Intracranial Studies Of Human Epilepsy In A Surgical Setting

Intracranial Studies Of Human Epilepsy In A Surgical Setting Department of Neurology David Geffen School of Medicine at UCLA

Presentation Goals Epilepsy and seizures Basics of the electroencephalogram or EEG Mesial temporal lobe epilepsy (MTLE) Intracranial depth electrode and microelectrode studies in presurgical patients with medically refractory epilepsy In vivo single neuron studies in patients with MTLE

Epilepsy - what is it? Epilepsy is a disorder of the central nervous system characterized by recurrent seizures unprovoked by acute systemic or neurologic insult. A seizure is abnormally excessive or synchronous neuronal activity in the brain.

Fast facts on epilepsy ~3 million in U.S. 1, 50 million worldwide 2 have epilepsy Epilepsy 3 rd most common neurological disorder in U.S. (stroke and Alzheimer s), and equal in prevalence to cerebral palsy, multiple sclerosis and Parkinson s combined No racial or gender preference Affects all ages 60-70% of newly diagnosed successfully treated with antiepileptic drugs 1 Begley et al. Epilepsia 2000; 2 World Health Organization

Causes of epilepsy Genetic, e.g. mutation in genes encoding ion channels Structural or metabolic, e.g. lesion resulting from stroke or trauma Unknown, i.e. the nature of the underlying has not been identified

Electroencephalogram (EEG) is an important test to diagnosis seizure disorders Standard EEG High density EEG Standardized placements Electrodes

EEG of epileptic seizure Patararia et al. 1998

Neurophysiological basis of EEG Consists primarily of excitatory and inhibitory postsynaptic potentials. Smaller contributions from Ca 2+ - mediated events, e.g. calcium spikes and afterhyperpolarization (Ca 2+ - mediated K + conductance). Minor contribution from Na+-mediated action potentials, except during physiological (sleep) or pathological (epilepsy) synchronous activity.

EEG reflect spatiotemporal summation of extracellular ion currents

Neurons and intercellular communication presynaptic postsynaptic Figure 1-3 from The Human Brain, Nolte

Proteins form channels that regulate the movement of ions across the plasma membrane Figures 10-1 & 11-4 from The Molecular Biology of The Cell 1994

Passive and active responses of the plasma membrane Figures 3-4, 3-5 & 3-11 from The Neuron, 1997

Classification of epileptic seizures Focal seizures begin within networks limited to one cerebral hemisphere. Generalized seizures begin within and rapidly involve networks in both hemispheres. Unknown, e.g. epileptic spasms

Some focal seizures begin with alteration in consciousness or awareness, then evolve to bilateral, convulsive behavior

Treatments for epilepsy Anti-seizure drugs Including carbamazepine, phenobarbital, phenytoin (Dilantin), valproate (Depakote) Drug-related side effects Surgical treatment Option for some patients when AEDs fail Removal of epileptogenic brain region Electrical/deep brain stimulation Vagal nerve, trigeminal nerve stimulation Ketogenic diet high fat, low carbohydrate diet; adjunctive therapy in children with refractory epilepsy

Mesial temporal lobe epilepsy Most common medically intractable seizure disorder. Seizures begin in hippocampus and/or adjacent structures. Often associated with hippocampal sclerosis. Epilepsy surgery can eliminate seizures in up to 80% of patients with MTLE and HS.

Mesial temporal lobe structures Lateral view right side Anterior view Amygdala Hippocampus Parahippocampal gyrus Ventral surface with portion of the right temporal lobe removed

Hippocampal sclerosis associated with neuron loss and synaptic reorganization Salmenpera & Duncan, J Neurol Neurosurg Psychiatry 2005

Stereotatic frame used to place depth electrodes in situ Z X Y

Surgical implantation of depth electrodes

Depth electrodes specially adapted with microelectrodes A-P Skull X-ray

Depth electrode-recorded seizure in hippocampus and entorhinal cortex

Neuronal disturbances associated with epileptogenicity Results from several different experimental models of epilepsy suggest burst firing is the neuronal correlate of epileptogenicity.

