Laser interstitial thermal therapy in drug-resistant epilepsy.

PURPOSE OF REVIEW: MRI-guided stereotactic laser interstitial thermal therapy (LiTT) has been utilized in the surgical treatment of discrete, small epileptogenic lesions. This review summarizes the current literature and addresses the clinical application of this technique. RECENT FINDINGS: LiTT has the potential to reduce the morbidity and discomfort of epilepsy surgery. Review of data from retrospective, uncontrolled studies suggests that LiTT may offer benefit when treating drug-resistant epilepsy because of mesial temporal sclerosis, hypothalamic hamartoma, cavernous hemangioma, and small cortical dysplasias and malformations. It is now being offered as initial therapy in place of anterior temporal lobectomy in many centers, and a prospective study is underway to compare it with historical temporal lobectomy reports. SUMMARY: LiTT appears promising and has potential for reduced morbidity and improved tolerability compared with open surgery. Studies must be done to compare efficacy and safety of LiTT with open surgery, and further investigation is needed to optimize this technique.

Ripple oscillations in the left temporal neocortex are associated with impaired verbal episodic memory encoding.

BACKGROUND: We sought to determine if ripple oscillations (80-120 Hz), detected in intracranial electroencephalogram (iEEG) recordings of patients with epilepsy, correlate with an enhancement or disruption of verbal episodic memory encoding. METHODS: We defined ripple and spike events in depth iEEG recordings during list learning in 107 patients with focal epilepsy. We used logistic regression models (LRMs) to investigate the relationship between the occurrence of ripple and spike events during word presentation and the odds of successful word recall following a distractor epoch and included the seizure onset zone (SOZ) as a covariate in the LRMs. RESULTS: We detected events during 58,312 word presentation trials from 7630 unique electrode sites. The probability of ripple on spike (RonS) events was increased in the SOZ (p < 0.04). In the left temporal neocortex, RonS events during word presentation corresponded with a decrease in the odds ratio (OR) of successful recall, however, this effect only met significance in the SOZ (OR of word recall: 0.71, 95% confidence interval (CI): 0.59-0.85, n = 158 events, adaptive Hochberg, p < 0.01). Ripple on oscillation (RonO) events that occurred in the left temporal neocortex non-SOZ also correlated with decreased odds of successful recall (OR: 0.52, 95% CI: 0.34-0.80, n = 140, adaptive Hochberg, p < 0.01). Spikes and RonS that occurred during word presentation in the left middle temporal gyrus (MTG) correlated with the most significant decrease in the odds of successful recall, irrespective of the location of the SOZ (adaptive Hochberg, p < 0.01). CONCLUSION: Ripples and spikes generated in the left temporal neocortex are associated with impaired verbal episodic memory encoding. Although physiological and pathological ripple oscillations were not distinguished during cognitive tasks, our results show an association of undifferentiated ripples with impaired encoding. The effect was sometimes specific to regions outside the SOZ, suggesting that widespread effects of epilepsy outside the SOZ may contribute to cognitive impairment.

A method for the topographical identification and quantification of high frequency oscillations in intracranial electroencephalography recordings.

OBJECTIVE: To develop a reliable software method using a topographic analysis of time-frequency plots to distinguish ripple (80-200 Hz) oscillations that are often associated with EEG sharp waves or spikes (RonS) from sinusoid-like waveforms that appear as ripples but correspond with digital filtering of sharp transients contained in the wide bandwidth EEG. METHODS: A custom algorithm distinguished true from false ripples in one second intracranial EEG (iEEG) recordings using wavelet convolution, identifying contours of isopower, and categorizing these contours into sets of open or closed loop groups. The spectral and temporal features of candidate groups were used to classify the ripple, and determine its duration, frequency, and power. Verification of detector accuracy was performed on the basis of simulations, and visual inspection of the original and band-pass filtered signals. RESULTS: The detector could distinguish simulated true from false ripple on spikes (RonS). Among 2934 visually verified trials of iEEG recordings and spectrograms exhibiting RonS the accuracy of the detector was 88.5% with a sensitivity of 81.8% and a specificity of 95.2%. The precision was 94.5% and the negative predictive value was 84.0% (N = 12). Among, 1,370 trials of iEEG recording exhibiting RonS that were reviewed blindly without spectrograms the accuracy of the detector was 68.0%, with kappa equal to 0.01 ±â€¯0.03. The detector successfully distinguished ripple from high spectral frequency 'fast ripple' oscillations (200-600 Hz), and characterize ripple duration and spectral frequency and power. The detector was confounded by brief bursts of gamma (30-80 Hz) activity in 7.31 ±â€¯6.09% of trials, and in 30.2 ±â€¯14.4% of the true RonS detections ripple duration was underestimated. CONCLUSIONS: Characterizing the topographic features of a time-frequency plot generated by wavelet convolution is useful for distinguishing true oscillations from false oscillations generated by filter ringing. SIGNIFICANCE: Categorizing ripple oscillations and characterizing their properties can improve the clinical utility of the biomarker.

