Shahin Hakimian

Functional definition of seizure provides new insight into post-traumatic epileptogenesis

Experimental animals’ seizures are often defined arbitrarily based on duration, which may lead to misjudgement of the syndrome and failure to develop a cure. We employed a functional definition of seizures based on the clinical practice of observing epileptiform electrocorticography and simultaneous ictal behaviour, and examined post-traumatic epilepsy induced in rats by rostral parasagittal fluid percussion injury and epilepsy patients evaluated with invasive monitoring. We showed previously that rostral parasagittal fluid percussion injury induces different types of chronic recurrent spontaneous partial seizures that worsen in frequency and duration over the months post injury. However, a remarkable feature of rostral parasagittal fluid percussion injury is the occurrence, in the early months post injury, of brief (<2 s) focal, recurrent and spontaneous epileptiform electrocorticography events (EEEs) that are never observed in sham-injured animals and have electrographic appearance similar to the onset of obvious chronic recurrent spontaneous partial seizures. Simultaneous epidural-electrocorticography and scalp-electroencephalography recordings in the rat demonstrated that these short EEEs are undetectable by scalp electrocorticography. Behavioural analysis performed blinded to the electrocorticography revealed that (i) brief EEEs lasting 0.8–2 s occur simultaneously with behavioural arrest; and (ii) while behavioural arrest is part of the rats behavioural repertoire, the probability of behavioural arrest is greatly elevated during EEEs. Moreover, spectral analysis showed that EEEs lasting 0.8–2 s occurring during periods of active behaviour with dominant theta activity are immediately followed by loss of such theta activity. We thus conclude that EEEs lasting 0.8–2 s are ictal in the rat. We demonstrate that the assessment of the time course of fluid percussion injury-induced epileptogenesis is dramatically biased by the definition of seizure employed, with common duration-based arbitrary definitions resulting in artificially prolonged latencies for epileptogenesis. Finally, we present four human examples of electrocorticography capturing short (<2 s), stereotyped, neocortically generated EEEs that occurred in the same ictal sites as obvious complex partial seizures, were electrographically similar to rat EEEs and were not noted during scalp electroencephalography. When occurring in the motor cortex, these short EEEs were accompanied by ictal behaviour detectable with simultaneous surface electromyography. These data demonstrate that short (<2 s) focal recurrent spontaneous EEEs are seizures in both rats and humans, that they are undetectable by scalp electroencephalography, and that they are typically associated with subtle and easily missed behavioural correlates. These findings define the earliest identifiable markers of progressive post-traumatic epilepsy in the rat, with implications for mechanistic and prophylactic studies, and should prompt a re-evaluation of the concept of post-traumatic silent period in both animals and humans.

Comparing noninvasive dense array and intracranial electroencephalography for localization of seizures.

OBJECTIVETo compare the localization of the seizure onset zone estimated from ictal recordings with high spatial resolution, 256-channel scalp dense array electroencephalographic video long-term monitoring (LTM) with the aid of source analysis with that obtained from subsequent intracranial ictal recordings. METHODSTen patients with medically refractory epilepsy, all surgical candidates, underwent intracranial LTM after standard noninvasive evaluation failed to provide adequate localizing information regarding ictal origins. Before invasive studies, all patients underwent dense array electroencephalographic LTM in which habitual clinical seizures were recorded for each patient. Source analysis was applied to ictal onsets. Intracranial electrode placement followed conventional guidelines, although the neurosurgeon was aware of the dense array electroencephalographic results. Patients ranged in age from 10 to 49 years (mean age, 24 y); 7 were male. Identified risk factors included closed head injury in 1 patient and childhood meningitis in another. No focal neurological signs were found in any patient. Magnetic resonance imaging findings were normal in 6 patients; 1 patient had cerebellar hypoplasia, 1 had right frontoparietal dysplasia, 1 had bilateral nonspecific white matter abnormalities, and 1 had bilateral cavernous angiomas. RESULTSIctal onsets, based on invasive recordings, were in the mesiotemporal lobe (3 patients), lateroparietal (2 patients), mesioparietal (1 patient), laterofrontal (1 patient), superolateral frontocentral (1 patient), frontopolar (1 patient), and posteroinferior temporo-occipital neocortex (1 patient). Dense array electroencephalography localized ictal onsets to the same region as intracranial monitoring in 8 of 10 cases; invasive studies disclosed an additional ictal focus in 2 of these patients. Surgical resections were based only on intracranial electroencephalographic findings. CONCLUSIONDense array electroencephalography has the potential to assist in the noninvasive localization of epileptic seizures and to guide the placement of invasive electrodes for localizing seizure onset.

