Abstracts

Rationale: Complex partial seizures originating in the limbic system can impair consciousness even when seizure activity does not propagate to neocortex. During these seizures, high-frequency, poly-spike seizure activity dominates the temporal lobe while normal neocortical EEG is replaced with low frequency oscillations similar to those seen in non-REM sleep. We hypothesized that the transition to sleep-like cortical slow waves is due to depressed activity in subcortical arousal systems and tested this hypothesis in a rat limbic seizure model. Methods: As described previously, limbic seizures were induced by a 2-second, 60 Hz electrical stimulus in the dorsal hippocampus. To map areas of increased and decreased neuronal activity we recorded blood oxygen level dependent (BOLD) fMRI data at 9.4 T. To investigate the neuronal changes underlying the BOLD signal changes, we conducted multiunit recordings from the hypothalamus, thalamus and brainstem. Within the brainstem, we recorded and labeled individual cells in the pedunculopontine tegmental nucleus using the juxtacellular method. We identified cholinergic cells using immunohistochemistry for choline acetyltransferase. Results: During BOLD experiments, hippocampal, septal and hypothalamic BOLD increases were associated with widespread cortical, thalamic, and brainstem BOLD decreases. Multiunit electrophysiology recordings confirmed that BOLD increases represent increased neuronal activity in hypothalamus while BOLD decreases represent decreased neuronal activity. Multiunit recordings in thalamus showed decreased firing in intralaminar thalamus and spindle-like activity in thalamic relay nuclei. Our juxtacellular recordings in the pedunculopontine tegmental nucleus showed that cholinergic neurons decreased their firing dramatically during seizures during which the cortex converted to slow oscillations. Conclusions: These direct recordings in brainstem and thalamus suggest a mechanism to explain loss of consciousness during complex partial seizures: (1) seizure activity spreads from hippocampal to inhibitory structures including the lateral septal nuclei and hypothalamus, (2) increased activity in GABAergic neurons in lateral septum and anterior hypothalamus depress subcortical arousal systems, and (3) suppression of ascending arousal systems including the brainstem cholinergic nuclei leads to hyperpolarized thalamic nuclei and cortical rhythms normally present during non-REM sleep.