Utilization of independent component analysis for accurate pathological ripple detection in intracranial EEG recordings recorded extra- and intra-operatively.

OBJECTIVE: To develop and validate a detector that identifies ripple (80-200 Hz) events in intracranial EEG (iEEG) recordings in a referential montage and utilizes independent component analysis (ICA) to eliminate or reduce high-frequency artifact contamination. Also, investigate the correspondence of detected ripples and the seizure onset zone (SOZ). METHODS: iEEG recordings from 16 patients were first band-pass filtered (80-600 Hz) and Infomax ICA was next applied to derive the first independent component (IC1). IC1 was subsequently pruned, and an artifact index was derived to reduce the identification of high-frequency events introduced by the reference electrode signal. A Hilbert detector identified ripple events in the processed iEEG recordings using amplitude and duration criteria. The identified ripple events were further classified and characterized as true or false ripple on spikes, or ripples on oscillations by utilizing a topographical analysis to their time-frequency plot, and confirmed by visual inspection. RESULTS: The signal to noise ratio was improved by pruning IC1. The precision of the detector for ripple events was 91.27 ±â€¯4.3%, and the sensitivity of the detector was 79.4 ±â€¯3.0% (N = 16 patients, 5842 ripple events). The sensitivity and precision of the detector was equivalent in iEEG recordings obtained during sleep or intra-operatively. Across all the patients, true ripple on spike rates and also the rates of false ripple on spikes, that were generated due to filter ringing, classified the seizure onset zone (SOZ) with an area under the receiver operating curve (AUROC) of >76%. The magnitude and spectral content of true ripple on spikes generated in the SOZ was distinct as compared with the ripples generated in the NSOZ (p < .001). CONCLUSIONS: Utilizing ICA to analyze iEEG recordings in referential montage provides many benefits to the study of high-frequency oscillations. The ripple rates and properties defined using this approach may accurately delineate the seizure onset zone. SIGNIFICANCE: Strategies to improve the spatial resolution of intracranial EEG and reduce artifact can help improve the clinical utility of HFO biomarkers.

Spike voltage topography in temporal lobe epilepsy.

We investigated the voltage topography of interictal spikes in patients with temporal lobe epilepsy (TLE) to see whether topography was related to etiology for TLE. Adults with TLE, who had epilepsy surgery for drug-resistant seizures from 2011 until 2014 at Jefferson Comprehensive Epilepsy Center were selected. Two groups of patients were studied: patients with mesial temporal sclerosis (MTS) on MRI and those with other MRI findings. The voltage topography maps of the interictal spikes at the peak were created using BESA software. We classified the interictal spikes as polar, basal, lateral, or others. Thirty-four patients were studied, from which the characteristics of 340 spikes were investigated. The most common type of spike orientation was others (186 spikes; 54.7%), followed by lateral (146; 42.9%), polar (5; 1.5%), and basal (3; 0.9%). Characteristics of the voltage topography maps of the spikes between the two groups of patients were somewhat different. Five spikes in patients with MTS had polar orientation, but none of the spikes in patients with other MRI findings had polar orientation (odds ratio=6.98, 95% confidence interval=0.38 to 127.38; p=0.07). Scalp topographic mapping of interictal spikes has the potential to offer different information than visual inspection alone. The present results do not allow an immediate clinical application of our findings; however, detecting a polar spike in a patient with TLE may increase the possibility of mesial temporal sclerosis as the underlying etiology.

Subthalamic nucleus neurons are synchronized to primary motor cortex local field potentials in Parkinson's disease.

In Parkinson's disease (PD), striatal dopamine denervation results in a cascade of abnormalities in the single-unit activity of downstream basal ganglia nuclei that include increased firing rate, altered firing patterns, and increased oscillatory activity. However, the effects of these abnormalities on cortical function are poorly understood. Here, in humans undergoing deep brain stimulator implantation surgery, we use the novel technique of subdural electrocorticography in combination with subthalamic nucleus (STN) single-unit recording to study basal ganglia-cortex interactions at the millisecond time scale. We show that in patients with PD, STN spiking is synchronized with primary motor cortex (M1) local field potentials in two distinct patterns: first, STN spikes are phase-synchronized with M1 rhythms in the theta, alpha, or beta (4-30 Hz) bands. Second, STN spikes are synchronized with M1 gamma activity over a broad spectral range (50-200 Hz). The amplitude of STN spike-synchronized gamma activity in M1 is itself rhythmically modulated by the phase of a lower-frequency rhythm (phase-amplitude coupling), such that "waves" of phase-synchronized gamma activity precede the occurrence of STN spikes. We show the disease specificity of these phenomena in PD, by comparison with STN-M1 paired recordings performed in a group of patients with a different disorder, primary craniocervical dystonia. Our findings support a model of the basal ganglia-thalamocortical loop in PD in which gamma activity in primary motor cortex, modulated by the phase of low-frequency rhythms, drives STN unit discharge.

