A novel theta-controlled vibrotactile brain-computer interface to treat chronic pain: a pilot study.

Limitations in chronic pain therapies necessitate novel interventions that are effective, accessible, and safe. Brain-computer interfaces (BCIs) provide a promising modality for targeting neuropathology underlying chronic pain by converting recorded neural activity into perceivable outputs. Recent evidence suggests that increased frontal theta power (4-7 Hz) reflects pain relief from chronic and acute pain. Further studies have suggested that vibrotactile stimulation decreases pain intensity in experimental and clinical models. This longitudinal, non-randomized, open-label pilot study's objective was to reinforce frontal theta activity in six patients with chronic upper extremity pain using a novel vibrotactile neurofeedback BCI system. Patients increased their BCI performance, reflecting thought-driven control of neurofeedback, and showed a significant decrease in pain severity (1.29 ± 0.25 MAD, p = 0.03, q = 0.05) and pain interference (1.79 ± 1.10 MAD p = 0.03, q = 0.05) scores without any adverse events. Pain relief significantly correlated with frontal theta modulation. These findings highlight the potential of BCI-mediated cortico-sensory coupling of frontal theta with vibrotactile stimulation for alleviating chronic pain.

Anterior Cingulate Cortex and the Control of Dynamic Behavior in Primates.

The brain mechanism for controlling continuous behavior in dynamic contexts must mediate action selection and learning across many timescales, responding differentially to the level of environmental uncertainty and volatility. In this review, we argue that a part of the frontal cortex known as the anterior cingulate cortex (ACC) is particularly well suited for this function. First, the ACC is interconnected with prefrontal, parietal, and subcortical regions involved in valuation and action selection. Second, the ACC integrates diverse, behaviorally relevant information across multiple timescales, producing output signals that temporally encapsulate decision and learning processes and encode high-dimensional information about the value and uncertainty of future outcomes and subsequent behaviors. Third, the ACC signals behaviorally relevant information flexibly, displaying the capacity to represent information about current and future states in a valence-, context-, task- and action-specific manner. Fourth, the ACC dynamically controls instrumental- and non-instrumental information seeking behaviors to resolve uncertainty about future outcomes. We review electrophysiological and circuit disruption studies in primates to develop this point, discuss its relationship to novel therapeutics for neuropsychiatric disorders in humans, and conclude by relating ongoing research in primates to studies of medial frontal cortical regions in rodents.

Glioblastoma Treated With Magnetic Resonance Imaging-Guided Laser Interstitial Thermal Therapy: Safety, Efficacy, and Outcomes.

BACKGROUND: Despite the multitude of available treatments, glioblastoma (GBM) remains an aggressive and uniformly fatal tumor. Laser interstitial thermal therapy (LITT) is a novel, minimally invasive treatment that holds promise for treating patients with GBM who are not candidates for traditional open craniotomy. However, due to the recent introduction of LITT into clinical practice, large series that evaluate safety and long-term outcomes after LITT are lacking. OBJECTIVE: To present our institution's series of over 50 GBM patients treated with LITT, with regard to safety, efficacy, and outcomes. METHODS: We performed a retrospective descriptive study of patients with histologically proven GBM who underwent LITT. Data collected included demographics, tumor location and volume, tumor genetic markers, treatment volume, perioperative complications, and long-term follow-up data. RESULTS: We performed 58 LITT treatments for GBM in 54 patients over 5.5 yr. Forty-one were recurrent tumors while 17 were frontline treatments. Forty GBMs were lobar in location, while 18 were in deep structures (thalamus, insula, corpus callosum). Average tumor volume was 12.5 ± 13.4 cm3. Average percentage of tumor treated with the yellow thermal damage threshold (TDT) line (dose equivalent of 43°C for 2 min) was 93.3% ± 10.6%, and with the blue TDT line (dose equivalent of 43°C for 10 min) was 88.0% ± 14.2%. There were 7 perioperative complications (12%) and 2 mortalities (3.4%). Median overall survival after LITT for the total cohort was 11.5 mo, and median progression-free survival 6.6 mo. CONCLUSION: LITT appears to be a safe and effective treatment for GBM in properly selected patients.

Novel spinal instrumentation to enhance osteogenesis and fusion: a preliminary study.

OBJECTIVE Instrumented spinal fusion continues to exhibit high failure rates in patients undergoing multilevel lumbar fusion or pseudarthrosis revision; with Grade II or higher spondylolisthesis; or in those possessing risk factors such as obesity, tobacco use, or metabolic disorders. Direct current (DC) electrical stimulation of bone growth represents a unique surgical adjunct in vertebral fusion procedures, yet existing spinal fusion stimulators are not optimized to enhance interbody fusion. To develop an advanced method of applying DC electrical stimulation to promote interbody fusion, a novel osteogenic spinal system capable of routing DC through rigid instrumentation and into the vertebral bodies was fabricated. A pilot study was designed to assess the feasibility of osteogenic instrumentation and compare the ability of osteogenic instrumentation to promote successful interbody fusion in vivo to standard spinal instrumentation with autograft. METHODS Instrumented, single-level, posterior lumbar interbody fusion (PLIF) with autologous graft was performed at L4-5 in adult Toggenburg/Alpine goats, using both osteogenic spinal instrumentation (plus electrical stimulation) and standard spinal instrumentation (no electrical stimulation). At terminal time points (3 months, 6 months), animals were killed and lumbar spines were explanted for radiographic analysis using a SOMATOM Dual Source Definition CT Scanner and high-resolution Microcat II CT Scanner. Trabecular continuity, radiodensity within the fusion mass, and regional bone formation were examined to determine successful spinal fusion. RESULTS Quantitative analysis of average bone density in pedicle screw beds confirmed that electroactive pedicle screws used in the osteogenic spinal system focally enhanced bone density in instrumented vertebral bodies. Qualitative and quantitative analysis of high-resolution CT scans of explanted lumbar spines further demonstrated that the osteogenic spinal system induced solid bony fusion across the L4-5 disc space as early as 6 weeks postoperatively. In comparison, inactive spinal instrumentation with autograft was unable to promote successful interbody fusion by 6 months postoperatively. CONCLUSIONS Results of this study demonstrate that novel osteogenic spinal instrumentation supports interbody fusion through the focal delivery of DC electrical stimulation. With further technical development and scientific/clinical validation, osteogenic spinal instrumentation may offer a unique alternative to biological scaffolds and pharmaceutical adjuncts used in spinal fusion procedures.

