Deep-brain stimulation (DBS) is an established treatment for medically refractory essential tremor (ET). This article reviews the current evidence supporting the efficacy and safety of DBS targets, including the ventral intermediate (VIM) nucleus and posterior subthalamic area (PSA) in treatment of ET.
A structured PubMed search was performed through December 2012 with keywords “deep brain stimulation (DBS),” “essential tremor (ET),” “ventral intermediate (VIM) nucleus,” “posterior subthalamic area (PSA),” “safety,” and “efficacy.”
Based on level IV evidence, both VIM and PSA DBS targets appear to be safe and efficacious in ET patients in tremor reduction and improving activities of daily living, though the literature on PSA DBS is limited in terms of bilateral stimulation and long-term follow-up. DBS-related adverse effects are typically mild and stimulation-related. Hardware-related complications after DBS may not be uncommon, and often require additional surgical procedures. Few studies assessed quality-of-life and cognition outcomes in ET patients undergoing DBS stimulation.
DBS appears to be a safe and effective treatment for medically refractory ET. More systematic studies comparing VIM and PSA targets are needed to ascertain the most safe and effective DBS treatment for medically refractory ET. More research is warranted to assess quality-of-life and cognition outcomes in ET patients undergoing DBS.
deep-brain stimulation (DBS); essential tremor (ET); ventral intermediate (VIM) nucleus; posterior subthalamic area (PSA); safety; efficacy
Focal seizures are thought to reflect simultaneous activation of a large population of neurons within a discrete region of pathological brain. Resective surgery targeting this focus is an effective treatment in carefully selected patients, but not all. While in vivo recordings of single-neuron (i.e., “unit”) activity in patients with epilepsy have a long history, no studies have examined long–term firing rates leading into seizures and the spatial relationship of unit activity with respect to the seizure onset zone.
Microelectrode arrays recorded action potentials from neurons in mesial temporal structures (often including contralateral mesial temporal structures) in seven patients with mesial temporal lobe epilepsy.
Only 7.6% of microelectrode recordings showed increased firing rates prior to seizure onset and only 32.4% of microelectrodes showed any seizure-related activity changes. Surprisingly, firing rates on the majority of microelectrodes (67.6%) did not change throughout the seizure, including some microelectrodes located within the seizure onset zone. Furthermore, changes in firing rate prior to and at seizure onset were observed on microelectrodes located outside the seizure onset zone and even in contralateral mesial temporal lobe. These early changes varied from seizure to seizure, demonstrating the heterogeneity of ensemble activity underlying the generation of focal seizures. Increased neuronal synchrony was primarily observed only following seizure onset.
These results suggest that cellular correlates of seizure initiation and sustained ictal discharge in mesial temporal lobe epilepsy involve a small subset of the neurons within and outside the seizure onset zone. These results further suggest that the “epileptic ensemble or network” responsible for seizure generation are more complex and heterogeneous than previously thought and that future studies may find mechanistic insights and therapeutic treatments outside the clinical seizure onset zone.
multi-unit; ictogenesis; ensemble; microelectrode; electrophysiology; mesial temporal lobe
Deep brain stimulation (DBS) is a novel and effective surgical intervention for refractory Parkinson’s disease (PD).
We review the current literature to identify the clinical correlates associated with STN DBS-induced hypomania/mania in PD patients.
Ventromedial electrode placement has been most consistently implicated in the induction of STN DBS-induced mania. There is some evidence of symptom amelioration when electrode placement is switched to a more dorsolateral contact. Additional clinical correlates may include unipolar stimulation, higher voltage (>3 V), male patients and/or early onset PD.
STN DBS-induced psychiatric adverse events emphasize the need for comprehensive psychiatric presurgical evaluation and follow-up in PD patients. Animal studies and prospective clinical research, combined with advanced neuroimaging techniques, are needed to identify clinical correlates and underlying neurobiological mechanism(s) of STN DBS-induced mania. Such working models would serve to further our understanding of the neurobiological underpinnings of mania and contribute valuable new insight towards development of future DBS mood stabilization therapies.
