Quantitative Multimodal Mapping Of Seizure Networks In Drug-Resistant Epilepsy

Over 15 million people worldwide suffer from localization-related drug-resistant epilepsy. These patients are candidates for targeted surgical therapies such as surgical resection, laser thermal ablation, and neurostimulation. While seizure localization is needed prior to surgical intervention, this process is challenging, invasive, and often inconclusive. In this work, I aim to exploit the power of multimodal high-resolution imaging and intracranial electroencephalography (iEEG) data to map seizure networks in drug-resistant epilepsy patients, with a focus on minimizing invasiveness. Given compelling evidence that epilepsy is a disease of distorted brain networks as opposed to well-defined focal lesions, I employ a graph-theoretical approach to map structural and functional brain networks and identify putative targets for removal. The first section focuses on mesial temporal lobe epilepsy (TLE), the most common type of localization-related epilepsy. Using high-resolution structural and functional 7T MRI, I demonstrate that noninvasive neuroimaging-based network properties within the medial temporal lobe can serve as useful biomarkers for TLE cases in which conventional imaging and volumetric analysis are insufficient. The second section expands to all forms of localization-related epilepsy. Using iEEG recordings, I provide a framework for the utility of interictal network synchrony in identifying candidate resection zones, with the goal of reducing the need for prolonged invasive implants. In the third section, I generate a pipeline for integrated analysis of iEEG and MRI networks, paving the way for future large-scale studies that can effectively harness synergy between different modalities. This multimodal approach has the potential to provide fundamental insights into the pathology of an epileptic brain, robustly identify areas of seizure onset and spread, and ultimately inform clinical decision making

Structure specific analysis of the hippocampus in temporal lobe epilepsy

The hippocampus is a major structure of interest affected by temporal lobe epilepsy (TLE). Region of interest (ROI)-based analysis has traditionally been used to study hippocampal involvement in TLE, although spatial variation of structural and functional pathology have been known to exist within the ROI. In this article, structure-specific analysis (Yushkevich et al. (2007) Neuroimage 35:1516–1530) is applied to the study of both structure and function in TLE patients. This methodology takes into account information about the spatial correspondence of voxels within ROIs on left and right sides of the same subject as well as between subjects. Hippocampal thickness is studied as a measure of structural integrity, and functional activation in a functional magnetic resonance imaging (fMRI) experiment in which subjects performed a memory encoding task is studied as a measure of functional integrity. Pronounced disease-related decrease in thickness is found in posterior and anterior hippocampus. A region in the body also shows increased thickness in patients' healthy hippocampi compared with controls. Functional activation in diseased hippocampi is reduced in the body region compared to controls, whereas a region in the tail showing greater right-lateralized activation in controls also shows greater activation in healthy hippocampi compared with the diseased side in patients. Summary measurements generated by integrating quantities of interest over the entire hippocampus can also be used, as is done in conventional ROI analysis. © 2009 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63055/1/20620_ftp.pd

Involvement of hippocampal subfields and anterior-posterior subregions in encoding and retrieval of item, spatial, and associative memories: Longitudinal versus transverse axis

The functional role of the hippocampal formation in episodic memory has been studied using functional magnetic resonance imaging (fMRI) for many years. The hippocampus can be segmented into three major anteroposterior sections, called head, body and tail, and into the Cornu Ammonis (CA), dentate gyrus (DG), and subiculum (Sub) subfields based on its transverse axis. However, the exact role of these subregions and subfields in memory processes is less understood. In the present study we combined ultra-high resolution structural Magnetic Resonance Imaging (MRI) at 4.7 T with an event-related high-resolution fMRI paradigm based on the ‘Designs’ subtest of the Wechsler Memory Scale to investigate how the hippocampal subfields and longitudinal subregions are involved in encoding and retrieval of item, spatial, and associative memories. Our results showed that during memory encoding, regardless of the type of memory being learned, all subregions and all subfields were active. During the retrieval phase, on the other hand, we observed an anterior to posterior gradient in hippocampal activity for all subfields and all types of memory. Our findings also confirmed presence of an anterior to posterior gradient in hippocampal activity during spatial learning. Comparing subfield activities to each other revealed that the DG was more active than the CA1-3 and Sub during both encoding and retrieval. Finally, our results showed that for every subfield, encoding vs. retrieval activity differences were larger in the hippocampal head than in the hippocampal body and tail. Furthermore, these encoding vs. retrieval activity differences were similar in all subfields, highlighting the importance of studying both the longitudinal and transverse axis specialization simultaneously. Current findings further elucidate the structure–function relationship between the human hippocampus and episodic memory

