5 Combining Neurophysiology and Behavioral Measures to Identify Biomarkers of Clinical and Preclinical Hippocampus-Dependent Memory Dysfunction

Objective:Memory is a critical piece of the human experience and impairments in neural memory networks can have devastating consequences for the affected person. A subtype of memory, episodic memory generates context for the present based on past experience and allows us to make predictions about the future. Episodic memories become stable fixtures through long-term memory consolidation. It is believed that consolidation of episodic memory requires a dynamic interplay between connected hippocampal-cortical networks, mainly during sleep. Sleep oscillations, slow oscillations and thalamocortical spindles, coupled with hippocampal sharp wave ripples (SWR) is proposed to be mechanistically involved in establishing the crucial cortical-subcortical dialog. The current study aimed to determine alterations in typical sleep oscillations and oscillation coupling in patients with and without structural hippocampal damage and correlate them with neuropsychological measures believed to be sensitive to hippocampal dysfunction, i.e., Rey Auditory Verbal Learning Task (RAVLT) and Verbal Paired Associates (VPA-II).Participants and Methods:We used intracranial electroencephalography (iEEG) in 14 patients with epilepsy to directly record hippocampal and neocortical oscillations and neuropsychological measures obtained prior to implantation. Half of the participants were diagnosed with mesial temporal sclerosis (MTS) in the left hippocampus and healthy tissue in the right hippocampus. The other half did not have MTS and had either mesial temporal epilepsy without MTS or extra-temporal seizures. We analyzed hippocampal SWR output from both hippocampi and characterized neocortical slow oscillations and spindles and their coupling for each participant. We correlated electrophysiological data with behavioral results of neuropsychological testing in order to characterize the clinical relevance.Results:SWR analysis revealed significant differences in the frequency, t(7639) = 15.52, p>.001, p > .001), amplitude, t(7664) = -23.93, p > .001, and waveforms (p > .001) of SWR in the sclerotic versus healthy hippocampi. Patients with a sclerotic hippocampus but relatively preserved verbal memory scores (RAVLT, VPA-II) showed increased SWR amplitudes in the contralateral hippocampus compared to patients with low verbal memory scores. Additionally, we found differences between hemispheres in phase amplitude coupling of SWRs to spindles and SOs (p > 0.001). Results of our correlational analysis were variable and dependent upon additional factors, such as age of onset and diagnosis duration.Conclusions:Results from this work will aid in establishing a criterion for characterizing a relationship between subcortical and cortical oscillations as they relate to memory performance. Besides aiding our understanding of the neural mechanisms underpinning memory consolidation this will ideally help with developing neurophysiological biomarkers that may predict possible memory decline in resective or ablative neurosurgery absent of structural lesion. In addition, this work may potentially provide first evidence of a neurophysiological biomarker directly recorded from the human hippocampus to support possible reorganization of memory functioning in the non-sclerotic hippocampus.