Aberrant fast spiking interneuronal activity precedes seizure transitions in humans.

There is active debate regarding how GABAergic function changes during seizure initiation and propagation, and whether interneuronal activity drives or impedes the pathophysiology. Here, we track cell-type specific firing during spontaneous human seizures to identify neocortical mechanisms of inhibitory failure. Fast-spiking interneuron activity was maximal over 1 second before equivalent excitatory increases, and showed transitions to out-of-phase firing prior to local tissue becoming incorporated into the seizure-driving territory. Using computational modeling, we linked this observation to transient saturation block as a precursor to seizure invasion, as supported by multiple lines of evidence in the patient data. We propose that transient blocking of inhibitory firing due to selective fast-spiking interneuron saturation-resulting from intense excitatory synaptic drive-is a novel mechanism that contributes to inhibitory failure, allowing seizure propagation.

Neuronal Firing and Waveform Alterations through Ictal Recruitment in Humans.

Analyzing neuronal activity during human seizures is pivotal to understanding mechanisms of seizure onset and propagation. These analyses, however, invariably using extracellular recordings, are greatly hindered by various phenomena that are well established in animal studies: changes in local ionic concentration, changes in ionic conductance, and intense, hypersynchronous firing. The first two alter the action potential waveform, whereas the third increases the "noise"; all three factors confound attempts to detect and classify single neurons. To address these analytical difficulties, we developed a novel template-matching-based spike sorting method, which enabled identification of 1239 single neurons in 27 patients (13 female) with intractable focal epilepsy, that were tracked throughout multiple seizures. These new analyses showed continued neuronal firing with widespread intense activation and stereotyped action potential alterations in tissue that was invaded by the seizure: neurons displayed increased waveform duration (p < 0.001) and reduced amplitude (p < 0.001), consistent with prior animal studies. By contrast, neurons in "penumbral" regions (those receiving intense local synaptic drive from the seizure but without neuronal evidence of local seizure invasion) showed stable waveforms. All neurons returned to their preictal waveforms after seizure termination. We conclude that the distinction between "core" territories invaded by the seizure versus "penumbral" territories is evident at the level of single neurons. Furthermore, the increased waveform duration and decreased waveform amplitude are neuron-intrinsic hallmarks of seizure invasion that impede traditional spike sorting and could be used as defining characteristics of local recruitment.SIGNIFICANCE STATEMENT Animal studies consistently show marked changes in action potential waveform during epileptic discharges, but acquiring similar evidence in humans has proven difficult. Assessing neuronal involvement in ictal events is pivotal to understanding seizure dynamics and in defining clinical localization of epileptic pathology. Using a novel method to track neuronal firing, we analyzed microelectrode array recordings of spontaneously occurring human seizures, and here report two dichotomous activity patterns. In cortex that is recruited to the seizure, neuronal firing rates increase and waveforms become longer in duration and shorter in amplitude as the neurons are recruited to the seizure, while penumbral tissue shows stable action potentials, in keeping with the "dual territory" model of seizure dynamics.

