produced an immediate excitation followed by inhibition in prefrontal pyramidal cells (with a reverse profile in putative interneurons). The same short-latency excitation was not seen in REM or awake states following IEDs. In all states, however, a prominent delta wave—characteristic of cortical down states and matching the suppression of neuronal firing—followed hippocampal IEDs and proceeded cortical spindles, leading the authors to conclude that recovery from the provoked down state induced thalamocortical spindles, and explaining the time delay from IEDs to spindles (which started ~410 ms after the offset of IEDs). The mechanism for the induction of down states was not addressed, but it is tempting to speculate on the role of neurogliaform cells and/ or GABAB receptors (7). Finally, to show that these findings are not limited to a rat kindling model but are also applicable to the human condition, Gelinas et al. examined sleep recordings from four epilepsy patients with subdural grid, strip and depth electrodes. Detected IEDs (the electrode with the largest IED amplitude was examined) were associated with sleep spindles in discrete regions of the cortical surface. Interestingly, this was also found in one patient whose electrode with the greatest IED amplitude was located outside of the temporal lobe. Mimicking findings in the rats, increases in delta power and a resetting of delta phase occurred following IEDs in cortical areas showing IED-spindle coupling. Therefore, the IED-delta-down-
326
state-spindle association is a finding with direct applicability to the human condition. Hippocampal ripples co-occur with hippocampal sharp waves, forming sharp-wave-ripple (SPW-R) complexes. A recent study found that different SPW-R types (distinguished by the relative timing of the sharp wave and the ripple components) show differential engagement of other brain regions, including the neocortex (8). It will be interesting to see, in future work, if particular subtypes of SPW-Rs are especially vulnerable in epilepsy or if there may be different flavors of IEDs with different downstream consequences. Downsides of IEDs for cognition have been demonstrated, and we now know that a downstream effect of IEDs is the induction of a cortical down state, followed by spindle activity. Given the timing delay between IED and spindle, Gelinas et al. note the potential for on-demand interruption (9), which could provide additional insight into the consequences of these aberrant oscillatory events and the potential benefits of preventing them. by Esther Krook-Magnuson, PhD References 1. Girardeau G, Benchenane K, Wiener SI, Buzsaki G, Zugaro MB. Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci 2009;12:1222–1223. 2. Ego-Stengel V, Wilson MA. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 2010;20:1–10. 3. Peyrache A, Khamassi M, Benchenane K, Wiener SI, Battaglia FP. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nat Neurosci 2009;12:919–926. 4. Gulyas AI, Freund TT. Generation of physiological and pathological high frequency oscillations: The role of perisomatic inhibition in sharp-wave ripple and interictal spike generation. Curr Opin Neurobiol 2015;31:26–32. 5. Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol 2010;67:250–257. 6. Kleen JK, Scott RC, Holmes GL, Roberts DW, Rundle MM, Testorf M, Lenck-Santini PP, Jobst BC. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology 2013;81:18–24. 7. Craig MT, McBain CJ. The emerging role of GABAB receptors as regulators of network dynamics: Fast actions from a ‘slow’ receptor? Curr Opin Neurobiol 2014:26:15–21. 8. Ramirez-Villegas JF, Logothetis NK, Besserve M. Diversity of sharpwave-ripple LFP signatures reveals differentiated brain-wide dynamical events. Proc Natl Acad Sci U S A 2015;112:E6379–6387. 9. Krook-Magnuson E, Gelinas JN, Soltesz I, Buzsaki G. Neuroelectronics and biooptics: Closed-loop technologies in neurological disorders. JAMA Neurol 2015:72:823–829.
Downsides and Downstream Effects of Interictal Epileptiform Discharges
Interictal Epileptiform Discharges Induce Hippocampal-Cortical Coupling in Temporal Lobe Epilepsy. Gelinas JN, Khodagholy D, Thesen T, Devinsky O, Buzsáki G. Nat Med 2016;22:641–648.
