Transcranial Stimulation During Sleep to Improve Cognition in Epilepsy

Epilepsy and cognitive dysfunction Recent investigations suggest that more than 60% of patients with epilepsy suffer cognitive impairment, such as memory, attentional and executive dysfunction (Elger et al., 2004, Lin et al., 2012). The severity and profile of cognitive impairment are heterogeneous and depend on the epilepsy syndrome, age of onset, seizure control, frequency of interictal activity, structural brain abnormalities, and antiepileptic medication use (Elger et al., 2004, Helmstaedter and Witt, 2012, Zeman et al., 2012).

Impairment in declarative memory is the most common cognitive complaint in patients with temporal lobe epilepsy and other localization-related epilepsies (Oyegbile et al., 2004, Hoppe et al., 2007, Helmstaedter and Witt, 2012). Three types of memory deficits associated with epilepsy have been described: transient epileptic amnesia, accelerated long-term forgetting and remote memory loss (Butler and Zeman, 2008, Zeman et al., 2012). In particular, accelerated long-term forgetting - defined as a difficulty in retaining memories that were initially able to be acquired - has been recently reported to be more prevalent than previously recognized (Witt et al., 2012).

Current therapeutic approaches include management of antiepileptic drugs, monitoring for side- effects, and decreasing seizure and interictal frequency. However, even when optimized, treatments have shown only limited effectiveness and do not modulate the underlying pathophysiology (Meador, 2011, Lin et al., 2012). Indeed, despite the prevalence of cognitive comorbidity among epilepsy patients, no effective therapies exist.

Sleep-related memory consolidation There are two major steps in learning: 1) attending to and encoding the information and 2) stabilizing or consolidating the transiently coded information (Squire, 1992). These steps involve different physiological mechanisms, different brain states and different types of interactions among hippocampal-neocortical circuits. Acquiring new information can be affected in either the acquisition or consolidation phase. Therefore, strategies to enhance memory formation can target either of these steps.

Sleep, increasingly recognized for its critical role in memory consolidation, provides an intriguing opportunity for therapeutic intervention. Memory consolidation, the second stage in the learning process, is the activity of transforming short-term memory traces into stable long-term representations (Dudai, 2012). One of the predominant views is that consolidation occurs via hippocampal-neocortical interaction during the brain's 'offline' state of sleep (Buzsaki, 1989; Diekelmann and Born, 2010). The key electrophysiological pattern responsible for this interaction is the hippocampal sharp wave ripple (SPW-R), during which the spatio-temporal patterns of neuronal firing associated with preceded learning are replayed in compressed time scales (O'Neill et al., 2010). Learning affects both the incidence and neuronal contents of SPW-Rs in subsequent sleep. Conversely, modification of SPW-Rs by various means affects the consolidation process. For example, selective elimination of SPW-Rs in rodents impairs learning as dramatically as surgical removal of the hippocampus, even though such experimental manipulation leaves other aspects of post-learning sleep unaltered (Girardeau et al., 2009). In addition to SPW-Rs, two other SWS-related oscillations have been implicated in memory consolidation: the amplitude and coherence of slow oscillations and sleep spindle density are increased when SWS is preceded by hippocampally-dependent declarative memory tasks (Gais et al., 2002, Molle et al., 2004) or procedural skill learning (Huber et al., 2004). SPW-Rs are modulated by sleep spindles (12-16 Hz), which are in turn orchestrated by slow (0.5-1.5 Hz) and ultraslow (0.1 Hz) oscillations (Steriade 1993, Sirota 2003, Isomura 2006, Molle 2006, Sullivan 2011). Such cross-frequency coupling suggests that a complex and distributed neuronal system coordinates neocortical-entorhinal cortex (EC)-hippocampal activity.