Investigating the mechanisms of action of phytocannabinoids and a novel cognitive enhancer to target the comorbidity of temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is the most common type of epilepsy and exists with memory loss as a comorbidity. The conventional therapy available to treat these disorders achieves only modest therapeutic efficacy at best. This study investigates two potential treatments: phytocannabinoids to alleviate seizures, and a novel cognitive enhancer to restore/halt memory deficits. The anti-convulsant properties of cannabidiol (CBD) were first examined with regards to the neuropathology of two major types of hippocampal interneurons expressing parvalbumin (PV) and cholecystokinin (CCK) which are thought to dysfunction during epilepsy. Immunohistochemistry experiments using an in vivo kainic-acid induced epileptic rat model, revealed that PV- and CCK-immunopositive interneurons were significantly affected during epilepsy. This effect was greatly reduced following CBD treatment, suggesting that CBD exerts a neuroprotective function. The effects of CBD on the intrinsic membrane properties of these interneurons, together with hippocampal pyramidal cells, were further investigated in acute brain slices of rat seizure models of TLE (in vivo kainic acid-induced and in vitro Mg2+ free-induced). Whole-cell recordings revealed that bath application of CBD (10 µM) normalised the firing frequency of epileptic adapting pyramidal cells to healthy control levels. A similar effect was seen in hippocampal CCK-immunopositive Schaffer collateral associated (SCA) interneurons. In contrast, CBD resulted in an increased firing of PV-immunopositive interneurons, thus increasing their excitability and restoring the impaired membrane properties of the cells apparent in the epileptic models. The effects of cannabidivarin (CBDV), a similar cannabinoid compound, on the intrinsic membrane properties of these cell types were also evaluated. Additionally, CBDV affected excitatory postsynaptic currents by reducing excitation. In an attempt to address the memory impairment aspect associated with TLE, I investigated the neuronal effects of a5AM21, a novel potential memory enhancer. Electrophysiological experiments revealed that a5AM21 preferentially acts on 5-containing gamma (γ)-aminobutyric acid (GABA) type A (GABAA) receptors, reducing their inhibitory effects. Furthermore, data obtained using behavioural experiment paradigm, the eight-arm radial maze, suggest a significant improvement in short- and long-term memory retrieval in rats treated with a5AM21. In conclusion, the results reveal the potential mechanisms of action of two therapies to alleviate seizures and memory impairment, and the future goals would be to combine CBD/CBDV and a5AM21 as a promising novel targeted therapy for TLE

Verbal Learning and Longitudinal Hippocampal Network Connectivity in Temporal Lobe Epilepsy Surgery