Oscillations in sensorimotor cortex in movement disorders: an electrocorticography study.

Movement disorders of basal ganglia origin may arise from abnormalities in synchronized oscillatory activity in a network that includes the basal ganglia, thalamus and motor cortices. In humans, much has been learned from the study of basal ganglia local field potentials recorded from temporarily externalized deep brain stimulator electrodes. These studies have led to the theory that Parkinson's disease has characteristic alterations in the beta frequency band (13-30 Hz) in the basal ganglia-thalamocortical network. However, different disorders have rarely been compared using recordings in the same structure under the same behavioural conditions, limiting straightforward assessment of current hypotheses. To address this, we utilized subdural electrocorticography to study cortical oscillations in the three most common movement disorders: Parkinson's disease, primary dystonia and essential tremor. We recorded local field potentials from the arm area of primary motor and sensory cortices in 31 subjects using strip electrodes placed temporarily during routine surgery for deep brain stimulator placement. We show that: (i) primary motor cortex broadband gamma power is increased in Parkinson's disease compared with the other conditions, both at rest and during a movement task; (ii) primary motor cortex high beta (20-30 Hz) power is increased in Parkinson's disease during the 'stop' phase of a movement task; (iii) the alpha-beta peaks in the motor and sensory cortical power spectra occur at higher frequencies in Parkinson's disease than in the other two disorders; and (iv) patients with dystonia have impaired movement-related beta band desynchronization in primary motor and sensory cortices. The findings support the emerging hypothesis that disease states reflect abnormalities in synchronized oscillatory activity. This is the first study of sensorimotor cortex local field potentials in the three most common movement disorders.

Pallidal neuronal discharge in Parkinson's disease following intraputamenal fetal mesencephalic allograft.

BACKGROUND: Human intrastriatal fetal allografts survive over long periods of time in the brains of Parkinson's disease (PD) patients and integrate into host circuitry. However, some grafted patients with a prior history of levodopa-induced dyskinesias have developed off-medication dyskinesias and dystonias following allografting whose mechanism remains poorly understood. The authors present single-unit discharge characteristics in the external and internal globus pallidus (GPe and GPi) in an awake patient with PD undergoing microelectrode-guided surgery for pallidal deep brain stimulation, 10 years following bilateral intraputamenal fetal mesencephalic allografting in an NIH-funded protocol. METHODS: Pallidal single-unit activity at 'rest' and during active movement was evaluated and compared with data sets from 13 PD patients in the 'off-medication' state and from one non-dyskinetic PD patient in the 'on-medication' state. RESULTS AND DISCUSSION: Analysis of firing rate, bursting discharge and oscillatory activity showed that the graft corrected some, but not all, of the abnormalities associated with the off-medication state. Additionally, in the transplanted patient, voluntary hand movement produced a marked reduction in pallidal discharge rate at multiple GPi recording sites, which was not observed during active movement in other patients. These findings are consistent with a persistent effect of transplanted dopamine cells on basal ganglia outflow and suggest a mechanism for the graft-induced dystonic phenotype.

The subthalamic nucleus in primary dystonia: single-unit discharge characteristics.

Most models of dystonia pathophysiology predict alterations of activity in the basal ganglia thalamocortical motor circuit. The globus pallidus interna (GPi) shows bursting and oscillatory neuronal discharge in both human dystonia and in animal models, but it is not clear which intrinsic basal ganglia pathways are implicated in this abnormal output. The subthalamic nucleus (STN) receives prominent excitatory input directly from cortical areas implicated in dystonia pathogenesis and inhibitory input from the external globus pallidus. The goal of this study was to elucidate the role of the STN in dystonia by analyzing STN neuronal discharge in patients with idiopathic dystonia. Data were collected in awake patients undergoing microelectrode recording for implantation of STN deep brain stimulation electrodes. We recorded 62 STN neurons in 9 patients with primary dystonia. As a comparison group, we recorded 143 STN neurons in 20 patients with Parkinson's disease (PD). Single-unit activity was discriminated off-line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity. The mean STN discharge rate in dystonia patients was 26.3 Hz (SD 13.6), which was lower than that in the PD patients (35.6 Hz, SD 15.2), but higher than published values for subjects without basal ganglia dysfunction. Oscillatory activity was found in both disorders, with a higher proportion of units oscillating in the beta range in PD. Bursting discharge was a prominent feature of both dystonia and PD, whereas sensory receptive fields were expanded in PD compared with dystonia. The STN firing characteristics, in conjunction with those previously published for GPi, suggest that bursting and oscillatory discharge in basal ganglia output may be transmitted via pathways involving the STN and provide a pathophysiologic rationale for STN as a surgical target in dystonia.

