Objective: The proposed study will investigate the relationship between memory deficits and abnormal electrical activity seen on electroencephalography (EEG) in patients with seizures. Patients with temporal lobe epilepsy (TLE) often demonstrate memory dysfunction in the setting of otherwise normal intelligence. This finding is consistent with the theory that establishing new memories is dependent to a large extent on the function of the hippocampus and other mesial temporal lobe structures, a network known to be dysfunctional in TLE. Prior studies found an association between disruptions of cognitive task performance and the presence of interictal epileptiform discharges (IEDs). IEDs are intermittent spikes or sharp waves that reflect abnormal neuronal firing, but do not organize into a seizure. Embedded within the IEDs may be pathological high frequency gamma oscillations (HFOs), distinct from the normal high frequency activity that is thought to underlie memory formation. In clinical practice, IEDs are considered only to be markers of epilepsy and are not suppressed with medications. Little is known, however, regarding the properties of IEDs that pose the greatest risk to cognitive function or the mechanism by which IEDs cause cognitive deficits. The present study examines the effects of IEDs during encoding on subsequent memory for the stimulus items.
The first aim of the study is to determine the spatial and temporal characteristics of IEDs within the hippocampus that will predict poorer delayed recall and recognition, as well as identify the effect of embedded pathological HFOs.
The second aim i s to identify the mechanism by which IEDs interrupt memory encoding. The hypothesis is that IEDs disrupt the normal EEG rhythms that underlie memory formation. More specifically, the prediction is that IEDs will cause a decrease in the amount of normal high frequency gamma activity induced during memory encoding. Furthermore, it is proposed that IEDs and their associated pathological HFOs will disrupt the synchronous timing, or coherence, of normal gamma oscillations throughout the hippocampus. Research Plan/Methods: To test these hypotheses, subjects with TLE will complete memory tasks during intracranial EEG recordings. Testing will include verbal and non-verbal encoding, working memory, and delayed recall and recognition tasks. The electrodes will be implanted within or alongside the hippocampus for clinical evaluations prior to possible resective epilepsy surgery. IEDs will be identified by manual review, with temporal and spatial properties quantified using Neuroscan software. HFO power and coherence will be assessed using spectral analysis. Clinical Relevance: The interruption of normal EEG oscillations by IEDs would help to explain both transient and long-term memory dysfunction in this patient population. The proposed study will also determine if pathological HFOs within the IEDs contribute to their adverse cognitive effects. Evidence that IEDs disrupt electrical activity necessary for memory encoding may indicate the need for suppression of discharges or point the way to new treatments for memory dysfunction. These findings could direct future investigations aimed at therapeutic approaches to improve cognition in epilepsy patients by alteration of abnormal oscillatory activity.

Public Health Relevance

Evidence that interictal epileptiform discharges (IEDs) disrupt the normal brain activity underlying memory formation in epilepsy patients may indicate a need for intervention. Findings of this study may suggest pathways for treatment of memory deficits, including suppression of IEDs with medications or use of brain stimulation strategies to alter abnormal electrical activity. Results will be of particular importance to combat Veterans and others with head injuries, as the most common sequelae of traumatic brain injury (TBI) are seizures and neuropsychological dysfunction. While cognitive deficits are likely multifactorial, it is important to assess the possble role of IEDs, and the mechanism of their effects, as they are a potentially treatable factor. Defining a mechanism to help explain memory dysfunction and identifying possible treatment approaches may have a positive impact on quality of life and independence in epilepsy patients.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Veterans Administration (IK2)
Project #
5IK2CX001255-02
Application #
9378722
Study Section
Neurobiology B (NURB)
Project Start
2016-10-01
Project End
2021-09-30
Budget Start
2017-10-01
Budget End
2018-09-30
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
VA Medical Center
Department
Type
DUNS #
070501002
City
New York
State
NY
Country
United States
Zip Code
10010