Gregory L. Holmes, M.D.
Gregory L. Holmes, M.D.
Professor and Chair
Department of Neurological Sciences
426 Health Science Research Facility, Burlington, VT 05405
Phone: (802) 656-4588
University of Vermont
Although seizures are the most striking clinical manifestation of the epilepsies, children with epilepsy are at risk not only for seizures, but also for a myriad of co-morbid health problems. Among the co-morbidities associated with epilepsy in children, cognitive abnormalities are among the most common and devastating. Our laboratory has vigorously addressed the pathophysiological mechanisms responsible for these seizure-related cognitive deficits. We have shown that recurrent seizures as a result of a variety of etiologies can lead to decreases in neurogenesis, increases in sprouting, persistent decreases in GABA currents in the hippocampus and neocortex, enhanced excitation in the neocortex, impairment in spike frequency adaptation, marked reductions in after-hyperpolarizing potentials following spike trains, and altered LTP. Paralleling these morphological and physiological changes rats with early-life seizures have impaired spatial cognition, attention, sociability and behavioral flexibility. These studies have had a marked influence on how seizures are viewed and treated by clinicians. It had been conventional wisdom for many decades that while the immature brain is prone to seizures, there are few consequences of early-life seizures. Our studies have shown convincingly than recurrent seizures during development can result in severe consequences in regards to cognitive function.
Recognizing that the developing brain is dynamic and complex and predicting cognitive function from the physiological and morphological changes of individual ensembles of cells is difficult, we have used a system biology approach to quantitatively measure behavior of groups of interacting components, using both single cell and network oscillations properties to describe and predict dynamical behavior. We and others have shown that following pilocarpine-induced status epilepticus in adult rats there are pronounced impairments in spatial cognition and therefore be used this model to understand the cognitive consequences of status epilepticus. We were the first group to show that following status epilepticus rats have abnormalities in both rate coding, with impaired place cell coherence and firing rates, and temporal coding, with marked abnormalities in phase precession and time compression of firing among pairs of neurons. These deficits in rate and temporal coding parallel deficits in the Morris water maze task. In normal rats there is a direct relationship between theta frequency and running speed. Helping to explaining the abnormalities in temporal coding we found after status epilepticus rats had impaired speed/theta frequency correlation coefficients compared to control animals. This impaired speed/theta frequency relationship is directly related to performance in task of spatial memory, indicating that in rats with epilepsy there is a deficit in the integration of locomotor information into memory processes. Sequential reactivation of neurons occurs after spatial experience, for example after the rat has explored a new environment. This reactivation, also termed replay by some, has a unique form, in which recent episodes of spatial experience are replayed in a temporally reversed order during a physiological sharp-wave ripple. We have found that rats with epilepsy performing in a spatial task have less neuronal reactivation, demonstrating impaired online processing of spatial memory. Unlike during the wake state, the temporal structure of pyramidal cell activation during sleep in the hippocampus is intact in rats with epilepsy.
There is increasing human and animal evidence that brain oscillations play a critical role in the development of spatial cognition. In rat pups, disruption of hippocampal rhythms via optogenetic stimulation during the critical period for memory development impairs spatial cognition. Early-life seizures are associated with long-term deficits in spatial cognition and aberrant hippocampal oscillatory activity. We studied whether modulation of hippocampal rhythms following early-life seizures can reverse or improve hippocampal connectivity and spatial cognition. We used optogenetic stimulation of the medial septum to induce physiological 7Hz theta oscillations in the hippocampus during the critical period of spatial cognition following early-life seizures. Optogenetic stimulation of the medial septum in control and rats subjected to early-life seizures resulted in precisely regulated frequency-matched hippocampal oscillations. Rat pups receiving active blue light stimulation performed better than the rats receiving inert yellow light in a test of spatial cognition. The improvement in spatial cognition in these rats was associated with a faster theta frequency and higher theta power, coherence and phase locking value in the hippocampus than rats with early-life seizures receiving inert yellow light. These findings indicate that following early life seizures, modification of hippocampal rhythms may be a potential novel therapeutic modality.
Key Research Areas:
Epilepsy, Neuroplasticity, Critical Period, Spatial Cognition, Network Maturation, Temporal Coordination, Dysrhythmias