Parkinson’s disease; mania; subthalamic nucleus (STN); deep brain stimulation (DBS)
Tc-99m ethyl cysteinate diethylester (ECD) and Tc-99m hexamethyl propylene amine oxime (HMPAO) are commonly used for single-photon emission computed tomography (SPECT) studies of a variety of neurologic disorders. Although these tracers have been very helpful in diagnosing and guiding treatment of neurologic disease, data describing the distribution and laterality of these tracers in normal resting brain are limited. Advances in quantitative functional imaging have demonstrated the value of using resting studies from control populations as a baseline to account for physiologic fluctuations in cerebral perfusion. Here, we report results from 30 resting Tc-99m ECD SPECT scans and 14 resting Tc-99m HMPAO scans of normal volunteers with no history of neurologic disease. Scans were analyzed with regions of interest and with statistical parametric mapping, with comparisons performed laterally (left vs. right), as well as for age, gender, and handedness. The results show regions of significant asymmetry in the normal controls affecting widespread areas in the cerebral hemispheres, but most marked in superior parietotemporal region and frontal lobes. The results have important implications for the use of normal control SPECT images in the evaluation of patients with neurologic disease.
brain asymmetry; brain imaging; SPECT
Transient high-frequency (100–500 Hz) oscillations of the local field potential have been studied extensively in human mesial temporal lobe. Previous studies report that both ripple (100–250 Hz) and fast ripple (250–500 Hz) oscillations are increased in the seizure-onset zone of patients with mesial temporal lobe epilepsy. Comparatively little is known, however, about their spatial distribution with respect to seizure-onset zone in neocortical epilepsy, or their prevalence in normal brain. We present a quantitative analysis of high-frequency oscillations and their rates of occurrence in a group of nine patients with neocortical epilepsy and two control patients with no history of seizures. Oscillations were automatically detected and classified using an unsupervised approach in a data set of unprecedented volume in epilepsy research, over 12 terabytes of continuous long-term micro- and macro-electrode intracranial recordings, without human preprocessing, enabling selection-bias-free estimates of oscillation rates. There are three main results: (i) a cluster of ripple frequency oscillations with median spectral centroid = 137 Hz is increased in the seizure-onset zone more frequently than a cluster of fast ripple frequency oscillations (median spectral centroid = 305 Hz); (ii) we found no difference in the rates of high frequency oscillations in control neocortex and the non-seizure-onset zone neocortex of patients with epilepsy, despite the possibility of different underlying mechanisms of generation; and (iii) while previous studies have demonstrated that oscillations recorded by parenchyma-penetrating micro-electrodes have higher peak 100–500 Hz frequencies than penetrating macro-electrodes, this was not found for the epipial electrodes used here to record from the neocortical surface. We conclude that the relative rate of ripple frequency oscillations is a potential biomarker for epileptic neocortex, but that larger prospective studies correlating high-frequency oscillations rates with seizure-onset zone, resected tissue and surgical outcome are required to determine the true predictive value.
high-frequency oscillations; epilepsy; intracranial EEG
Deep brain stimulation (DBS) is an established neurosurgical technique used to treat a variety of neurological disorders, including Parkinson disease, essential tremor, dystonia, epilepsy, depression, and obsessive-compulsive disorder. This study reports on the use of intraoperative MR imaging during DBS surgery to evaluate acute hemorrhage, intracranial air, brain shift, and accuracy of lead placement.
During a 46-month period, 143 patients underwent 152 DBS surgeries including 289 lead placements utilizing intraoperative 1.5-T MR imaging. Imaging was supervised by an MR imaging physicist to maintain the specific absorption rate below the required level of 0.1 W/kg and always included T1 magnetization-prepared rapid gradient echo and T2* gradient echo sequences with selected use of T2 fluid attenuated inversion recovery (FLAIR) and T2 fast spin echo (FSE). Retrospective review of the intraoperative MR imaging examinations was performed to quantify the amount of hemorrhage and the amount of air introduced during the DBS surgery.
Intraoperative MR imaging revealed 5 subdural hematomas, 3 subarachnoid hemorrhages, and 1 intra-parenchymal hemorrhage in 9 of the 143 patients. Only 1 patient experiencing a subarachnoid hemorrhage developed clinically apparent symptoms, which included transient severe headache and mild confusion. Brain shift due to intracranial air was identified in 144 separate instances.
