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Epilepsia  2013;55(1):137-145.
Temporal Lobe Epilepsy (TLE) affects brain areas beyond the temporal lobes due to connections of the hippocampi and other temporal lobe structures. Using functional connectivity MRI, we determined the changes of hippocampal networks in TLE to assess for a more complete distribution of abnormality.
Regions of interest (ROIs) were defined in the right and left hippocampi in three groups of participants- left TLE (n=13), right TLE (n=11) and healthy controls (n=16). Brain regions functionally connected to these ROIs were identified by correlating resting-state low-frequency fMRI Blood Oxygenation Level Dependent (BOLD) signal fluctuations. The grouped results were compared using independent sample t-test.
TLE was associated with increased hippocampal connectivity involving several key areas of the limbic network (temporal lobe, insula, thalamus), frontal lobes, angular gyrus, basal ganglia, brainstem and cerebellum along with reduced connectivity involving areas of the sensorimotor cortex (visual, somatosensory, auditory, primary motor) and the default mode network (precuneus). Left TLE had more marked connectivity changes than right TLE.
The observed connectivity changes in TLE indicate dysfunctional networks that underlie widespread brain involvement in TLE. There are identifiable differences in the connectivity of the hippocampi between left and right TLE.
PMCID: PMC3946924  PMID: 24313597
Temporal Lobe Epilepsy (TLE); Hippocampal networks; fMRI; Functional Connectivity; Epilepsy psychopathology; Epileptic Networks
2.  Graph theory findings in the pathophysiology of temporal lobe epilepsy 
Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy. Accumulating evidence has shown that TLE is a disorder of abnormal epileptogenic networks, rather than focal sources. Graph theory allows for a network-based representation of TLE brain networks, and has potential to illuminate characteristics of brain topology conducive to TLE pathophysiology, including seizure initiation and spread. We review basic concepts which we believe will prove helpful in interpreting results rapidly emerging from graph theory research in TLE. In addition, we summarize the current state of graph theory findings in TLE as they pertain its pathophysiology. Several common findings have emerged from the many modalities which have been used to study TLE using graph theory, including structural MRI, diffusion tensor imaging, surface EEG, intracranial EEG, magnetoencephalography, functional MRI, cell cultures, simulated models, and mouse models, involving increased regularity of the interictal network configuration, altered local segregation and global integration of the TLE network, and network reorganization of temporal lobe and limbic structures. As different modalities provide different views of the same phenomenon, future studies integrating data from multiple modalities are needed to clarify findings and contribute to the formation of a coherent theory on the pathophysiology of TLE.
PMCID: PMC4281254  PMID: 24831083
Graph theory; Temporal lobe epilepsy; Pathophysiology; Functional connectivity; Diffusion tensor imaging; Small-world networks
3.  Clinical correlates of graph theory findings in temporal lobe epilepsy 
Seizure  2014;23(10):809-818.
Temporal lobe epilepsy (TLE) is considered a brain network disorder, additionally representing the most common form of pharmaco-resistant epilepsy in adults. There is increasing evidence that seizures in TLE arise from abnormal epileptogenic networks, which extend beyond the clinico-radiologically determined epileptogenic zone and may contribute to the failure rate of 30–50% following epilepsy surgery. Graph theory allows for a network-based representation of TLE brain networks using several neuroimaging and electrophysiologic modalities, and has potential to provide clinicians with clinically useful biomarkers for diagnostic and prognostic purposes.
We performed a review of the current state of graph theory findings in TLE as they pertain to localization of the epileptogenic zone, prediction of pre- and post-surgical seizure frequency and cognitive performance, and monitoring cognitive decline in TLE.
Although different neuroimaging and electrophysiologic modalities have yielded occasionally conflicting results, several potential biomarkers have been characterized for identifying the epileptogenic zone, pre-/post-surgical seizure prediction, and assessing cognitive performance. For localization, graph theory measures of centrality have shown the most potential, including betweenness centrality, outdegree, and graph index complexity, whereas for prediction of seizure frequency, measures of synchronizability have shown the most potential. The utility of clustering coefficient and characteristic path length for assessing cognitive performance in TLE is also discussed.
Future studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.
PMCID: PMC4281255  PMID: 25127370
Graph theory; Temporal lobe epilepsy; Functional connectivity; Diffusion tensor imaging; Small-world networks; Seizures
4.  Effect of lateralized temporal lobe epilepsy on the default mode network 
Epilepsy & behavior : E&B  2012;25(3):350-357.
The default mode network (DMN) is composed of cerebral regions involved in conscious, resting state cognition. The hippocampus is an essential component of this network. Here, the DMN in TLE is compared to control subjects to better understand its involvement in TLE. We performed resting state connectivity analysis using regions of interest (ROIs) in the retrosplenium/precuneus (Rsp/PCUN) and the ventro-medial pre-frontal cortex (vmPFC) in 36 subjects (11 with right TLE, 12 with left TLE, 13 controls) to delineate the posterior and anterior DMN regions respectively. We found reduced connectivity of the posterior to the anterior DMN in patients with both right and left TLE. However, the posterior and anterior networks were found to be individually preserved. Lateralization of TLE affects the DMN with left TLE demonstrating more extensive networks. These DMN changes may be relevant to altered cognition and memory in TLE and may be relevant to right vs. left TLE differences in cognitive involvement.