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.
Commentary Oscillations with superficially similar properties can have different underlying neuronal mechanisms as well as different consequences for downstream regions and cognition. Differences between physiological and pathological oscillations are of obvious importance in epilepsy. One important physiological oscillation in the hippocampus, termed ripples, appears during periods of rest and NREM sleep and is associated with replay of previously experienced neuronal firing sequences. Ripple replay is believed to play an important role in memory consolidation, as hippocampal ripples increase the likelihood of cortical spindles (also associated with sequential replay of neuronal firing), and disruption of ripples impairs performance on spatial memory tasks (1–3). Using a rat kindling model of temporal lobe epilepsy, Gelinas and colleagues found that kindling reduced the frequency of hippocampal ripples. Fitting with the importance of ripples, they also found a reduction in the rats’ spatial memory consolidation, as assessed using the cheeseboard maze. As ripple frequency decreased over the course of kindling, a different phenomenon, with likely different underlying neural mechanisms (4), increased in parallel: spontaneous interictal epileptiform discharges (IEDs). While the frequency of ripple occurrence was positively correlated with performance on the cheeseboard maze, the frequency of IED occurEpilepsy Currents, Vol. 16, No. 5 (September/October) 2016 pp. 325–326 © American Epilepsy Society
rence was negatively correlated. This provides further (albeit correlative) support to the growing recognition that IEDs can have a negative impact on cognition (5, 6). After the completion of kindling, animals were given a recovery period. During this time period, ripple frequency rebounded, IED frequency dropped, and performance on the cheeseboard task improved. This indicates that, at least to some extent, the system can recover from the plasticity induced by kindling, and provides further support for the correlations between IED frequency, decreased ripples, and impaired memory consolidation. However, as detailed below, despite these indications of “recovery,” changes in the system—and importantly in hippocampalcortical interaction—remained. As hippocampal ripples show a temporal correlation with cortical spindle events, Gelinas and colleagues looked beyond the hippocampus to examine the downstream effects of IEDs on the cortex, in particular, the medial prefrontal cortex. They found that, like hippocampal ripples, hippocampal IEDs also induced cortical spindles. In fact, IEDs induced cortical spindles more robustly than did physiological ripples. Like ripples, IEDs preferentially occurred during NREM sleep, a brain state during which cortical spindles appear; however, IEDs did occasionally occur outside of NREM sleep. Remarkably, even though these are states in which cortical spindles do not typically occur, IEDs during REM or awake states still produced cortical spindles. The average filtered waveforms of spindles occurring after IEDs in NREM, REM, and awake states were indistinguishable, indicating a remarkable ability of IEDs to induce spindle-like activity even in brain states not normally conducive to spindle activity.
325
Kindling and Spindling
Importantly, this finding may reflect not only the difference between IEDs and physiological ripple events but also a large network change in the epileptic animal. Evidence supporting this idea comes from experiments by the authors using artificial IEDs (aIEDs), induced by stimulating the hippocampal commissure. Low intensity stimulation of the hippocampal commissure has been used in previous studies to disrupt hippocampal ripples without inducing large changes in cortical activity (1). (When such low stimulation is applied outside of ripples, no negative impact on performance was noted, suggesting the critical aspect in these prior studies was disruption of ripple events.) Higher intensity stimulation, however, causes excitation followed by inhibition of firing in prefrontal cortex (1) and the induction of ripples. However, in non-kindled animals, Gelinas et al. found this to happen only during NREM sleep, a state during which spindles naturally occur. In kindled animals, aIEDs, just like spontaneous IEDs, were able to induce spindles even in REM and awake