Intraoperative MR imaging can be safely performed and may assist in demonstrating acute changes involving intracranial hemorrhage and air during DBS surgery. These findings are rarely clinically significant and typically resolve prior to follow-up imaging. Selective use of T2 FLAIR and T2 FSE imaging can confirm the presence of hemorrhage or air and preclude the need for CT examinations.
deep brain stimulation; intraoperative MR imaging; Parkinson disease; intracranial hemorrhage; functional neurosurgery
Tourette syndrome (TS) is a complex neuropsychiatric disorder often starting in childhood and characterized by the presence of multiple motor and vocal tics and psychiatric comorbidities. Patients with TS usually respond to medical treatment, and the condition often improves during adolescence; however, surgery has been considered a possible approach for the subset of patients with ongoing medically refractory disease. Ablative procedures have been associated with unsatisfactory results and major adverse effects, prompting trials of deep brain stimulation (DBS) as an alternative therapy. It remains unclear which of the various nuclear targets is most effective in TS. We describe 3 patients with TS who underwent DBS targeting the bilateral thalamic centromedian/parafascicular complex (CM/Pf) with an excellent clinical outcome. At 1-year follow-up, the mean reduction in the total Yale Global Tic Severity Scale score in the 3 patients was 70% (range, 60%-80%).Our study further supports the role of the CM/Pf DBS target in medically intractable TS.
Focal cortical epilepsy is currently most effectively studied in humans. However, improvement in cortical monitoring and investigational device development is limited by lack of an animal model mimicking human acute focal cortical epileptiform activity under epilepsy surgery conditions. Therefore, we assessed the swine model for translational epilepsy research. Swine were used due to their cost effectiveness, convoluted cortex, and comparative anatomy similar to humans. Focal subcortical injection of benzyl-penicillin produced clinical seizures correlating with epileptiform activity demonstrating temporal and spatial progression. Swine were evaluated under 5 different anesthesia regimens. Of the 5 regimens, conditions similar to human intraoperative anesthesia, including continuous fentanyl with low dose isoflorane, was the most effective for eliciting complex, epileptiform activity after benzyl-penicillin injection. The most complex epileptiform activity (spikes, and high frequency activity) was then repeated reliably in 9 animals, utilizing 14 swine total. There were 20.1 ± 10.8 (95% CI: 11.8–28.4) epileptiform events with greater than 3.5 hertz activity occurring per animal. Average duration of each event was 46.3 ± 15.6 (95% CI: 44.0 to 48.6) seconds, ranging from 20 to 100 seconds. In conclusion, the acute swine model of focal cortical epilepsy surgery provides an animal model mimicking human surgical conditions with a large brain, gyrated cortex, and is relatively cheap among animal models. Therefore, we feel this model provides a valuable, reliable, and novel platform for translational studies of implantable hardware for intracranial monitoring.
Epilepsy; Animal Model; Electroencephalography; Swine; Pig; Translational Research
Focal seizures appear to start abruptly and unpredictably when recorded from volumes of brain probed by clinical intracranial electroencephalograms. To investigate the spatiotemporal scale of focal epilepsy, wide-bandwidth electrophysiological recordings were obtained using clinical macro- and research microelectrodes in patients with epilepsy and control subjects with intractable facial pain. Seizure-like events not detectable on clinical macroelectrodes were observed on isolated microelectrodes. These ‘microseizures’ were sparsely distributed, more frequent in brain regions that generated seizures, and sporadically evolved into large-scale clinical seizures. Rare microseizures observed in control patients suggest that this phenomenon is ubiquitous, but their density distinguishes normal from epileptic brain. Epileptogenesis may involve the creation of these topographically fractured microdomains and ictogenesis (seizure generation), the dynamics of their interaction and spread.
