Impaired Serotonergic Brainstem Function during and after Seizures.

Impaired breathing, cardiac function, and arousal during and after seizures are important causes of morbidity and mortality. Previous work suggests that these changes are associated with depressed brainstem function in the ictal and post-ictal periods. Lower brainstem serotonergic systems are postulated to play an important role in cardiorespiratory changes during and after seizures, whereas upper brainstem serotonergic and other systems regulate arousal. However, direct demonstration of seizure-associated neuronal activity changes in brainstem serotonergic regions has been lacking. Here, we performed multiunit and single-unit recordings from medullary raphe and midbrain dorsal raphe nuclei in an established rat seizure model while measuring changes in breathing rate and depth as well as heart rate. Serotonergic neurons were identified by immunohistochemistry. Respiratory rate, tidal volume, and minute ventilation were all significantly decreased during and after seizures in this model. We found that population firing of neurons in the medullary and midbrain raphe on multiunit recordings was significantly decreased during the ictal and post-ictal periods. Single-unit recordings from identified serotonergic neurons in the medullary raphe revealed highly consistently decreased firing during and after seizures. In contrast, firing of midbrain raphe serotonergic neurons was more variable, with a mixture of increases and decreases. The markedly suppressed firing of medullary serotonergic neurons supports their possible role in simultaneously impaired cardiorespiratory function in seizures. Decreased arousal likely arises from depressed population activity of several neuronal pools in the upper brainstem and forebrain. These findings have important implications for preventing morbidity and mortality in people living with epilepsy. SIGNIFICANCE STATEMENT: Seizures often cause impaired breathing, cardiac dysfunction, and loss of consciousness. The brainstem and, specifically, brainstem serotonin neurons are thought to play an important role in controlling breathing, cardiac function, and arousal. We used an established rat seizure model to study the overall neuronal activity in the brainstem as well as firing of specific serotonin neurons while measuring cardiorespiratory function. Our results demonstrated overall decreases in brainstem neuronal activity and marked downregulation of lower brainstem serotonin neuronal firing in association with decreased breathing and heart rate during and after seizures. These findings point the way toward new treatments to augment brainstem function and serotonin, aiming to prevent seizure complications and reduce morbidity and mortality in people living with epilepsy.

Epilepsy and driving: potential impact of transient impaired consciousness.

Driving is an important part of everyday life for most adults, and restrictions on driving can place a significant burden on individuals diagnosed with epilepsy. Although sensorimotor deficits during seizures may impair driving, decreased level of consciousness often has a more global effect on patients' ability to respond appropriately to the environment. Better understanding of the mechanisms underlying alteration of consciousness in epilepsy is important for decision-making by people with epilepsy, their physicians, and regulators in regard to the question of fitness to drive. Retrospective cohort and cross-sectional studies based on surveys or crash records can provide valuable information about driving in epilepsy. However, prospective objective testing of ictal driving ability during different types of seizures is needed to more fully understand the role of impaired consciousness and other deficits in disrupting driving. Driving simulators adapted for use in the epilepsy video-EEG monitoring unit may be well suited to provide both ictal and interictal data in patients with epilepsy. Objective information about impaired driving in specific types of epilepsy and seizures can provide better informed recommendations regarding fitness to drive, potentially improving the quality of life of people living with epilepsy.

Decreased but diverse activity of cortical and thalamic neurons in consciousness-impairing rodent absence seizures.

Absence seizures are brief episodes of impaired consciousness, behavioral arrest, and unresponsiveness, with yet-unknown neuronal mechanisms. Here we report that an awake female rat model recapitulates the behavioral, electroencephalographic, and cortical functional magnetic resonance imaging characteristics of human absence seizures. Neuronally, seizures feature overall decreased but rhythmic firing of neurons in cortex and thalamus. Individual cortical and thalamic neurons express one of four distinct patterns of seizure-associated activity, one of which causes a transient initial peak in overall firing at seizure onset, and another which drives sustained decreases in overall firing. 40-60 s before seizure onset there begins a decline in low frequency electroencephalographic activity, neuronal firing, and behavior, but an increase in higher frequency electroencephalography and rhythmicity of neuronal firing. Our findings demonstrate that prolonged brain state changes precede consciousness-impairing seizures, and that during seizures distinct functional groups of cortical and thalamic neurons produce an overall transient firing increase followed by a sustained firing decrease, and increased rhythmicity.

Reliability of patient self-report of cognition, awareness, and consciousness during seizures.

OBJECTIVE: Clinicians rely on patient self-report of impairment during seizures for decisions including driving eligibility. However, the reliability of patient reports on cognitive and behavioral functions during seizures remains unknown. METHODS: We administered a daily questionnaire to epilepsy patients undergoing continuous video-EEG monitoring, asking about responsiveness, speech, memory, awareness, and consciousness during seizures in the preceding 24 hours. We also administered a questionnaire upon admission about responsiveness, speech, and awareness during seizures. Subjective questionnaire answers were compared with objective behavioral ratings on video review. Criteria for agreement were Cohen's kappa >0.60 and proportions of positive and negative agreement both >0.75. RESULTS: We analyzed 86 epileptic seizures in 39 patients. Memory report on the daily questionnaire met criteria for agreement with video review (κ = 0.674 for early, 0.743 for late recall). Subjective report of awareness also met agreement criteria with video ratings of memory (κ = 0.673 early, 0.774 late). Concordance for speech was relatively good (κ = 0.679) but did not meet agreement criteria, nor did responsiveness or consciousness. On the admission questionnaire, agreement criteria were met for subjective report of awareness versus video ratings of memory (κ = 0.814 early, 0.806 late), but not for other comparisons. INTERPRETATION: Patient self-report of memory or awareness showed the best concordance with objective memory impairment during seizures. Self-report of impairment in other categories was less reliable. These findings suggest that patient reports about impaired memory during seizures may be most reliable, and otherwise determining functional impairments should be based on objective observations.