Paroxysmal depolarization shift (PDS) and generation of epileptiform discharges Matsumoto & Ajmone Marsan, 1964 Goldensohn & Purpura, 1963

Neuronal disturbances associated with epileptogenicity Results from several different experimental models of epilepsy suggest burst firing is the neuronal correlate of epileptogenicity. In vitro studies on resected human tissue shows little evidence of spontaneous activity and abnormal burst firing.

In vitro evoked PDS from human epileptogenic neocortex Hwa et al., 1991

Neuronal disturbances associated with epileptogenicity Results from several different experimental models of epilepsy suggest burst firing is the neuronal correlate of epileptogenicity. In vitro studies on resected human tissue shows little evidence of spontaneous activity and abnormal burst firing. In vivo single neuron studies have not consistently demonstrated burst firing within the seizure onset zone (SOZ).

Significantly greater single neuron burst firing within SOZ during sleep-wake states Staba et al., J Neurosci 2002

Spike detection and separation

Unfolding the human mesial temporal lobe

Significant reductions in MTL gray matter thickness inside and outside the SOZ

Interictal neuronal hyperexcitability inside the seizure onset zone

Greater interictal burst firing inside than outside the seizure onset zone

Summary Epilepsy is a disorder of the CNS characterized by recurrent, unprovoked spontaneous seizures. EEG and intracranial depth electrode studies provide valuable information for the diagnosis and treatment of epilepsy. In vivo single neuron studies provide evidence for greater neuronal excitability within the SOZ. The link between reduced GM thickness and greater bursting (and synchrony of discharges) suggests GM structural alteration could contribute to neuronal hyperexcitability in MTL areas capable of generating seizures.

Additional slides

Traditional and high frequency bands associated with EEG Curio, J Clin Neurophysiol 2000

millivolts millivolts Synchronous ROF neuronal activity contributes to the generation of local field potentials REC Human REC.5mV 5 mv 1 sec 300 Hz Ripple 100 msec Fast Ripple 15 msec

millivolts Abnormal interictal bursts of population spikes associated with seizure generating areas

Analysis of high frequency oscillations (HFOs) Bandpass filter wideband signal between 100 and 500Hz (FIR). Compute root-mean-square using 3 msec sliding window. Threshold set at 5 SD above grand mean RMS. Confirmed detection using 6 successive peaks greater than 3 SD above mean of bandpass filtered rectified signal.

Fast Ripples (FR) strongly associated with brain areas where seizures begin

FR occur during the onset of some complex partial seizures 400 Hz

In animal models of MTLE, shorter latency to occurrence of FR correlate with shorter latency to 1 st spontaneous seizure & seizure frequency Bragin et al. 2004

Higher ratios of FR to Ripple discharge correlate with reduced hippocampal volumes & neuronal densities CA2 Hipp. sclerosis SS End Folium Pro Sub Staba et al. 2007

Are Fast Ripple generating sites associated with local anatomical disturbances? Microelectrode registration Atrophy map Analysis of local atrophy

Fast Ripple-generating sites strongly associated with local atrophy Significantly higher rates of Fast Ripple occurrences in local atrophic vs. nonatrophic areas. Higher rates of Fast Ripple discharge correlate with greater atrophy. Ogren et al. Annals of Neurol 2009

No significant association between Ripple occurrence and local atrophy

Synchronous neuronal discharge associated with human Ripples resembles activity in non-primate hippocampus Le Van Quyen et al., J Neurosci 2008

Microelectrode registration and measurement of tissue thickness using 2D hippocampal maps CT Ekstrom et al., J Neurosurg 2008

Networks supporting Fast Ripples may contribute to establishment of seizure generating networks IPE Silent period Occurrence of FR / hippocampal seizures? Clinical SZ onset MC DG SZ EC