epilepsy; seizure; intracranial EEG; microseizure; microcircuit; seizure generation; ictogenesis; epileptogenesis
The degree of synchronization in electroencephalography (EEG) signals is commonly characterized by the time-series measures, namely, correlation, phase synchrony, and magnitude squared coherence (MSC). However, it is now well established that the interpretation of the results from these measures are confounded by the recording reference signal and that this problem is not mitigated by the use of other EEG montages, such as bipolar and average reference. In this paper, we analyze the impact of reference signal amplitude and power on EEG signal correlation, phase synchrony, and MSC. We show that, first, when two nonreferential signals have negative correlation, the phase synchrony and the absolute value of the correlation of the two referential signals may have two regions of behavior characterized by a monotonic decrease to zero and then a monotonic increase to one as the amplitude of the reference signal varies in [0, +∞). It is notable that even a small change of the amplitude may lead to significant impact on these two measures. Second, when two nonreferential signals have positive correlation, the correlation and phase-synchrony values of the two referential signals can monotonically increase to one (or monotonically decrease to some positive value and then monotonically increase to one) as the amplitude of the reference signal varies in [0, +∞). Third, when two nonreferential signals have negative cross-power, the MSC of the two referential signals can monotonically decrease to zero and then monotonically increase to one as reference signal power varies in [0, +∞). Fourth, when two nonreferential signals have positive cross-power, the MSC of the two referential signals can monotonically increase to one as the reference signal power varies in [0, +∞). In general, the reference signal with small amplitude or power relative to the signals of interest may decrease or increase the values of correlation, phase synchrony, and MSC. However, the reference signal with high relative amplitude or power will always increase each of the three measures. In our previous paper, we developed a method to identify and extract the reference signal contribution to intracranial EEG (iEEG) recordings. In this paper, we apply this approach to referential iEEG recorded from human subjects and directly investigate the contribution of recording reference on correlation, phase synchrony, and MSC. The experimental results demonstrate the significant impact that the recording reference may have on these bivariate measures.
Bipolar electroencephalography (EEG); coherence; corrected EEG; correlation; phase synchrony; referential EEG; scalp reference signal; spectral power
The use of large-scale electrophysiology to obtain high spatiotemporal resolution brain recordings (>100 channels) capable of probing the range of neural activity from local field potential oscillations to single neuron action potentials presents new challenges for data acquisition, storage, and analysis. Our group is currently performing continuous, long-term electrophysiological recordings in human subjects undergoing evaluation for epilepsy surgery using hybrid intracranial electrodes composed of up to 320 micro- and clinical macroelectrode arrays. DC-capable amplifiers, sampling at 32 kHz per channel with 18-bits of A/D resolution are capable of resolving extracellular voltages spanning single neuron action potentials, high frequency oscillations, and high amplitude ultraslow activity, but this approach generates 3 terabytes of data per day (at 4 bytes per sample) using current data formats. Data compression can provide several practical benefits, but only if data can be compressed and appended to files in real-time in a format that allows random access to data segments of varying size. Here we describe a state-of-the-art, scalable, electrophysiology platform designed for acquisition, compression, encryption, and storage of large-scale data. Data are stored in a file format that incorporates lossless data compression using range encoded differences, a 32-bit cyclically redundant checksum to ensure data integrity, and 128-bit encryption for protection of patient information.
Quantitative analysis; EEG analysis; Data compression; Range encoding; Data encryption; Cyclic redundancy codes; Multiscale Electrophysiology Format
To determine the long-term efficacy of anterior temporal lobectomy for medically refractory temporal lobe epilepsy in patients with nonlesional magnetic resonance imaging (MRI).
We identified a retrospective cohort of 44 patients with a nonlesional modern “seizure protocol” MRI who underwent anterior temporal lobectomy for treatment of medically refractory partial epilepsy. Postoperative seizure freedom was determined by Kaplan-Meyer survival analysis. Noninvasive preoperative diagnostic factors potentially associated with excellent surgical outcome were examined by univariate analysis in the 40 patients with follow-up of >1 year.
Engel class I outcomes (free of disabling seizures) were observed in 60% (24 of 40) patients. Preoperative factors associated with Engel class I outcome were: (1) absence of contralateral or extratemporal interictal epileptiform discharges, (2) subtraction ictal single photon emission computed tomography (SPECT) Coregistered to MRI (SISCOM) abnormality localized to the resection site, and (3) subtle nonspecific MRI findings in the mesial temporal lobe concordant to the resection.
In carefully selected patients with temporal lobe epilepsy and a nonlesional MRI, anterior temporal lobectomy can often render patients free of disabling seizures. This favorable rate of surgical success is likely due to the detection of concordant abnormalities that indicate unilateral temporal lobe epilepsy in patients with nonlesional MRI.