PMCID: PMC4209897  PMID: 23103309
Temporal Lobe Epilepsy (TLE); Default mode network (DMN); fMRI; Functional connectivity; Epilepsy psychopathology; Epileptic networks
5.  Electroencephalography and Quantitative Electroencephalography in Mild Traumatic Brain Injury 
Journal of Neurotrauma  2013;30(8):653-656.
Mild traumatic brain injury (mTBI) causes brain injury resulting in electrophysiologic abnormalities visible in electroencephalography (EEG) recordings. Quantitative EEG (qEEG) makes use of quantitative techniques to analyze EEG characteristics such as frequency, amplitude, coherence, power, phase, and symmetry over time independently or in combination. QEEG has been evaluated for its use in making a diagnosis of mTBI and assessing prognosis, including the likelihood of progressing to the postconcussive syndrome (PCS) phase. We review the EEG and qEEG changes of mTBI described in the literature. An attempt is made to separate the findings seen during the acute, subacute, and chronic phases after mTBI. Brief mention is also made of the neurobiological correlates of qEEG using neuroimaging techniques or in histopathology. Although the literature indicates the promise of qEEG in making a diagnosis and indicating prognosis of mTBI, further study is needed to corroborate and refine these methods.
PMCID: PMC3638533  PMID: 23249295
EEG; mild traumatic brain injury; postconcussive syndrome; quantitative EEG; TBI
6.  Functional neuro-imaging as a pre-surgical tool in epilepsy 
Annals of Indian Academy of Neurology  2014;17(Suppl 1):S56-S64.
Functional neuro-imaging techniques are helpful in the pre-surgical evaluation of epilepsy for localization of the epileptogenic zone as ancillary tools to electroencephalography (EEG) and magnetic resonance imaging (MRI) or when other localization techniques are normal, non-concordant or discordant. Positron emission tomography (PET) and ictal single photon emission computed tomography (ictal SPECT) imaging are traditional tests that have been reported to have good sensitivity and specificity although the results are better with more expertise as is true for any technique. More recently magnetoencephalogram/magnetic source imaging (MEG/MSI), diffusion tensor imaging and functional magnetic resonance imaging (fMRI) have been used in localization and functional mapping during the pre-surgical work-up of epilepsy. Newer techniques such as fMRI-EEG, functional connectivity magnetic resonance imaging and near infra-red spectroscopy, magnetic resonance spectroscopy and magneto nanoparticles hold promise for further development that could then be applied in the work-up of epilepsy surgery. In this manuscript, we review these techniques and their current position in the pre-surgical evaluation of epilepsy.
PMCID: PMC4001213  PMID: 24791091
Diffusion tensor imaging; functional connectivity magnetic resonance imaging; functional magnetic resonance imaging; functional magnetic resonance imaging-electroencephalography; magnetoencephalogram; positron emission tomography; single photon emission computed tomography; temporal lobe epilepsy
7.  Vitamin-Responsive Epileptic Encephalopathies in Children 
Untreated epileptic encephalopathies in children may potentially have disastrous outcomes. Treatment with antiepileptic drugs (AEDs) often may not control the seizures, and even if they do, this measure is only symptomatic and not specific. It is especially valuable to identify potential underlying conditions that have specific treatments. Only a few conditions have definitive treatments that can potentially modify the natural course of disease. In this paper, we discuss the few such conditions that are responsive to vitamin or vitamin derivatives.
PMCID: PMC3745849  PMID: 23984056
8.  Functional MRI of Sleep Spindles and K-complexes 
Clinical Neurophysiology  2011;123(2):303-309.
Sleep spindles and K-complexes are EEG hallmarks of non-REM sleep. However, the brain regions generating these discharges and the functional connections of their generators to other regions are not fully known. We investigated the neuroanatomical correlates of spindles and K-complexes using simultaneous EEG and fMRI.
EEGs recorded during EEG-fMRI studies of 7 individuals were used for fMRI analysis. Higher-level group analyses were performed, and images were thresholded at Z≥2.3.
fMRI of 106 spindles and 60 K-complexes was analyzed. Spindles corresponded to increased signal in thalami and posterior cingulate, and right precuneus, putamen, paracentral cortex, and temporal lobe. K-complexes corresponded to increased signal in thalami, superior temporal lobes, paracentral gyri, and medial regions of the occipital, parietal and frontal lobes. Neither corresponded to regions of decreased signal.
fMRI of both spindles and K-complexes depicts signal subjacent to the vertex, which likely indicates each discharges’ source. The thalamic signal is consistent with thalamic involvement in sleep homeostasis. The limbic region’s signal is consistent with roles in memory consolidation. Unlike the spindle, the K-complex corresponds to extensive signal in primary sensory cortices.
