Fred A. Lado

Neurophysiological investigation of spontaneous correlated and anticorrelated fluctuations of the BOLD signal.

Analyses of intrinsic fMRI BOLD signal fluctuations reliably reveal correlated and anticorrelated functional networks in the brain. Because the BOLD signal is an indirect measure of neuronal activity and anticorrelations can be introduced by preprocessing steps, such as global signal regression, the neurophysiological significance of correlated and anticorrelated BOLD fluctuations is a source of debate. Here, we address this question by examining the correspondence between the spatial organization of correlated BOLD fluctuations and correlated fluctuations in electrophysiological high γ power signals recorded directly from the cortical surface of 5 patients. We demonstrate that both positive and negative BOLD correlations have neurophysiological correlates reflected in fluctuations of spontaneous neuronal activity. Although applying global signal regression to BOLD signals results in some BOLD anticorrelations that are not apparent in the ECoG data, it enhances the neuronal-hemodynamic correspondence overall. Together, these findings provide support for the neurophysiological fidelity of BOLD correlations and anticorrelations.

The Effect of Electrical Stimulation of the Subthalamic Nucleus on Seizures Is Frequency Dependent

Summary:  Purpose: Animal studies and anecdotal human case reports have indicated that the subthalamic nucleus (STN) may be a site of anticonvulsant action.

Chronic bilateral stimulation of the anterior thalamus of kainate-treated rats increases seizure frequency.

Summary:  Purpose: Electrical stimulation of the anterior nucleus of the thalamus (ANT) is receiving increased attention as a novel means of controlling intractable epilepsy, and has entered human clinical trial. Animal data supporting the anticonvulsant benefit of ANT stimulation, however, has been obtained from acute chemoconvulsant models of epilepsy rather than models of chronic epilepsy with spontaneous seizures. It is unknown whether ANT stimulation is effective in models of chronic epilepsy.

Are early myoclonic encephalopathy (EME) and the Ohtahara syndrome (EIEE) independent of each other

BACKGROUND Early myoclonic encephalopathy (EME) and the Ohtahara syndrome are currently listed as two separate syndromes in the classification of epilepsies. The most prominent differentiating points are the observations that patients with Ohtahara syndrome experience predominantly tonic seizures; their seizures evolve to infantile spasms and the prognosis is often worse than patients with EME. SUMMARY POINTS We performed a literature review of published cases. Although syndromes may have distinct courses, the differentiation early on may be impossible as both myoclonus and tonic seizures may coexist. There is also an overlap in the etiologies. Tonic seizures are considered a manifestation of brainstem dysfunction and it is possible that this is more prominent in Ohtahara syndrome. To date, there are 17 autopsy cases (12 presumed to be Ohtahara cases and 5 EME). Evidence of hindbrain pathology was present in all. Tonic seizures or tonic posturing was a feature of all cases. We suggest that the two syndromes may represent a continuum and that the prominence of tonic seizures in the Ohtahara syndrome may be an indication of brainstem dysfunction which may play an important role in the subsequent transition to infantile spasms.

Corticocortical Evoked Potentials Reveal Projectors and Integrators in Human Brain Networks

The cerebral cortex is composed of subregions whose functional specialization is largely determined by their incoming and outgoing connections with each other. In the present study, we asked which cortical regions can exert the greatest influence over other regions and the cortical network as a whole. Previous research on this question has relied on coarse anatomy (mapping large fiber pathways) or functional connectivity (mapping inter-regional statistical dependencies in ongoing activity). Here we combined direct electrical stimulation with recordings from the cortical surface to provide a novel insight into directed, inter-regional influence within the cerebral cortex of awake humans. These networks of directed interaction were reproducible across strength thresholds and across subjects. Directed network properties included (1) a decrease in the reciprocity of connections with distance; (2) major projector nodes (sources of influence) were found in peri-Rolandic cortex and posterior, basal and polar regions of the temporal lobe; and (3) major receiver nodes (receivers of influence) were found in anterolateral frontal, superior parietal, and superior temporal regions. Connectivity maps derived from electrical stimulation and from resting electrocorticography (ECoG) correlations showed similar spatial distributions for the same source node. However, higher-level network topology analysis revealed differences between electrical stimulation and ECoG that were partially related to the reciprocity of connections. Together, these findings inform our understanding of large-scale corticocortical influence as well as the interpretation of functional connectivity networks.