Partial seizures; Epilepsy surgery; Temporal lobe; Nonlesional–MRI
Continuous, long-term (up to 10 days) electrophysiological monitoring using hybrid intracranial electrodes is an emerging tool for presurgical epilepsy evaluation and fundamental investigations of seizure generation. Detection of high-frequency oscillations and microseizures could provide valuable insights into causes and therapies for the treatment of epilepsy, but requires high spatial and temporal resolution. Our group is currently using hybrid arrays composed of up to 320 micro- and clinical macroelectrode arrays sampled at 32 kHz per channel with 18-bits of A/D resolution. Such recordings produce approximately 3 terabytes of data per day. Existing file formats have limited data compression capabilities, and do not offer mechanisms for protecting patient identifying information or detecting data corruption during transmission or storage. We present a novel file format that employs range encoding to provide a high degree of data compression, a three-tiered 128-bit encryption system for patient information and data security, and a 32-bit cyclic redundancy check to verify the integrity of compressed data blocks. Open-source software to read, write, and process these files are provided.
The increasing use of high-frequency (kHz), long-duration (days) intracranial monitoring from multiple electrodes during pre-surgical evaluation for epilepsy produces large amounts of data that are challenging to store and maintain. Descriptive metadata and clinical annotations of these large data sets also pose challenges to simple, often manual, methods of data analysis. The problems of reliable communication of metadata and annotations between programs, the maintenance of the meanings within that information over long time periods, and the flexibility to re-sort data for analysis place differing demands on data structures and algorithms. Solutions to these individual problem domains (communication, storage and analysis) can be configured to provide easy translation and clarity across the domains. The Multi-scale Annotation Format (MAF) provides an integrated metadata and annotation environment that maximizes code reuse, minimizes error probability and encourages future changes by reducing the tendency to over-fit information technology solutions to current problems. An example of a graphical utility for generating and evaluating metadata and annotations for “big data” files is presented.
Electrode arrays are sometimes implanted in the brains of patients with intractable epilepsy to better localize seizure foci before epilepsy surgery. Analysis of intracranial EEG (iEEG) recordings is typically performed in the electrode channel domain without explicit separation of the sources that generate the signals. However, intracranial EEG signals, like scalp EEG signals, could be linear mixtures of local activity and volume-conducted activity arising in multiple source areas. Independent component analysis (ICA) has recently been applied to scalp EEG data, and shown to separate the signal mixtures into independently generated brain and non-brain source signals. Here, we applied ICA to unmix source signals from intracranial EEG recordings from four epilepsy patients during a visually cued finger movement task in the presence of background pathological brain activity. This ICA decomposition demonstrated that the iEEG recordings were not maximally independent, but rather are linear mixtures of activity from multiple sources. Many of the independent component (IC) projections to the iEEG recording grid were consistent with sources from single brain regions, including components exhibiting classic movement-related dynamics. Notably, the largest IC projection to each channel accounted for no more than 20–80% of the channel signal variance, implying that in general intracranial recordings cannot be accurately interpreted as recordings of independent brain sources. These results suggest that ICA can be used to identify and monitor major field sources of local and distributed functional networks generating iEEG data. ICA decomposition methods are useful for improving the fidelity of source signals of interest, likely including distinguishing the sources of pathological brain activity.
ICA; intracranial; EEG; electrocorticography; ECoG; epilepsy; mu
Neuronal oscillations span a wide range of spatial and temporal scales that extend beyond traditional clinical EEG. Recent research suggests that high-frequency oscillations (HFO), in the ripple (80–250Hz) and fast ripple (250–1000Hz) frequency range, may be signatures of epileptogenic brain and involved in the generation of seizures. However, most research investigating HFO in humans comes from microwire recordings, whose relationship to standard clinical intracranial EEG (iEEG) has not been explored. In this study iEEG recordings (DC − 9000Hz) were obtained from human medial temporal lobe using custom depth electrodes containing both microwires and clinical macroelectrodes. Ripple and fast-ripple HFO recorded from both microwires and clinical macroelectrodes were increased in seizure generating brain regions compared to control regions. The distribution of HFO frequencies recorded from the macroelectrodes was concentrated in the ripple frequency range, compared to a broad distribution of HFO frequencies recorded from microwires. The average frequency of ripple HFO recorded from macroelectrodes was lower than that recorded from microwires (143.3 ± 49.3 Hz versus 116.3 ± 38.4, Wilcoxon rank sum P<0.0001). Fast-ripple HFO were most often recorded on a single microwire, supporting the hypothesis that fast-ripple HFO are primarily generated by highly localized, sub-millimeter scale neuronal assemblies that are most effectively sampled by microwire electrodes. Future research will address the clinical utility of these recordings for localizing epileptogenic networks and understanding seizure generation.
high-frequency oscillations; ripple; fast ripple; intracranial EEG; epilepsy