states. This indicates a kindling induced change in prefrontal circuits and that normal brain-state restrictions on oscillations can be altered in epilepsy. Alteration of cortical activity was not limited to the induction of ripples. During NREM sleep, spontaneous hippocampal IEDs, like aIEDs, produced an immediate excitation followed by inhibition in prefrontal pyramidal cells (with a reverse profile in putative interneurons). The same short-latency excitation was not seen in REM or awake states following IEDs. In all states, however, a prominent delta wave—characteristic of cortical down states and matching the suppression of neuronal firing—followed hippocampal IEDs and proceeded cortical spindles, leading the authors to conclude that recovery from the provoked down state induced thalamocortical spindles, and explaining the time delay from IEDs to spindles (which started ~410 ms after the offset of IEDs). The mechanism for the induction of down states was not addressed, but it is tempting to speculate on the role of neurogliaform cells and/ or GABAB receptors (7). Finally, to show that these findings are not limited to a rat kindling model but are also applicable to the human condition, Gelinas et al. examined sleep recordings from four epilepsy patients with subdural grid, strip and depth electrodes. Detected IEDs (the electrode with the largest IED amplitude was examined) were associated with sleep spindles in discrete regions of the cortical surface. Interestingly, this was also found in one patient whose electrode with the greatest IED amplitude was located outside of the temporal lobe. Mimicking findings in the rats, increases in delta power and a resetting of delta phase occurred following IEDs in cortical areas showing IED-spindle coupling. Therefore, the IED-delta-down-
326
state-spindle association is a finding with direct applicability to the human condition. Hippocampal ripples co-occur with hippocampal sharp waves, forming sharp-wave-ripple (SPW-R) complexes. A recent study found that different SPW-R types (distinguished by the relative timing of the sharp wave and the ripple components) show differential engagement of other brain regions, including the neocortex (8). It will be interesting to see, in future work, if particular subtypes of SPW-Rs are especially vulnerable in epilepsy or if there may be different flavors of IEDs with different downstream consequences. Downsides of IEDs for cognition have been demonstrated, and we now know that a downstream effect of IEDs is the induction of a cortical down state, followed by spindle activity. Given the timing delay between IED and spindle, Gelinas et al. note the potential for on-demand interruption (9), which could provide additional insight into the consequences of these aberrant oscillatory events and the potential benefits of preventing them. by Esther Krook-Magnuson, PhD References 1. Girardeau G, Benchenane K, Wiener SI, Buzsaki G, Zugaro MB. Selective suppression of hippocampal ripples impairs spatial memory. Nat Neurosci 2009;12:1222–1223. 2. Ego-Stengel V, Wilson MA. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat. Hippocampus 2010;20:1–10. 3. Peyrache A, Khamassi M, Benchenane K, Wiener SI, Battaglia FP. Replay of rule-learning related neural patterns in the prefrontal cortex during sleep. Nat Neurosci 2009;12:919–926. 4. Gulyas AI, Freund TT. Generation of physiological and pathological high frequency oscillations: The role of perisomatic inhibition in sharp-wave ripple and interictal spike generation. Curr Opin Neurobiol 2015;31:26–32. 5. Kleen JK, Scott RC, Holmes GL, Lenck-Santini PP. Hippocampal interictal spikes disrupt cognition in rats. Ann Neurol 2010;67:250–257. 6. Kleen JK, Scott RC, Holmes GL, Roberts DW, Rundle MM, Testorf M, Lenck-Santini PP, Jobst BC. Hippocampal interictal epileptiform activity disrupts cognition in humans. Neurology 2013;81:18–24. 7. Craig MT, McBain CJ. The emerging role of GABAB receptors as regulators of network dynamics: Fast actions from a ‘slow’ receptor? Curr Opin Neurobiol 2014:26:15–21. 8. Ramirez-Villegas JF, Logothetis NK, Besserve M. Diversity of sharpwave-ripple LFP signatures reveals differentiated brain-wide dynamical events. Proc Natl Acad Sci U S A 2015;112:E6379–6387. 9. Krook-Magnuson E, Gelinas JN, Soltesz I, Buzsaki G. Neuroelectronics and biooptics: Closed-loop technologies in neurological disorders. JAMA Neurol 2015:72:823–829.