Subthalamic nucleus deep brain stimulation with a multiple independent constant current-controlled device in Parkinson's disease (INTREPID): a multicentre, double-blind, randomised, sham-controlled study.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus is an established therapeutic option for managing motor symptoms of Parkinson's disease. We conducted a double-blind, sham-controlled, randomised controlled trial to assess subthalamic nucleus DBS, with a novel multiple independent contact current-controlled (MICC) device, in patients with Parkinson's disease. METHODS: This trial took place at 23 implanting centres in the USA. Key inclusion criteria were age between 22 and 75 years, a diagnosis of idiopathic Parkinson's disease with over 5 years of motor symptoms, and stable use of anti-parkinsonian medications for 28 days before consent. Patients who passed screening criteria were implanted with the DBS device bilaterally in the subthalamic nucleus. Patients were randomly assigned in a 3:1 ratio to receive either active therapeutic stimulation settings (active group) or subtherapeutic stimulation settings (control group) for the 3-month blinded period. Randomisation took place with a computer-generated data capture system using a pre-generated randomisation table, stratified by site with random permuted blocks. During the 3-month blinded period, both patients and the assessors were masked to the treatment group while the unmasked programmer was responsible for programming and optimisation of device settings. The primary outcome was the difference in mean change from baseline visit to 3 months post-randomisation between the active and control groups in the mean number of waking hours per day with good symptom control and no troublesome dyskinesias, with no increase in anti-parkinsonian medications. Upon completion of the blinded phase, all patients received active treatment in the open-label period for up to 5 years. Primary and secondary outcomes were analysed by intention to treat. All patients who provided informed consent were included in the safety analysis. The open-label phase is ongoing with no new enrolment, and current findings are based on the prespecified interim analysis of the first 160 randomly assigned patients. The study is registered with ClinicalTrials.gov, NCT01839396. FINDINGS: Between May 17, 2013, and Nov 30, 2017, 313 patients were enrolled across 23 sites. Of these 313 patients, 196 (63%) received the DBS implant and 191 (61%) were randomly assigned. Of the 160 patients included in the interim analysis, 121 (76%) were randomly assigned to the active group and 39 (24%) to the control group. The difference in mean change from the baseline visit (post-implant) to 3 months post-randomisation in increased ON time without troublesome dyskinesias between the active and control groups was 3·03 h (SD 4·52, 95% CI 1·3-4·7; p<0·0001). 26 serious adverse events in 20 (13%) patients occurred during the 3-month blinded period. Of these, 18 events were reported in the active group and 8 in the control group. One death was reported among the 196 patients before randomisation, which was unrelated to the procedure, device, or stimulation. INTERPRETATION: This double-blind, sham-controlled, randomised controlled trial provides class I evidence of the safety and clinical efficacy of subthalamic nucleus DBS with a novel MICC device for the treatment of motor symptoms of Parkinson's disease. Future trials are needed to investigate potential benefits of producing a more defined current field using MICC technology, and its effect on clinical outcomes. FUNDING: Boston Scientific.

Interleaved deep brain stimulation for dyskinesia management in Parkinson's disease.

BACKGROUND: In patients with Parkinson's disease, stimulation above the subthalamic nucleus (STN) may engage the pallidofugal fibers and directly suppress dyskinesia. OBJECTIVES: The objective of this study was to evaluate the effect of interleaving stimulation through a dorsal deep brain stimulation contact above the STN in a cohort of PD patients and to define the volume of tissue activated with antidyskinesia effects. METHODS: We analyzed the Core Assessment Program for Surgical Interventional Therapies dyskinesia scale, Unified Parkinson's Disease Rating Scale parts III and IV, and other endpoints in 20 patients with interleaving stimulation for management of dyskinesia. Individual models of volume of tissue activated and heat maps were used to identify stimulation sites with antidyskinesia effects. RESULTS: The Core Assessment Program for Surgical Interventional Therapies dyskinesia score in the on medication phase improved 70.9 ± 20.6% from baseline with noninterleaved settings (P < 0.003). With interleaved settings, dyskinesia improved 82.0 ± 27.3% from baseline (P < 0.001) and 61.6 ± 39.3% from the noninterleaved phase (P = 0.006). The heat map showed a concentration of volume of tissue activated dorsally to the STN during the interleaved setting with an antidyskinesia effect. CONCLUSION: Interleaved deep brain stimulation using the dorsal contacts can directly suppress dyskinesia, probably because of the involvement of the pallidofugal tract, allowing more conservative medication reduction. © 2019 International Parkinson and Movement Disorder Society.

Reduced Repertoire of Cortical Microstates and Neuronal Ensembles in Medically Induced Loss of Consciousness.

Medically induced loss of consciousness (mLOC) during anesthesia is associated with a macroscale breakdown of brain connectivity, yet the neural microcircuit correlates of mLOC remain unknown. To explore this, we applied different analytical approaches (t-SNE/watershed segmentation, affinity propagation clustering, PCA, and LZW complexity) to two-photon calcium imaging of neocortical and hippocampal microcircuit activity and local field potential (LFP) measurements across different anesthetic depths in mice, and to micro-electrode array recordings in human subjects. We find that in both cases, mLOC disrupts population activity patterns by generating (1) fewer discriminable network microstates and (2) fewer neuronal ensembles. Our results indicate that local neuronal ensemble dynamics could causally contribute to the emergence of conscious states.