Rufinamide: a new anti-epileptic medication

Rufinamide (1-[2,6-difluorobenzyl]-1H-1,2,3-triazole-4-carboxamide) is a new anti-epileptic drug with a novel triazole derivative structure. The suspected mechanism of action is limitation of sodium-dependent action potentials, thought to result in a membrane stabilizing effect. Rufinamide is extensively metabolized in the liver by non-CYP450 enzymes with an elimination half-life of 8 – 12 h. Three randomized, placebo-controlled trials have shown that rufinamide is effective against partial seizures in adults. Efficacy in the Lennox-Gastaut syndrome, a severe, disabling childhood onset epilepsy syndrome, was shown in a single, randomized, placebo-controlled trial. It has recently been approved for treatment of Lennox-Gastaut syndrome in Europe. In the US it is under regulatory review. Most common adverse effects are somnolence, fatigue, dizziness, dipolopia, nausea and ataxia. Rufinamide has shown promise as adjunctive treatment for Lennox-Gastaut syndrome and may have some role in localization related epilepsies as well.

Steps Toward Developing an EEG Biofeedback Treatment for Chronic Pain

Chronic pain, usually refractory to analgesics, is a significant problem for many individuals with spinal cord injury (SCI). Preliminary studies suggest that electroencephalography (EEG) biofeedback (also known as neurofeedback, NF) has the potential to help patients with otherwise refractory chronic pain. However, there remain many unanswered questions about the effects and mechanisms of this treatment. We studied 13 individuals with SCI and chronic pain with NF. Ten of the 13 individuals completed 4 sessions each of three different neurofeedback protocols assigned in random order for a total of 12 NF sessions. All three protocols had similar immediate effects on pain intensity. In addition, the participants reported modest pre- to post-treatment decreases in worst pain and pain unpleasantness following completion of the 12 NF sessions. These improvements were maintained at 3-month follow-up. The majority of the participants felt they benefited from and were satisfied with the treatment. No significant effects on measures of other outcome domains (sleep quality, pain interference and fatigue) were observed, although there was a non-significant trend for an increase in fatigue. Finally, pre- to post-treatment changes in EEG bandwidth activity, consistent with the training protocols, were observed in θ and α but not β frequencies. The findings provide preliminary support for the potential efficacy of NF for the treatment of SCI-related pain, and suggest that further clinical studies are warranted.

Brain EEG activity correlates of chronic pain in persons with spinal cord injury: clinical implications

Study design:Group comparison and cross-sectional study.Objectives:To replicate previous findings regarding electroencephalographic (EEG) pattern differences in a larger sample of patients with spinal cord injury (SCI) and chronic pain than previously studied, and examine associations between pain severity and EEG activity in a sample of patients with SCI and chronic pain.Setting:USA.Methods:EEG data were collected in an eyes-closed condition from 38 individuals with SCI and chronic pain, 16 individuals with SCI who did not have chronic pain and 28 healthy controls. Pain intensity experienced during the EEG assessment was assessed in the chronic pain group. Absolute and relative power in four frequency bands (delta, theta, alpha, and beta) were compared between the groups, and correlation coefficients between bandwidth activity and pain intensity in the pain group were computed.Results:Previously identified activity pattern differences (that is, more theta and less alpha) in those with SCI and chronic pain versus individuals with SCI and no pain and healthy controls were largely replicated. However, few significant associations between pain severity and EEG activity measures activity were found, and those that were found (more alpha activity associated with more pain as measured from frontal electrode sites) was in a direction opposite than predicted.Conclusion:The findings indicate that certain EEG activity patterns may be associated with more pain or a vulnerability to experience chronic pain in persons with SCI. Research examining the extent to which changes in this EEG activity may result in pain relief is warranted.

Effects of non-pharmacological pain treatments on brain states

OBJECTIVE To (1) evaluate the effects of a single session of four non-pharmacological pain interventions, relative to a sham tDCS procedure, on pain and electroencephalogram- (EEG-) assessed brain oscillations, and (2) determine the extent to which procedure-related changes in pain intensity are associated with changes in brain oscillations. METHODS 30 individuals with spinal cord injury and chronic pain were given an EEG and administered measures of pain before and after five procedures (hypnosis, meditation, transcranial direct current stimulation [tDCS], neurofeedback, and a control sham tDCS procedure). RESULTS Each procedure was associated with a different pattern of changes in brain activity, and all active procedures were significantly different from the control procedure in at least three bandwidths. Very weak and mostly non-significant associations were found between changes in EEG-assessed brain activity and pain. CONCLUSIONS Different non-pharmacological pain treatments have distinctive effects on brain oscillation patterns. However, changes in EEG-assessed brain oscillations are not significantly associated with changes in pain, and therefore such changes do not appear useful for explaining the benefits of these treatments. SIGNIFICANCE The results provide new findings regarding the unique effects of four non-pharmacological treatments on pain and brain activity.

