Multisensory Flicker Modulates Widespread Brain Networks and Reduces Interictal Epileptiform Discharges in Humans Restricted; Files Only

Abstract

Modulating brain oscillations has strong therapeutic potential. However, commonly used noninvasive interventions such as transcranial magnetic or direct current stimulation have limited effects on deeper cortical structures like the medial temporal lobe. Repetitive audio-visual stimulation, or sensory flicker, modulates such structures in mice, but most studies of its neurophysiological extent in humans are limited by either spatial or temporal resolution. Using stereoelectroencephalography, we mapped and quantified the neurophysiological effects of sensory flicker in human subjects undergoing presurgical intracranial seizure monitoring. We found that flicker modulates both local field potential and single neurons in higher cognitive regions, including the medial temporal lobe and prefrontal cortex, and that local field potential modulation is likely mediated via resonance of involved circuits. We then assessed how flicker affects pathological neural activity, specifically interictal epileptiform discharges, a biomarker of epilepsy also implicated in neurodegenerative disorders including Alzheimer’s disease. In our patient population with focal seizure onsets, sensory flicker decreased the rate interictal epileptiform discharges. Our findings support the use of sensory flicker to modulate deeper cortical structures and mitigate pathological activity in humans.

Table of Contents

Chapter 1: Introduction .......................................................................................................... 1 1.1. A Need for Non-invasive Neurostimulation Therapies..........................................................2 1.1.1. The Burden of Brain Disorders............................................................................................................. 2 1.1.2. Therapeutic Approaches...................................................................................................................... 2 1.1.3. The Promises and Challenges of Neurostimulation ............................................................................ 4 1.2. Therapeutic Appeal of Sensory Flicker..................................................................................7 1.2.1. Therapeutic Effects in AD Mouse Models............................................................................................ 7 1.2.2. Therapeutic Mechanisms................................................................................................................... 11 1.2.3. Human Clinical Trials.......................................................................................................................... 16 1.2.4. Sensory Flicker Beyond AD................................................................................................................. 19 1.3. Human Neurophysiology of Sensory flicker ........................................................................22 1.3.1. Sensory Evoked Potentials................................................................................................................. 23 1.3.2. Non-invasive Study of the Steady-State EP ....................................................................................... 25 1.3.3. Intracranial EEG: the Gold Standard of Human Neurophysiology .................................................... 29 1.3.4. Intracranial Studies of the Steady-State EP....................................................................................... 32 1.4. Mechanisms of the Steady-State EP ...................................................................................35 1.4.1. Linear Superposition of Single-Pulse Evoked Potentials................................................................... 37 1.4.2. Resonance of Circuit Oscillators......................................................................................................... 38 1.4.3. Entrainment of Endogenous Oscillations........................................................................................... 42 1.5. Effects of Flicker on Pathological Neurophysiology.............................................................45 1.5.1. IEDs in Epilepsy................................................................................................................................... 45 1.5.2. IEDs Beyond Epilepsy ......................................................................................................................... 47 1.5.3. Effects of Sensory Stimulation on IEDs.............................................................................................. 49 1.6. Study Objectives ................................................................................................................51 Chapter 2: Approaches and Methods.....................................................................................53 2.1. Clinical Research Context ...................................................................................................54 2.1.1. Patient Population.............................................................................................................................. 54 2.1.2. Cohort Characteristics........................................................................................................................ 55 2.1.3. Intracranial Recordings ...................................................................................................................... 59 2.2. Localization of the Signal....................................................................................................60 2.2.1. Electrode Localization ........................................................................................................................ 60 2.2.2. Anatomical Characterization of the Sensory Response .................................................................... 62 2.3. Sensory Stimulation ...........................................................................................................64 2.3.1. Risk Consideration in Epilepsy Patients............................................................................................. 64 2.3.2. General Paradigm............................................................................................................................... 64 2.3.3. Flicker 5.5-40-80Hz Paradigm............................................................................................................. 67 2.3.4. Single-Pulse Paradigm........................................................................................................................ 68 2.3.5. Flicker 5.5-80Hz Range Paradigm....................................................................................................... 68 2.4. Neurophysiological Analyses..............................................................................................70 2.4.1. Exclusion of LFP Channels .................................................................................................................. 71 2.4.2. Re-referencing of LFP Recordings ...................................................................................................... 71 2.4.3. Analysis of the LFP.............................................................................................................................. 72 2.4.4. Analysis of Single Neuron Activity ..................................................................................................... 76 Chapter 3: Extent of Sensory Flicker Modulation in the Human Brain....................................79 3.1. Controls .............................................................................................................................80 3.1.1. Negative Control: Occluded Condition .............................................................................................. 80 3.1.2. Positive Control: Modulation of Early Sensory Regions.................................................................... 81 3.2. Sensory Flicker Modulates the Medial Temporal Lobe and Prefrontal Cortex .....................84 3.3. Sensory Flicker Modulates Single Neurons in the Hippocampus and Cingulate Cortex ........88 3.4. Sensory Flicker Modulates Widespread Functional Networks.............................................90 Chapter 4: Mechanism of Sensory Flicker Modulation...........................................................94 4.1. Single Pulses Evoke a Sensory Response in Widespread Brain Networks ............................95 4.2. Flicker Modulation Does Not Result From Linear Superposition of Single Pulse EPs............96 4.3. Resonance of Circuits to Specific Flicker Frequencies........................................................101 Chapter 5: Effects of Sensory Flicker on Interictal Epileptiform Discharges..........................109 5.1. Sensory Flicker Decreases Interictal Epileptiform Discharges............................................110 Chapter 6: Discussion ..........................................................................................................114 6.1. High Spatiotemporal Resolution of Sensory Response......................................................115 6.1.1. The Steady-State EP ......................................................................................................................... 115 6.1.2. The Single Pulse EP........................................................................................................................... 118 6.2. The Steady-State EP Implicates Circuit Resonance............................................................120 6.3. Sensory Flicker as a Potential to Modulate Epileptiform Activity ......................................125 6.4. Conclusion .......................................................................................................................129 References...........................................................................................................................131

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Palavra-chave	sensory flicker interictal epileptiform discharges intracranial EEG non-invasive neurostimulation resonance
Committee Chair / Thesis Advisor	Annabelle C. Singer, Emory University Dr. Jon T. Willie, Emory University
Committee Members	Joseph R. Manns, Emory University Stephan B. Hamann, Emory University Nigel P. Pedersen, Emory University Ilya Nemenman, Emory University

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