Identification of these active regions contributes to the understanding of sleep networks and the physiology of awareness and memory during sleep.
PMCID: PMC3208090  PMID: 21775199
electroencephalography (EEG); functional MRI (fMRI); spindles; K-complexes; sleep; non-REM
9.  Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area 
The New England journal of medicine  2012;366(6):502-510.
The medial temporal structures, including the hippocampus and the entorhinal cortex, are critical for the ability to transform daily experience into lasting memories. We tested the hypothesis that deep-brain stimulation of the hippocampus or entorhinal cortex alters memory performance.
We implanted intracranial depth electrodes in seven subjects to identify seizure-onset zones for subsequent epilepsy surgery. The subjects completed a spatial learning task during which they learned destinations within virtual environments. During half the learning trials, focal electrical stimulation was given below the threshold that elicits an afterdischarge (i.e., a neuronal discharge that occurs after termination of the stimulus).
Entorhinal stimulation applied while the subjects learned locations of landmarks enhanced their subsequent memory of these locations: the subjects reached these landmarks more quickly and by shorter routes, as compared with locations learned without stimulation. Entorhinal stimulation also resulted in a resetting of the phase of the theta rhythm, as shown on the hippocampal electroencephalogram. Direct hippocampal stimulation was not effective. In this small series, no adverse events associated with the procedure were observed.
Stimulation of the entorhinal region enhanced memory of spatial information when applied during learning. (Funded by the National Institutes of Health and the Dana Foundation.)
PMCID: PMC3447081  PMID: 22316444
10.  Functional Imaging of Sleep Vertex Sharp Transients 
The vertex sharp transient (VST) is an electroencephalographic (EEG) discharge that is an early marker of non-REM sleep. It has been recognized since the beginning of sleep physiology research, but its source and function remain mostly unexplained. We investigated VST generation using functional MRI (fMRI).
Simultaneous EEG and fMRI were recorded from 7 individuals in drowsiness and light sleep. VST occurrences on EEG were modeled with fMRI using an impulse function convolved with a hemodynamic response function to identify cerebral regions correlating to the VSTs. A resulting statistical image was thresholded at Z>2.3.
Two hundred VSTs were identified. Significantly increased signal was present bilaterally in medial central, lateral precentral, posterior superior temporal, and medial occipital cortex. No regions of decreased signal were present.
The regions are consistent with electrophysiologic evidence from animal models and functional imaging of human sleep, but the results are specific to VSTs. The regions principally encompass the primary sensorimotor cortical regions for vision, hearing, and touch.
The results depict a network comprising the presumed VST generator and its associated regions. The associated regions functional similarity for primary sensation suggests a role for VSTs in sensory experience during sleep.
PMCID: PMC3105179  PMID: 21310653
electroencephalography (EEG); functional MRI (fMRI); sleep; vertex sharp transients
11.  Referral pattern for epilepsy surgery after evidence-based recommendations 
Neurology  2010;75(8):699-704.
Class I evidence for surgical effectiveness in refractory temporal lobe epilepsy (TLE) in 2001 led to an American Academy of Neurology practice parameter in 2003 recommending “referral to a surgical epilepsy center on failing appropriate trials of first-line antiepileptic drugs.” We examined whether this led to a change in referral patterns to our epilepsy center.
We compared referral data for patients with TLE at our center for 1995 to 1998 (group 1, n = 83) and 2005 to 2008 (group 2, n = 102) to determine whether these recommendations resulted in a change in referral patterns for surgical evaluation. Patients with brain tumors, previous epilepsy surgery evaluations, or brain surgery (including epilepsy surgery) were excluded.
We did not find a difference between the groups in the duration from the diagnosis of habitual seizures to referral (17.1 ± 10.0 vs 18.6 ± 12.6 years, p = 0.39) or the age at the time of evaluation (34.1 ± 10.3 vs 37.0 ± 11.8 years, p = 0.08). However, there was a difference in the distributions of age at evaluation (p = 0.03) and the duration of pharmacotherapy (p = 0.03) between the groups, with a greater proportion of patients in group 2 with drug-resistant epilepsy both earlier and later in their treatment course. Nonepileptic seizures were referred significantly earlier than TLE in either group or when combined.
Our analysis does not identify a significantly earlier referral for epilepsy surgery evaluation as recommended in the practice parameter, but suggests a hopeful trend in this direction.
= American Academy of Neurology;
= antiepileptic drug;
= Early Randomized Surgical Epilepsy Trial;
= nonepileptic seizures;
= randomized controlled trial;
= temporal lobe epilepsy;
= vagus nerve stimulator.
PMCID: PMC2931651  PMID: 20733145

Results 1-11 (11)