Sleep spindles are locally modulated by training on a brain–computer interface

The learning of a motor task is known to be improved by sleep, and sleep spindles are thought to facilitate this learning by enabling synaptic plasticity. In this study subjects implanted with electrocorticography (ECoG) arrays for long-term epilepsy monitoring were trained to control a cursor on a computer screen by modulating either the high-gamma or mu/beta power at a single electrode located over the motor or premotor area. In all trained subjects, spindle density in posttraining sleep was increased with respect to pretraining sleep in a remarkably spatially specific manner. The pattern of increased spindle activity reflects the functionally specific regions that were involved in learning of a highly novel and salient task during wakefulness, supporting the idea that sleep spindles are involved in learning to use a motor-based brain–computer interface device.

Identifying functional networks using endogenous connectivity in gamma band electrocorticography.

Correlations in spontaneous, infra-slow (<0.1 Hz) fluctuations in gamma band (70-100 Hz) signal recorded using electrocorticography (ECoG) reflect the functional organization of the brain, appearing in auditory and visual sensory cortex, motor cortex, and the default mode network (DMN). We have developed a data-driven method using co-modulation in spontaneous, infra-slow, and gamma band power fluctuations in ECoG to characterize the connectivity between cortical areas. A graph spectral clustering algorithm was used to identify networks that appear consistently. These networks were compared with clinical mapping results obtained using electrocortical stimulation (ECS). We identify networks corresponding to motor and visual cortex with good specificity. Anatomic and functional evidence indicates that other networks, such as the DMN, are also identified by this algorithm. These results indicate that it may be possible to map functional cortex using only spontaneous ECoG recordings. In addition, they support the hypothesis that infra-slow co-modulations of gamma band power represent the neurophysiological basis underlying resting-state networks. Methods examining infra-slow co-modulations in gamma band power will be useful for studying changes in brain connectivity in differing behavioral contexts. Our observations can be made in the absence of observable behavior, suggesting that the electrical mapping of functional cortex is feasible without the use of ECS or task-mediated evoked responses.

Brain Oscillations, Hypnosis, and Hypnotizability

This article summarizes the state-of-science knowledge regarding the associations between hypnosis and brain oscillations. Brain oscillations represent the combined electrical activity of neuronal assemblies, usually measured as specific frequencies representing slower (delta, theta, alpha) and faster (beta, gamma) oscillations. Hypnosis has been most closely linked to power in the theta band and changes in gamma activity. These oscillations are thought to play a critical role in both the recording and recall of declarative memory and emotional limbic circuits. The authors propose that this role may be the mechanistic link between theta (and perhaps gamma) oscillations and hypnosis, specifically, that the increases in theta oscillations and changes in gamma activity observed with hypnosis may underlie some hypnotic responses. If these hypotheses are supported, they have important implications for both understanding the effects of hypnosis and for enhancing response to hypnotic treatments.

Pharmacokinetic of antiepileptic drugs in patients with hepatic or renal impairment.

Many factors influence choice of antiepileptic drugs (AEDs), including efficacy of the drug for the indication (epilepsy, neuropathic pain, affective disorder, migraine), tolerability, and toxicity. The first-generation AEDs and some newer AEDs are predominately eliminated by hepatic metabolism. Other recent AEDs are eliminated by renal excretion of unchanged drug or a combination of hepatic metabolism and renal excretion. The effect of renal and hepatic disease on the dosing will depend on the fraction of the AED eliminated by hepatic and/or renal excretion, the metabolic isozymes involved, as well as the extent of protein binding, if therapeutic drug monitoring is used. For drugs that are eliminated by renal excretion, methods of estimating creatinine clearance can be used to determine dose adjustments. For drugs eliminated by hepatic metabolism, there are no specific markers of liver function that can be used to provide guidance in dosage adjustments. Based on studies with probe drugs, the hepatic metabolic enzymes are differentially affected depending on the cause and severity of hepatic disease, which can aid in predicting dose adjustment when clinical data are not available. Several AEDs are also associated with laboratory markers of mild hepatic dysfunction and, rarely, more severe hepatic injury. In contrast, the risk of renal injury from AEDs is generally low. In general, co-morbid hepatic or renal diseases influence the decision for the selection of an AED. For some patients dosing changes to their existing AEDs may be appropriate. For others, a change to another AED may be a better option.