Delayed high-frequency suppression after automated single-pulse electrical stimulation identifies the seizure onset zone in patients with refractory epilepsy.

OBJECTIVE: Single-pulse electrical stimulation (SPES) of intracranial electrodes evokes responses that may help identify the seizure onset zone (SOZ); however, lack of automation and response variability has limited clinical adoption of this technique. We evaluated whether automated delivery of low-current SPES could evoke delayed high-frequency suppression (DHFS) of ongoing electrocorticography (ECoG) signals that, when combined with objective analytic techniques, may provide a reliable marker of this zone. METHODS: Low-current SPES (1-ms, 3.5-mA biphasic pulses) was delivered to 652 electrodes across 10 patients undergoing ECoG for seizure focus localization. DHFS was measured by calculating the normalized trial-averaged time-frequency power (70-250 Hz) 0.4-1 sec post-stimulation. Electrodes that evoked suppression when stimulated or recorded suppression when stimulation was nearby were used to estimate the SOZ. RESULTS: The estimated SOZ significantly identified the clinical SOZ in 6 of 10 patients (5 of 7 temporal foci) with a false-positive rate of 0-0.06. Stimulation required <2 h, was undetectable by patients, and did not induce seizures or after-discharges. CONCLUSIONS: We show that DHFS provides accurate estimates of the clinical SOZ in patients with refractory epilepsy. SIGNIFICANCE: This approach may increase the safety, speed, and reproducibility of SOZ identification while reducing cost, subjectivity, and patient discomfort.

Intravenous acetaminophen for postoperative supratentorial craniotomy pain: a prospective, randomized, double-blinded, placebo-controlled trial.

OBJECTIVE: Acute pain control after cranial surgery is challenging. Prior research has shown that patients experience inadequate pain control post-craniotomy. The use of oral medications is sometimes delayed because of postoperative nausea, and the use of narcotics can impair the evaluation of brain function and thus are used judiciously. Few nonnarcotic intravenous (IV) analgesics exist. The authors present the results of the first prospective study evaluating the use of IV acetaminophen in patients after elective craniotomy. METHODS: The authors conducted a randomized, double-blinded, placebo-controlled investigation. Adults undergoing elective, supratentorial craniotomies between September 2013 and June 2015 were randomized into two groups. The experimental group received 1000 mg/100 ml IV acetaminophen every 8 hours for 48 hours. The placebo group received 100 ml of 0.9% normal saline on the same schedule. Both groups were also treated with a standardized pain control algorithm. The study was powered to detect a 30% difference in the primary outcome measures: narcotic consumption (morphine equivalents, ME) at 24 and 48 hours after surgery. Patient-reported pain scores immediately postoperatively and 48 hours after surgery were also recorded. RESULTS: A total of 204 patients completed the trial. No significant differences were found in narcotic consumption between groups at either time point (in the treatment and placebo groups, respectively, at 24 hours: 84.3 ME [95% CI 70.2­98.4] and 85.5 ME [95% CI 73­97.9]; and at 48 hours: 123.5 ME [95% CI 102.9­144.2] and 134.2 ME [95% CI 112.1­156.3]). The difference in improvement in patient-reported pain scores between the treatment and placebo groups was significant (p < 0.001). CONCLUSIONS: Patients who received postoperative IV acetaminophen after craniotomy did not have significantly decreased narcotic consumption but did experience significantly lower pain scores after surgery. The drug was well tolerated and safe in this patient population.

Thalamic Deep Brain Stimulation for Essential Tremor Also Reduces Voice Tremor.