IntroductionLearning new verbal information can be impaired in 20-40% of patients after mesial temporal lobe resection. In recent years, understanding epilepsy as a brain network disease, and investigating the relationship between large-scale resting networks and cognition has led to several advances. Aligned studies suggest that it is the integrity of the hippocampal connectivity with these large-scale networks what is relevant for cognition, with evidence showing a functional and structural heterogeneity along the long axis hippocampus bilaterally. ObjectiveOur aim is to examine whether pre-operative resting-state connectivity along the long hippocampal axis is associated with verbal learning decline after anterior temporal lobe resection. MethodsThirty-one patients with epilepsy who underwent an anterior temporal lobe resection were pre-surgically scanned at 3-tesla, and pre/post-surgery evaluated for learning deficits using the Rey Auditory Verbal Learning Task (RAVLT). Eighteen controls matched by age, gender and handedness were also scanned and evaluated with the RAVLT. We studied the functional connectivity along the (anterior/posterior) long axis hippocampal subregions and resting-state functionally-defined brain networks involved in learning [executive (EXE), dorsal attention (DAN) and default-mode (DMN) networks]. Functional connectivity differences between the two groups of patients (learning intact or with learning decline) and controls were investigated with MANOVA and discriminant analysis. ResultsThere were significant differences in the pattern of hippocampal connectivity among the groups. Regarding the anterior connectivity hippocampal pattern, our data showed an increase of connectivity in the pathological side with the DAN (p = 0.011) and the EXE (p = 0.008) when comparing learning-decline vs. learning-intact patients. Moreover, the non-pathological side showed an increase in the anterior connectivity pattern with the DAN (p = 0.027) between learning-decline vs. learning-intact patients. In contrast, the posterior hippocampus showed a reduction of connectivity in the learning-decline patients with the DMN, both in the pathological (p = 0.004) and the non-pathological sides (p = 0.036). Finally, the discriminant analysis based on the pre-operative connectivity pattern significantly differentiated the learning-decline patients from the other groups (p = 0.019). ConclusionOur findings reveal bilateral connectivity disruptions along the longitudinal axis of the hippocampi with resting-state networks, which could be key to identify those patients at risk of verbal learning decline after epilepsy surgery

Characterization And Perturbation Of Functional Networks That Support Human Memory

Episodic memory is essential to our daily lives, as it attaches meaning to the constant stream of sensory inputs to the brain. However, episodic memory often fails in a number of common neurocognitive disorders. Effective therapies remain elusive, owing to the complexity of brain networks and neural processes that support episodic encoding and retrieval. In particular, it is not understood how inter-regional communication within the brain supports memory function, though such communication may be critical to the highly integrative nature of episodic memory. To uncover the patterns of memory-related functional connectivity, we asked a large cohort of neurosurgical patients with indwelling electrodes to perform a verbal free-recall task, in which patients viewed lists of simple nouns and recalled them a short time later. As patients performed this task, we collected intracranial EEG (iEEG) from electrodes placed on the cortical surface and within the medial temporal lobe (MTL). First, we examined whole-brain functional networks that emerged during the encoding and retrieval phases of this task, using spectral methods to correlate frequency-specific signals between brain regions. We identified a dynamic network of regions that exhibited enhanced theta (3-8 Hz) connectivity during successful memory processing, whereas regions tended to desynchronize at high frequencies (30-100 Hz). Next, using only electrodes placed within the MTL, we asked whether functional coupling was also observed among this mesoscale subnetwork of highly specialized regions that play an outsize role in memory. Recapitulating our earlier findings, we noted broadly enhanced theta connectivity within the MTL, centering on the left entorhinal cortex during successful encoding operations. Finally, to determine whether such low-frequency functional connections reflect correlative or causal relations in the brain, we applied direct electrical stimulation via electrodes placed within the MTL. We found that low-frequency connections (5-13 Hz) predicted the emergence of theta activity at distant regions in the brain – particularly when stimulation occurred near white matter – indicating the potential causal relevance of iEEG-based functional connections. Taken together, these studies underscore the importance of low-frequency functional coupling to memory across spatial scales, and suggest this form of coupling indicates a causal relation between brain regions

GABAA/benzodiazepine receptor distribution and subunit mRNA expression in human temporal lobe epilepsy

