Zulfi Haneef

Memory Enhancement and Deep-Brain Stimulation of the Entorhinal Area

BACKGROUND 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. METHODS 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). RESULTS 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. CONCLUSIONS 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.).

Referral pattern for epilepsy surgery after evidence-based recommendations: a retrospective study.

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Functional connectivity of hippocampal networks in temporal lobe epilepsy.

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 magnetic resonance imaging (MRI), we determined the changes of hippocampal networks in TLE to assess for a more complete distribution of abnormality.

Effect of lateralized temporal lobe epilepsy on the default mode network.

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.

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.

Homocysteine and bone loss in epilepsy

Epidemiological studies reveal fracture incidence in epilepsy is twice that of the normal population. Much interest has been focused on Vitamin D, however, considering mixed results on non-enzyme inducing anti-epileptic drugs (AEDs) and bone mineral density (BMD) additional metabolic effects may be to blame. AEDs increase serum homocysteine (s-Hcy) by lowering blood folate levels. An association between elevated homocysteine, BMD and increased fracture incidence has been found in non-epilepsy populations. Additionally, folate and Vitamin B12 levels are independently related to bone mineral density in various non-epilepsy populations. This study supports previous research, which found elevated s-Hcy in subjects taking AEDs and that bone loss is related to the use of enzyme-inducing AEDs and changes in alkaline phosphatase. By one-way ANOVA, subjects on phenytoin monotherapy had significantly higher levels of s-Hcy than those on other AEDs (F=5.89, p=.016). Regression analyses revealed homocysteine, fracture history, length of years on AEDs, ethnicity were predictors of spine T scores. Weight and BMI were predictors of both BMD and DEXA T scores. Use of enzyme-inducing AEDs was a negative predictor of spine BMD and T scores, while phenytoin monotherapy was a positive predictor of spine BMD. Lamotrigine was found to be a negative predictor of spine T score. Ambulatory status, menopause and alcohol consumption were predictors of BMD but not T scores. In this study, persons with epilepsy who take nutritional supplementation have 25% lower s-Hcy levels than those who do not. Supplementation continues to be important in preventative epilepsy care.

Cardiovascular risk factors and homocysteine in epilepsy

Epidemiological studies have found the risk for heart disease and stroke are increased in persons with epilepsy. Anti-epileptic drugs (AEDs) have varying effects on serum lipids and homocysteine-an independent risk factor for coronary disease. The prevalence of cardiovascular risk factors (high cholesterol, hypertension, diabetes, obesity and smoking) and homocysteine were investigated in a multiethnic epilepsy population. Data included demographics, clinical factors, lab assessments and supplementation patterns. Mean age was 45 years (71 males and 94 females)-75 were African American, 27 Latino and 60 Caucasian. Fifty-two percent of participants had two or more cardiovascular risk factors when compared with rates for the general population of 28%. The Framingham risk score (FRS) assessment was also used to compare risk levels. Twenty-nine percent of men and 1% of women had a FRS indicating >5% level of risk, only 7% had a FRS>10%. Cardiovascular screening and primary preventative recommendations based on the American Heart Association and supplementation should be suggested for the adult epilepsy population when appropriate.

Correlation between child and parental perceptions of health-related quality of life in epilepsy using the PedsQL.v4.0 measurement model

Health-related quality-of-life measures in childhood epilepsy are typically limited to a particular functional domain, specific age group, parent proxy-report, or child self-report. Generic health-related quality-of-life instruments in paediatric epilepsy comparing child self-reports with simultaneous parent proxy-reports have not been previously investigated. A previously validated generic questionnaire, the Pediatric Quality of Life version 4 (PedsQL.v4.0), was used to prospectively assess parental and child perceptions of health-related quality of life in 100 children with epilepsy. The correlation between child and parental health-related quality-of-life perceptions across all domains was excellent (p < 0.001) and both were significantly lower than those for healthy controls (p < 0.001). Parents’ perceptions of their children’s healthrelated quality of life were lower than those for other chronic illnesses (p < 0.001), especially for refractory epilepsy. The presence of neurological or psychiatric comorbidities also had an adverse impact on health-related quality of life. The PedsQL.v4.0 measures health-related quality of life from both the parent’s and child’s perspective. Ease of use makes this instrument attractive for routine clinical use.

Clinical correlates of graph theory findings in temporal lobe epilepsy.

PURPOSE 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. METHODS 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. RESULTS 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. CONCLUSIONS Future studies integrating data from multiple modalities and testing predictive models are needed to clarify findings and develop graph theory for its clinical utility.

Functional Imaging of Sleep Vertex Sharp Transients

OBJECTIVE 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). METHODS Simultaneous EEG and fMRI were recorded from seven 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. RESULTS 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. CONCLUSION 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. SIGNIFICANCE 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.