OBJECTIVE: Voice tremor is a common feature of essential tremor (ET) that is difficult to treat medically and significantly affects quality of life. Deep brain stimulation (DBS) of the ventral intermediate nucleus (Vim) of the thalamus is effective in improving contralateral distal limb tremor and has been shown in limited studies to affect voice tremor. Our objective was to retrospectively evaluate whether Vim-DBS used to treat patients with essential motor tremor also effectively treated underlying concurrent voice tremor and assess whether particular lead locations were favorable for treating vocal tremor. MATERIALS AND METHODS: In this retrospective cohort study, patients had unilateral or bilateral lead placement and were monitored for up to 12 months. We used the Fahn-Tolosa-Marin (FTM) subscore to assess vocal tremor. Changes in vocal tremor before and after stimulation and over several sessions were assessed. RESULTS: Of the 77 patients who met the inclusion criteria and were treated for essential tremor, 20 (26%) patients had vocal tremor prior to stimulation. Active Vim-DBS decreased the amplitude of voice tremor by 80% (p < 0.001). The mean FTM score as 1.24 pre-operation, 1.08 post-implantation (consistent with a lesion effect), and 0.25 with stimulation. The effect magnitude was maintained at last follow-up with slight improvement over time (p < 0.05). Unilateral and bilateral stimulation resulted in similar degrees of tremor reduction. A model of the centroid of stimulation showed that Vim thalamic stimulation that is more anterior on average yielded better voice tremor control, significantly so on the left side (p < 0.05). Additionally, there was improvement in head, tongue, and face tremor scores (p < 0.05). CONCLUSIONS: Unilateral and bilateral Vim-DBS targeted to treat the motor component of essential tremor also dramatically decreased the amplitude of voice tremor in this group of patients, suggesting a potential benefit of this treatment for affected patients.

Multivariate regression methods for estimating velocity of ictal discharges from human microelectrode recordings.

OBJECTIVE: Epileptiform discharges, an electrophysiological hallmark of seizures, can propagate across cortical tissue in a manner similar to traveling waves. Recent work has focused attention on the origination and propagation patterns of these discharges, yielding important clues to their source location and mechanism of travel. However, systematic studies of methods for measuring propagation are lacking. APPROACH: We analyzed epileptiform discharges in microelectrode array recordings of human seizures. The array records multiunit activity and local field potentials at 400 micron spatial resolution, from a small cortical site free of obstructions. We evaluated several computationally efficient statistical methods for calculating traveling wave velocity, benchmarking them to analyses of associated neuronal burst firing. MAIN RESULTS: Over 90% of discharges met statistical criteria for propagation across the sampled cortical territory. Detection rate, direction and speed estimates derived from a multiunit estimator were compared to four field potential-based estimators: negative peak, maximum descent, high gamma power, and cross-correlation. Interestingly, the methods that were computationally simplest and most efficient (negative peak and maximal descent) offer non-inferior results in predicting neuronal traveling wave velocities compared to the other two, more complex methods. Moreover, the negative peak and maximal descent methods proved to be more robust against reduced spatial sampling challenges. Using least absolute deviation in place of least squares error minimized the impact of outliers, and reduced the discrepancies between local field potential-based and multiunit estimators. SIGNIFICANCE: Our findings suggest that ictal epileptiform discharges typically take the form of exceptionally strong, rapidly traveling waves, with propagation detectable across millimeter distances. The sequential activation of neurons in space can be inferred from clinically-observable EEG data, with a variety of straightforward computation methods available. This opens possibilities for systematic assessments of ictal discharge propagation in clinical and research settings.

The ictal wavefront is the spatiotemporal source of discharges during spontaneous human seizures.

The extensive distribution and simultaneous termination of seizures across cortical areas has led to the hypothesis that seizures are caused by large-scale coordinated networks spanning these areas. This view, however, is difficult to reconcile with most proposed mechanisms of seizure spread and termination, which operate on a cellular scale. We hypothesize that seizures evolve into self-organized structures wherein a small seizing territory projects high-intensity electrical signals over a broad cortical area. Here we investigate human seizures on both small and large electrophysiological scales. We show that the migrating edge of the seizing territory is the source of travelling waves of synaptic activity into adjacent cortical areas. As the seizure progresses, slow dynamics in induced activity from these waves indicate a weakening and eventual failure of their source. These observations support a parsimonious theory for how large-scale evolution and termination of seizures are driven from a small, migrating cortical area.

Approaches to a cortical vision prosthesis: implications of electrode size and placement.