Value of routine screening for bone demineralization in an urban population of patients with epilepsy

BACKGROUND Reduced bone mineral density (BMD) is increasingly recognized in patients receiving antiepileptic drug therapy. The precise prevalence is not known due to variability across populations studied. We set out to characterize the prevalence of abnormal BMD in an urban population of patients with epilepsy with the intent to determine the value of routine BMD screening. METHODS We performed a cross-sectional study of 130 consecutive patients seen thorough our Comprehensive Epilepsy Center. BMD was measured using dual X-ray absorptiometry and was reported as T-score and Z-score. Additional information collected for each patient included age, race, gender, current and prior AEDs, ambulatory state, menopausal state, concomitant medications potentially associated with reduced bone mineralization, and comorbid illness potentially associated with reduced bone mineralization. Associations between reduced bone mineralization and variables were tested for significance using Fishers exact test, Students t-test, and Wilcoxon rank sum test. RESULTS The average age of the entire study population was 43.5 (+/-12.5) years. Fifty-five percent of patients had T-score less than or equal to -1, the WHO criterion for osteopenia in postmenopausal women. The prevalence of Z-scores less than -2.0 was 15%, which is more than sixfold greater than expected. The markers for decreased BMD included older age or menopause in women, longer duration of therapy, and a history of use of phenytoin or phenobarbital. Assisted ambulation was also associated with low BMD. CONCLUSION Our results indicate that reduced bone mineralization is prevalent and a significant health concern in an urban population of patients with epilepsy. Because of the high prevalence of reduced bone mineralization reported in numerous studies including this study, routinely screening for reduced bone mineralization is warranted in patients receiving anticonvulsant therapy.

Pathophysiology of epileptic encephalopathies

The application of metabolic imaging and genetic analysis, and now the development of appropriate animal models, has generated critical insights into the pathogenesis of epileptic encephalopathies. In this article we present ideas intended to move from the lesions associated with epileptic encephalopathies toward understanding the effects of these lesions on the functioning of the brain, specifically of the cortex. We argue that the effects of focal lesions may be magnified through the interaction between cortical and subcortical structures, and that disruption of subcortical arousal centers that regulate cortex early in life may lead to alterations of intracortical synapses that affect a critical period of cognitive development. Impairment of interneuronal function globally through the action of a genetic lesion similarly causes widespread cortical dysfunction manifesting as increased delta slow waves on electroencephalography (EEG) and as developmental delay or arrest clinically. Finally, prolonged focal epileptic activity during sleep (as occurring in the syndrome of continuous spike‐wave in slow sleep, or CSWSS) might interfere with local slow wave activity at the site of the epileptic focus, thereby impairing the neural processes and, possibly, the local plastic changes associated with learning and other cognitive functions. Seizures may certainly add to these pathologic processes, but they are likely not necessary for the development of the cognitive pathology. Nevertheless, although seizures may be either a consequence or symptom of the underlying lesion, their effective treatment can improve outcomes as both clinical and experimental studies may suggest. Understanding their substrates may lead to novel, effective treatments for all aspects of the epileptic encephalopathy phenotype.