The GABAA/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. A functional impairment of GABAergic inhibition has been proposed as one mechanism which may underlie increased seizure susceptibility in human temporal lobe epilepsy (TLE). The objective of this study was to characterise abnormalities of the GABAA/cBZR in TLE with a correlative autoradiography, in-situ hybridisation, immunohistochemistry and quantitative neuropathology study. Hippocampal tissue was obtained at surgery from patients with intractable TLE due to hippocampal sclerosis (HS) and autopsies of neurologically normal controls. Neuronal densities were obtained using a 3-D counting method in paraffin-embedded sections. Saturation autoradiographic studies were performed on cryostat sections using [3H]-flumazenil and expression of mRNA encoding the α1-α6, β3 and γ2 subunits of the GABAA receptor was assessed using in-situ hybridisation histochemistry. Distribution of the receptor protein was also determined using immunohistochemistry with antibodies to the GABAA α1 and β2/3 subunits. A significant decrease in central benzodiazepine binding sites was demonstrated in all subfields of the human hippocampus in HS. This loss of cBZR binding sites would appear to be due primarily to changes in neuronal density characteristic of this pathology. However, in the CA 1 subfield, a reduced BZ receptor concentration was evident on surviving neurones in the HS group (p<0.05). Expression of mRNA encoding GABAA receptor subunits α1, α2, α4, α5, and γ2, was upregulated in surviving neurones of the granule cell layer of the dentate gyrus in HS. In addition, epilepsy-associated increases in the expression of mRNA encoding the α1 subunit were observed in the hilus and CA2 and α2 mRNA in the hilus and CA1. In contrast, an apparent decrease in expression of β3 mRNA per neurone was detected in CA1 in HS (p<0.07) and of γ2 in the CA2 in HS (p<0.10). These findings imply a functional abnormality of the GABAA/CBZR complex that may have a role in the pathophysiology of epileptogenicity in HS

Lateralized hippocampal oscillations underlie distinct aspects of human spatial memory and navigation

The hippocampus plays a vital role in various aspects of cognition including both memory and spatial navigation. To understand electrophysiologically how the hippocampus supports these processes, we recorded intracranial electroencephalographic activity from 46 neurosurgical patients as they performed a spatial memory task. We measure signals from multiple brain regions, including both left and right hippocampi, and we use spectral analysis to identify oscillatory patterns related to memory encoding and navigation. We show that in the left but not right hippocampus, the amplitude of oscillations in the 1–3-Hz “low theta” band increases when viewing subsequently remembered object–location pairs. In contrast, in the right but not left hippocampus, low-theta activity increases during periods of navigation. The frequencies of these hippocampal signals are slower than task-related signals in the neocortex. These results suggest that the human brain includes multiple lateralized oscillatory networks that support different aspects of cognition

Accelerated Forgetting in People with Epilepsy: Pathologic Memory Loss, Its Neural Basis, and Potential Therapies

While forgetting is vital to human functioning, delineating between normative and disordered forgetting can become incredibly complex. This thesis characterizes a pathologic form of forgetting in epilepsy, identifies a neural basis, and investigates the potential of stimulation as a therapeutic tool. Chapter 2 presents a behavioral characterization of the time course of Accelerated Long-Term Forgetting (ALF) in people with epilepsy (PWE). This chapter shows evidence of ALF on a shorter time scale than previous studies, with a differential impact on recall and recognition. Chapter 3 builds upon the work in Chapter 2 by extending ALF time points and investigating the role of interictal epileptiform activity (IEA) in ALF. These findings lend support for distinct forgetting patterns between recall and recognition memory. We also demonstrate the contribution of hippocampal IEA during slow-wave sleep to this aberrant forgetting. Chapter 4 investigates the potential of intracranial stimulation to ameliorate IEA burden. Our findings suggest that stimulation does not appear to have a direct effect on IEA rate. Further studies are necessary to explore the potential of stimulation as a therapeutic tool outside of seizure cessation. Overall, this thesis provides further evidence and classification of long-term memory impairment in epilepsy and identifies a neural correlate that can be targeted for future clinical intervention