OBJECTIVE: In order to move forward with the development of a cortical vision prosthesis, the critical issues in the field must be identified. APPROACH: To begin this process, we performed a brief review of several different cortical and retinal stimulation techniques that can be used to restore vision. MAIN RESULTS: Intracortical microelectrodes and epicortical macroelectrodes have been evaluated as the basis of a vision prosthesis. We concluded that an important knowledge gap necessitates an experimental in vivo performance evaluation of microelectrodes placed on the surface of the visual cortex. A comparison of the level of vision restored by intracortical versus epicortical microstimulation is necessary. Because foveal representation in the primary visual cortex involves more cortical columns per degree of visual field than does peripheral vision, restoration of foveal vision may require a large number of closely spaced microelectrodes. Based on previous studies of epicortical macrostimulation, it is possible that stimulation via surface microelectrodes could produce a lower spatial resolution, making them better suited for restoring peripheral vision. SIGNIFICANCE: The validation of epicortical microstimulation in addition to the comparison of epicortical and intracortical approaches for vision restoration will fill an important knowledge gap and may have important implications for surgical strategies and device longevity. It is possible that the best approach to vision restoration will utilize both epicortical and intracortical microstimulation approaches, applying them appropriately to different visual representations in the primary visual cortex.

Informative features of local field potential signals in primary visual cortex during natural image stimulation.

The local field potential (LFP) is of growing importance in neurophysiology as a metric of network activity and as a readout signal for use in brain-machine interfaces. However, there are uncertainties regarding the kind and visual field extent of information carried by LFP signals, as well as the specific features of the LFP signal conveying such information, especially under naturalistic conditions. To address these questions, we recorded LFP responses to natural images in V1 of awake and anesthetized macaques using Utah multielectrode arrays. First, we have shown that it is possible to identify presented natural images from the LFP responses they evoke using trained Gabor wavelet (GW) models. Because GW models were devised to explain the spiking responses of V1 cells, this finding suggests that local spiking activity and LFPs (thought to reflect primarily local synaptic activity) carry similar visual information. Second, models trained on scalar metrics, such as the evoked LFP response range, provide robust image identification, supporting the informative nature of even simple LFP features. Third, image identification is robust only for the first 300 ms following image presentation, and image information is not restricted to any of the spectral bands. This suggests that the short-latency broadband LFP response carries most information during natural scene viewing. Finally, best image identification was achieved by GW models incorporating information at the scale of ∼ 0.5° in size and trained using four different orientations. This suggests that during natural image viewing, LFPs carry stimulus-specific information at spatial scales corresponding to few orientation columns in macaque V1.

Acute human brain responses to intracortical microelectrode arrays: challenges and future prospects.

The emerging field of neuroprosthetics is focused on the development of new therapeutic interventions that will be able to restore some lost neural function by selective electrical stimulation or by harnessing activity recorded from populations of neurons. As more and more patients benefit from these approaches, the interest in neural interfaces has grown significantly and a new generation of penetrating microelectrode arrays are providing unprecedented access to the neurons of the central nervous system (CNS). These microelectrodes have active tip dimensions that are similar in size to neurons and because they penetrate the nervous system, they provide selective access to these cells (within a few microns). However, the very long-term viability of chronically implanted microelectrodes and the capability of recording the same spiking activity over long time periods still remain to be established and confirmed in human studies. Here we review the main responses to acute implantation of microelectrode arrays, and emphasize that it will become essential to control the neural tissue damage induced by these intracortical microelectrodes in order to achieve the high clinical potentials accompanying this technology.

The effects of propofol on local field potential spectra, action potential firing rate, and their temporal relationship in humans and felines.

Propofol is an intravenous sedative hypnotic, which, acting as a GABAA agonist, results in neocortical inhibition. While propofol has been well studied at the molecular and clinical level, less is known about the effects of propofol at the level of individual neurons and local neocortical networks. We used Utah Electrode Arrays (UEAs) to investigate the effects of propofol anesthesia on action potentials (APs) and local field potentials (LFPs). UEAs were implanted into the neocortex of two humans and three felines. The two human patients and one feline received propofol by bolus injection, while the other two felines received target-controlled infusions. We examined the changes in LFP power spectra and AP firing at different levels of anesthesia. Increased propofol concentration correlated with decreased high-frequency power in LFP spectra and decreased AP firing rates, and the generation of large-amplitude spike-like LFP activity; however, the temporal relationship between APs and LFPs remained relatively consistent at all levels of propofol. The probability that an AP would fire at this local minimum of the LFP increased with propofol administration. The propofol-induced suppression of neocortical network activity allowed LFPs to be dominated by low-frequency spike-like activity, and correlated with sedation and unconsciousness. As the low-frequency spike-like activity increased and the AP-LFP relationship became more predictable firing rate encoding capacity is impaired. This suggests a mechanism for decreased information processing in the neocortex that accounts for propofol-induced unconsciousness.