Anticonvulsant efficacy of gabapentin on kindling in the immature brain

Summary: The anticonvulsant and motor effects of gabapentin (GBP) were evaluated in rat pups aged 16–17 days. Fourteen‐day‐old rat pups received an implanted stimulating electrode in the amygdala unilaterally. Kindled seizures were produced on day 16 of life by repeatedly applying an electrical current stimulus to the amygdala electrode. Animals received kindling stimulation until they achieved three consecutive generalized convulsions. On day 17, rat pups received one of four doses of GBP 10, 25, 50, or 100 mg/kg. After receiving GBP, rat pups again received electrical stimulation to the amygdala electrode to determine the extent to which GBP prevented the kindled seizure. Anticonvulsant effects were found at doses as low as 10 mg/kg. A separate group of naïve rats received GBP to determine the motor effects of each treatment dose. Impaired motor performance, quantified as time on a balance beam, occurred at doses of ≥50 mg/kg. In summary, our data indicate that in immature rats, GBP exerts an anticonvulsant effect against kindled seizures at doses that do not significantly impair motor performance.

iELVis: An open source MATLAB toolbox for localizing and visualizing human intracranial electrode data

BACKGROUND Intracranial electrical recordings (iEEG) and brain stimulation (iEBS) are invaluable human neuroscience methodologies. However, the value of such data is often unrealized as many laboratories lack tools for localizing electrodes relative to anatomy. To remedy this, we have developed a MATLAB toolbox for intracranial electrode localization and visualization, iELVis. NEW METHOD: iELVis uses existing tools (BioImage Suite, FSL, and FreeSurfer) for preimplant magnetic resonance imaging (MRI) segmentation, neuroimaging coregistration, and manual identification of electrodes in postimplant neuroimaging. Subsequently, iELVis implements methods for correcting electrode locations for postimplant brain shift with millimeter-scale accuracy and provides interactive visualization on 3D surfaces or in 2D slices with optional functional neuroimaging overlays. iELVis also localizes electrodes relative to FreeSurfer-based atlases and can combine data across subjects via the FreeSurfer average brain. RESULTS It takes 30-60min of user time and 12-24h of computer time to localize and visualize electrodes from one brain. We demonstrate iELViss functionality by showing that three methods for mapping primary hand somatosensory cortex (iEEG, iEBS, and functional MRI) provide highly concordant results. COMPARISON WITH EXISTING METHODS: iELVis is the first public software for electrode localization that corrects for brain shift, maps electrodes to an average brain, and supports neuroimaging overlays. Moreover, its interactive visualizations are powerful and its tutorial material is extensive. CONCLUSIONS iELVis promises to speed the progress and enhance the robustness of intracranial electrode research. The software and extensive tutorial materials are freely available as part of the EpiSurg software project: https://github.com/episurg/episurg.

Evaluation of cortical local field potential diffusion in stereotactic electro-encephalography recordings: A glimpse on white matter signal

ABSTRACT While there is a strong interest in meso‐scale field potential recording using intracranial electroencephalography with penetrating depth electrodes (i.e. stereotactic EEG or S‐EEG) in humans, the signal recorded in the white matter remains ignored. White matter is generally considered electrically neutral and often included in the reference montage. Moreover, re‐referencing electrophysiological data is a critical preprocessing choice that could drastically impact signal content and consequently the results of any given analysis. In the present stereotactic electroencephalography study, we first illustrate empirically the consequences of commonly used references (subdermal, white matter, global average, local montage) on inter‐electrode signal correlation. Since most of these reference montages incorporate white matter signal, we next consider the difference between signals recorded in cortical gray matter and white matter. Our results reveal that electrode contacts located in the white matter record a mixture of activity, with part arising from the volume conduction (zero time delay) of activity from nearby gray matter. Furthermore, our analysis shows that white matter signal may be correlated with distant gray matter signal. While residual passive electrical spread from nearby matter may account for this relationship, our results suggest the possibility that this long distance correlation arises from the white matter fiber tracts themselves (i.e. activity from distant gray matter traveling along axonal fibers with time lag larger than zero); yet definitive conclusions about the origin of the white matter signal would require further experimental substantiation. By characterizing the properties of signals recorded in white matter and in gray matter, this study illustrates the importance of including anatomical prior knowledge when analyzing S‐EEG data.