Microelectrode recording in the posterior hypothalamic region in humans.

INTRODUCTION: Deep brain stimulation of the posterior hypothalamic region (PHR) is an emerging technique for the treatment of medically intractable cluster headache. Few reports have analyzed single unit neuronal recordings in the human PHR. We report properties of spontaneous neuronal discharge in PHR for 6 patients who underwent DBS for cluster headaches. METHODS: Initial target coordinates, determined by magnetic resonance imaging stereotactic localization, were 2 mm lateral, 3 mm posterior, and 5 mm inferior to the midpoint of the anterior commissure-posterior commissure plane. A single microelectrode penetration was performed beginning 10 mm above the anatomic target, without systemic sedation. Single units were discriminated off-line by cluster cutting in principal components space. Discharge rates, interspike intervals, and oscillatory activity were analyzed and compared between ventromedial thalamic and hypothalamic units. RESULTS: Six patients and 24 units were evaluated. Units in the PHR had a slow, regular spontaneous discharge with wide, low-amplitude action potentials. The mean discharge rate of hypothalamic neurons was significantly lower (mean +/- standard deviation, 13.2 +/- 12.2) than that of medial thalamic units (28.0 +/- 8.2). Oscillatory activity was not detected. Microelectrode recording in this region caused no morbidity. CONCLUSION: The single-unit discharge rate of neurons in the PHR of awake humans was 13.2 Hz and was significantly lower than medial thalamic neurons recorded dorsal to the target. The findings will be of use for microelectrode localization of the cluster headache target and for comparison with animal studies.

Single unit "pauser" characteristics of the globus pallidus pars externa distinguish primary dystonia from secondary dystonia and Parkinson's disease.

The presence of high frequency discharge neurons with long periods of silence or "pauses" in the globus pallidus pars externa (GPe) is a unique identifying feature of this nucleus. Prior studies have demonstrated that pause characteristics reflect synaptic inputs into GPe. We hypothesized that GPe pause characteristics should distinguish movement disorders whose basal ganglia network abnormalities are different. We examined pause characteristics in 224 GPe units in patients with primary generalized dystonia, Parkinson's disease (PD), and secondary dystonia, undergoing single unit microelectrode recording for DBS placement in the awake state. Pauses in neuronal discharge were identified using the Poisson surprise method. Mean pause length in primary dystonia (606.8373.3) was higher than in PD (557.4366.6) (p<0.05). Interpause interval (IPI) was lower in primary dystonia (2331.63874.1) than PD (3646.45894.5) (p<0.01), and mean pause frequency was higher in primary dystonia (0.140.10) than PD (0.070.12) (p<0.01). Comparison of pause characteristics in primary versus secondary generalized dystonia revealed a significantly longer mean pause length in primary (606.8373.3) than in secondary dystonia (495.6236.5) (p<0.01). IPI was shorter in primary (2331.6+/-3874.1) than in secondary dystonia (3484.5+/-3981.6) (p<0.01). The results show that pause characteristics recorded in the awake human GPe distinguish primary dystonia from Parkinson's disease and secondary dystonia. The differences may reflect increased phasic input from striatal D2 receptor positive cells in primary dystonia, and are consistent with a recent model proposing that GPe provides capacity scaling for cortical input.

Pallidal neuronal discharge in Huntington's disease: support for selective loss of striatal cells originating the indirect pathway.

Chorea is the predominant motor manifestation in the early symptomatic phase of adult onset Huntington's disease (HD). Pathologically, this stage is marked by differential loss of striatal neurons contributing to the indirect pathway. This pattern of neuronal loss predicts decreased neuronal firing rates in GPi and increased firing rates in GPe, the opposite of the changes in firing rate known to occur in Parkinson's disease (PD). We present single-unit discharge characteristics (33 neurons) observed in an awake patient with HD (41 CAG repeats) undergoing microelectrode guided surgery for pallidal deep brain stimulation. Pallidal single-unit activity at "rest" and during voluntary movement was discriminated off line by principal component analysis and evaluated with respect to discharge rate, bursting, and oscillatory activity in the 0-200 Hz range. 24 GPi and 9 GPe units were studied, and compared with 132 GPi and 50 GPe units from 14 patients with PD. The mean (+/-SEM) spontaneous discharge rate for HD was 58+/-4 for GPi and 73+/-5 for GPe. This contrasted with discharge rates in PD of 95+/-2 for GPi and 57+/-3 for GPe. HD GPi units showed more bursting than PD GPi units but much less oscillatory activity in the 2-35 Hz frequency range at rest. These findings are consistent with selective early loss of striatal cells originating the indirect pathway.