Recurrent, delayed hemorrhage associated with edoxaban after deep brain stimulation lead placement.

Factor-Xa inhibitors like edoxaban have been shown to have comparable or superior rates of stroke and systemic embolization prevention to warfarin while exhibiting lower clinically significant bleeding rates. The authors report a case of a man who presented with delayed, recurrent intracranial hemorrhage months after successful deep brain stimulator placement for Parkinson disease while on edoxaban for atrial fibrillation. Further reports on the use of novel anticoagulants after intracranial surgery are acutely needed to help assess the true relative risk they pose.

Decoding dexterous finger movements in a neural prosthesis model approaching real-world conditions.

Dexterous finger movements can be decoded from neuronal action potentials acquired from a nonhuman primate using a chronically implanted Utah Electrode Array. We have developed an algorithm that can, after training, detect and classify individual and combined finger movements without any a priori knowledge of the data, task, or behavior. The algorithm is based on changes in the firing rates of individual neurons that are tuned for one or more finger movement types. Nine different movement types, which consisted of individual flexions, individual extensions, and combined flexions of the thumb, index finger, and middle finger, were decoded. The algorithm performed reliably on data recorded continuously during movement tasks, including a no-movement state, with an overall average sensitivity and specificity that were both > 92%. These results demonstrate a viable algorithm for decoding dexterous finger movements under conditions similar to those required for a real-world neural prosthetic application.

The use of a novel carbon nanotube coated microelectrode array for chronic intracortical recording and microstimulation.

Micro-electrode arrays (MEAs) have been used in a variety of intracortical neural prostheses. While intracortical MEAs have demonstrated their utility in neural prostheses, in many cases MEA performance declines after several months to years of in vivo implantation. The application of carbon nanotubes (CNTs) may increase the functional longevity of intracortical MEAs through enhanced biocompatibility and charge injection properties. An MEA metalized with platinum (Pt) on all electrodes had a CNT coating applied to the electrodes on half of the array. This Pt/Pt-CNT MEA was implanted into feline motor cortex for >1 year. Recordings of action potentials and 1 kHz impedance measurements were made on all electrodes to evaluate device functionality. Additionally, electromyogram (EMG) responses were evoked using micro-stimulation via the MEA to measure device performance. These metrics were compared between Pt and Pt-CNT electrodes. There was no significant difference in the data acquisition or micro-stimulation performance of Pt and the Pt-CNT electrodes. However, impedances were lower on the Pt-CNT electrodes. These results demonstrate the functionality of CNT coatings during chronic in vivo implantation. The lower impedances suggest that for microstimulation applications CNT coatings may impart enhanced interface properties.

Decoding hand trajectories from micro-electrocorticography in human patients.

A Kalman filter was used to decode hand trajectories from micro-electrocorticography recorded over motor cortex in human patients. In two cases, signals were recorded during stereotyped tasks, and the trajectories were decoded offline, with maximum correlation coefficients between actual and predicted trajectories of 0.51 (x-direction position) and 0.54 (y-direction position). In a third setting, a human patient with full neural control of a computer cursor acquired onscreen targets within 6.24 sec on average, with no algorithmic constraints on the output trajectory. These practical results illustrate the potential utility of signals recorded at the cortical surface with high spatial resolution, demonstrating that surface potentials contain relevant and sufficient information to drive sophisticated brain-computer interface systems.

Information transfer along the ventral auditory processing stream in the awake macaque.

Few studies have examined the physiology of the auditory cortical processing streams in the context of information transfer among cortical areas. This study examines information transfer in two cortical areas in the ventral auditory processing stream in an awake macaque. We show conditional information examined over different durations of neural responses provides insight into the time scale and direction of cortical hierarchical processing.