Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle

Abstract

Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability.excitability | epilepsy | sleep N ormal functioning of cortical networks critically depends on a finely tuned level of excitability, the transient or steady-state response in which the brain reacts to a stimulus. Whereas small, local responses indicate a comparably small excitability, large and global responses consequently suggest excitability to be high. The importance of adequate excitability levels is highlighted by the pathological consequences and impaired performance resulting from aberrant network excitability. In epilepsy, changes in cortical network excitability are believed to be an important cause underlying the initiation and spread of seizures, that is, the large nonphysiological neuronal activity events across time and space (1-3). Evidence for changes of excitability in brain networks affected in epilepsy has come from a variety of observations. To assess the level of excitability under in vivo experimental conditions one usually measures the size of the evoked cortical activity to external perturbations, typically either by transcranial magnetic stimulation (TMS) or, in the case of epilepsy patients, by electrical stimulation. Studies of electrical stimulation with subdural electrodes during interictal periods found the evoked potentials to be larger in regions related to the cortical onset region of epileptiform activity (4-6). The enhanced responses to electrical stimulation in epileptogenic cortex were taken as indication of an increased excitability of neural tissue in these areas. Similarly, studies using TMS consistently reported a hyperexcitability in focal epilepsies (7-10). Consequently, changes in excitability have been helpful in identifying the se...

Quantifying antiepileptic drug effects using intrinsic excitability measures

“…7,13 In the current study, we extended this work by demonstrating that synchronization levels correlate with the cumulative AED load in a dosagedependent manner. 7,13 In the current study, we extended this work by demonstrating that synchronization levels correlate with the cumulative AED load in a dosagedependent manner.…”

“…7 To systematically explore the relationship between drug load and synchronization depending on the frequency band, we combined data from all 10 patients to calculate the average synchronization value for each AED load (Fig. 7 To systematically explore the relationship between drug load and synchronization depending on the frequency band, we combined data from all 10 patients to calculate the average synchronization value for each AED load (Fig.…”

“…7 These measures (termed intrinsic excitability measures, IEMs) were motivated by observations from computational 8,9 and in vitro 10 studies that demonstrated that the level of excitation/inhibition (E/I) or, more generally, the level of effective network connectivity, is closely linked to the amount of synchronization in brain networks. Although perturbational approaches to measure levels of excitability by electrical or transcranial magnetic stimulation (TMS) are a valuable research tool, they are currently impractical for regular clinical monitoring, due in large part to their complex design and the absence of well-established absolute reference values.…”

Sleep, synaptic homeostasis and neuronal firing rates

“…Specifically, a recent study measured the amplitude of the TMS-evoked EEG response using a constant routine protocol, which helps unmasking circadian influences [28]. In line with previous sleep deprivation experiments that measured the EEG reaction to TMS [7] or intrinsic measures of cortical excitability [29], it was found that EEG responses were larger at the end as compared to the beginning of 29 hours of continuous wake [28]. The same TMS-evoked responses, however, covaried with cortisol levels and showed a significant “dip” in the evening around the so-called wake-maintenance zone, indicating a circadian effect [28].…”

More Severe Insomnia Complaints in People with Stronger Long-Range Temporal Correlations in Wake Resting-State EEG

“…Sleep is hypothesized to regulate the complex organization of brain dynamics (Pearlmutter and Houghton, 2009), by keeping excitatory and inhibitory processes balanced (Huber et al, 2013). While prolonged wakefulness increases brain excitability, sleep reduces it, preventing an imbalance towards excitation that would favor runaway seizure-like activity (Meisel et al, 2013, 2015). Therefore, important pathophysiological mechanisms underlying insomnia complaints may be unveiled by studying the complex organization of brain dynamics.…”