Abstract
Altered Sleep Homeostasis Correlates with Cognitive Impairment in Patients with Focal Epilepsy
Boly M, Jones B, Findlay G, Plumley E, Mensen A, Hermann B, Tononi G, Maganti R. Brain 2017;140:1026–1040.
In animal studies, both seizures and interictal spikes induce synaptic potentiation. Recent evidence suggests that electroencephalogram slow wave activity during sleep reflects synaptic potentiation during wake, and that its homeostatic decrease during the night is associated with synaptic renormalization and its beneficial effects. Here we asked whether epileptic activity induces plastic changes that can be revealed by high-density electroencephalography recordings during sleep in 15 patients with focal epilepsy and 15 control subjects. Compared to controls, patients with epilepsy displayed increased slow wave activity power during nonrapid eye movement sleep over widespread, bilateral scalp regions. This global increase in slow wave activity power was positively correlated with the frequency of secondarily generalized seizures in the 3–5 days preceding the recordings. Individual patients also showed local increases in sleep slow wave activity power at scalp locations matching their seizure focus. This local increase in slow wave activity power was positively correlated with the frequency of interictal spikes during the last hour of wakefulness preceding sleep. By contrast, frequent interictal spikes during non-rapid eye movement sleep predicted a reduced homeostatic decrease in the slope of sleep slow waves during the night, which in turn predicted reduced daytime learning. Patients also showed an increase in sleep spindle power, which was negatively correlated with intelligence quotient. Altogether, these findings suggest that both seizures and interictal spikes may induce long-lasting changes in the human brain that can be sensitively detected by electroencephalographic markers of sleep homeostasis. Furthermore, abnormalities in sleep markers are correlated with cognitive impairment, suggesting that not only seizures, but also interictal spikes can have negative consequences.
Commentary
Electrical status epilepticus during sleep (ESES) of childhood, and density of interictal activity in both children and adults impact sleep homeostasis (1). Boly et al. hypothesized that the frequency and extent of epileptic activity can disrupt sleep homeostasis, and, in turn, potentially contribute to cognitive impairment in adults with focal-onset epilepsy. The authors capitalized on a neurophysiological measure known as slow wave activity (SWA) power, a scalp EEG-derived delta power range of 1 to 4 Hz (2). SWA power dramatically decreases through a night of sleep, and therefore is thought to be a sensitive indicator of sleep need, and its underlying homeostatically regulated recovery process (3). Because sleep, especially slow wave sleep, is in a quantitative and predictive relationship with prior wakefulness, sleep disruption is associated with a proportional increase in delta range power, and a decrease with adequate to excessive sleep (2).
A decrease in sleep SWA power during nonrapid eye movement (NREM) sleep is associated with promoting learning and memory consolidation (3). Enhanced synaptic strength is also associated with slow waves on EEG of larger amplitudes and steeper slopes, an example of synaptic potentiation (4, 5). In humans and animals, both global and regional sleep SWA power have been shown to increase after learning new tasks (6, 7). Boly et al. proposed that epileptic activity in adults can negatively impact sleep SWA power, and the negative slope of sleep slow waves, and correlate with cognitive impairment.
Neurophysiologically, the authors investigated the potential influence of both nocturnal interictal spikes and seizures on the homeostatic alterations of NREM sleep EEG markers of SWA. The patient group in the study displayed overall shorter sleep time and sleep efficiency compared with controls. In addition, at the group level, the frequency of interictal spikes during epochs of NREM sleep was negatively correlated with the overnight decrease in negative slow wave slope. The authors demonstrated a correlation of these sleep EEG biomarkers with neuropsychological outcomes of global (full-scale) intelligence quotient and visual learning measures using the Wechsler Adult Intelligence Scale and Brief Visuospatial Memory Test-Revised, respectively.
The cohort in the study included adults with either temporal or extratemporal focal-onset epilepsies. The pathophysiological underpinnings of sleep-associated thalamocortical networks, and their interplay with the ictal onset region, were inherent in the paper's discussion of the EEG biomarkers. The authors approached network connectivity from an electrophysiological perspective using high-density scalp EEG. That is, they facilitated visualization of regional changes by presenting averaged scalp topography maps at the group level for SWA power, negative slope of sleep slow waves, and sleep spindle power for electrophysiological comparisons between NREM and REM sleep. Frequent interictal epileptic complexes during NREM sleep were correlated with a dampened overnight decline in SWA. This finding contrasted with a more robust homeostatic decrease in SWA power during normal NREM sleep in the control group. Furthermore, a diminished decline in SWA power and slow wave slope correlated with measured cognitive impairment in the focal-onset epilepsy group. The authors also observed a robust positive correlation between the global increase in NREM sleep SWA power, slope of NREM sleep slow waves, and the number of secondarily generalized seizures occurring predominantly during NREM sleep during epilepsy monitoring unit (EMU) recording using standard 10–20 scalp electrodes (prior to high-density scalp EEG recording). The authors suggest that increased sleep SWA power following increased seizure frequency may be a pathophysiological correlate of synaptic plasticity, in that seizures could induce plastic changes leading to increased hyperexcitability and potentially contributing to epileptogenesis. However, many of the patients in the cohort did not seize during their EMU admission. This study demonstrated a ‘snapshot’ of significant group findings limited to adults over several days of scalp EEG recording. The relationship between the evolution of the epilepsies and neurocognitive development is crucial for better understanding long-term outcomes.
The ontogeny of active ‘focal-onset’ epileptic networks, approached from a functional neuroimaging perspective, rather than electrophysiologically, has been previously shown to correlate with neurocognitive and psychosocial development. Such neuroanatomical resolution was shown by Ciumas et al., (8) who investigated children with Rolandic epilepsy (RE). Approximately three-quarters of seizures in patients with RE are reported during NREM sleep. These children were compared with age-matched control subjects using diffusion tensor imaging (DTI). This work investigated transient diffusion-related changes measured by fractional anisotropy (FA) and mean diffusivity (MD) in conjunction with neurocognitive measures. During childhood, the authors reported subjects with RE performed at a lower level compared with controls on indices of hyperactivity/impulsivity and attention deficit hyperactivity disorder. In addition, subjects with RE demonstrated significantly lower performance scores than control subjects on multiple subscales of the Wechsler Intelligence Scale for Children (WISC-IV). FA in the precentral gyrus was negatively correlated with anxiety and learning scores, and was positively correlated with processing speed on the WISC-IV. Both correlations indicated greater FA abnormalities in subjects with lower cognitive performance. MD did not correlate with neurocognitive testing.
In a seminal population-based study by Camfield and Camfield (9), normalization of adult psychosocial outcomes following the resolution of RE in the mid to late teenage years suggest normalization of complex neural connectivity patterns as these children grew into adulthood. As adults, this cohort demonstrated an impressive high rate of employment (97%), low rate of poverty, well-adjusted relationships, and rare incidence of mental health problems. In comparison, those adults diagnosed with active primary generalized epilepsy, such as childhood absence epilepsy without clear-cut remission of the epilepsy into adulthood, demonstrated high rates of social problems comparable to individuals diagnosed with chronic rheumatoid arthritis (control group). Moreover, a marked association of poverty was seen with individuals diagnosed with juvenile myoclonic epilepsy (30%), idiopathic epilepsy (NOS) (40%), complex partial “dyscognitive” seizures (50%), and focal-onset seizures with generalization secondarily (26%).
These longitudinal studies reach beyond the scope of Boly et al. However, active epileptogenic networks, whether so-called focal-onset neocortical, or primary generalized thalamocortical circuits, demonstrate robust neurocognitive and psychosocial relationships unfolding over the lifespan. Incorporating neurophysiological and neuropsychological measures, functional neuroimaging techniques such as DTI-based analyses, and intracranial recording, including stereo-EEG for validating spatial connectivity (10) will provide a powerful suite of necessary tools for better understanding the impact that nocturnal interictal epileptiform activity and seizures play in disrupting sleep homeostasis and cognition. Boly et al. reveal, in a snapshot, the consequences of nocturnal epileptic activity, and poor seizure control hijacking the molecular underpinnings of synaptic plasticity. The authors further demonstrate the impact between maintaining sleep homeostasis and cognitive function. This study provides an incentive for detailed, longitudinal, population-based studies of epilepsies followed through the lifespan for predicting prognosis, and better understanding the relationship between sleep homeostasis and neuropsychological outcomes.