Hyperthermic Laser Ablation of Recurrent Glioblastoma Leads to Temporary Disruption of the Peritumoral Blood Brain Barrier.

BACKGROUND: Poor central nervous system penetration of cytotoxic drugs due to the blood brain barrier (BBB) is a major limiting factor in the treatment of brain tumors. Most recurrent glioblastomas (GBM) occur within the peritumoral region. In this study, we describe a hyperthemic method to induce temporary disruption of the peritumoral BBB that can potentially be used to enhance drug delivery. METHODS: Twenty patients with probable recurrent GBM were enrolled in this study. Fourteen patients were evaluable. MRI-guided laser interstitial thermal therapy was applied to achieve both tumor cytoreduction and disruption of the peritumoral BBB. To determine the degree and timing of peritumoral BBB disruption, dynamic contrast-enhancement brain MRI was used to calculate the vascular transfer constant (Ktrans) in the peritumoral region as direct measures of BBB permeability before and after laser ablation. Serum levels of brain-specific enolase, also known as neuron-specific enolase, were also measured and used as an independent quantification of BBB disruption. RESULTS: In all 14 evaluable patients, Ktrans levels peaked immediately post laser ablation, followed by a gradual decline over the following 4 weeks. Serum BSE concentrations increased shortly after laser ablation and peaked in 1-3 weeks before decreasing to baseline by 6 weeks. CONCLUSIONS: The data from our pilot research support that disruption of the peritumoral BBB was induced by hyperthemia with the peak of high permeability occurring within 1-2 weeks after laser ablation and resolving by 4-6 weeks. This provides a therapeutic window of opportunity during which delivery of BBB-impermeant therapeutic agents may be enhanced. TRIAL REGISTRATION: ClinicalTrials.gov NCT01851733.

The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: a multicenter study.

Surgical extent-of-resection has been shown to have an impact on high-grade glioma (HGG) outcomes; however, complete resection is rarely achievable in difficult-to-access (DTA) tumors. Controlled thermal damage to the tumor may have the same impact in DTA-HGGs. We report our multicenter results of laser interstitial thermal therapy (LITT) in DTA-HGGs. We retrospectively reviewed 34 consecutive DTA-HGG patients (24 glioblastoma, 10 anaplastic) who underwent LITT at Cleveland Clinic, Washington University, and Wake Forest University (May 2011-December 2012) using the NeuroBlate(®) System. The extent of thermal damage was determined using thermal damage threshold (TDT) lines: yellow TDT line (43 °C for 2 min) and blue TDT line (43°C for 10 min). Volumetric analysis was performed to determine the extent-of-coverage of tumor volume by TDT lines. Patient outcomes were evaluated statistically. LITT was delivered as upfront in 19 and delivered as salvage in 16 cases. After 7.2 months of follow-up, 71% of cases demonstrated progression and 34% died. The median overall survival (OS) for the cohort was not reached; however, the 1-year estimate of OS was 68 ± 9%. Median progression-free survival (PFS) was 5.1 months. Thirteen cases who met the following two criteria-(1) <0.05 cm(3) tumor volume not covered by the yellow TDT line and (2) <1.5 cm(3) additional tumor volume not covered by the blue TDT line-had better PFS than the other 21 cases (9.7 vs. 4.6 months; P = 0.02). LITT can be used effectively for treatment of DTA-HGGs. More complete coverage of tumor by TDT lines improves PFS which can be translated as the extent of resection concept for surgery.

The effect of age on human motor electrocorticographic signals and implications for brain-computer interface applications.

Electrocorticography (ECoG)-based brain-computer interface (BCI) systems have emerged as a new signal platform for neuroprosthetic application. ECoG-based platforms have shown significant promise for clinical application due to the high level of information that can be derived from the ECoG signal, the signal's stability, and its intermediate nature of surgical invasiveness. However, before long-term BCI applications can be realized it will be important to also understand how the cortical physiology alters with age. Such understanding may provide an appreciation for how this may affect the control signals utilized by a chronic implant. In this study, we report on a large population of adult and pediatric invasively monitored subjects to determine the impact that age will have on surface cortical physiology. We evaluated six frequency bands--delta (<4 Hz), theta (4-8 Hz), alpha (8-13 Hz), beta (13-30 Hz), low gamma band (30-50 Hz), and high gamma band (76-100 Hz)--to evaluate the effect of age on the magnitude of power change, cortical area of activation, and cortical networks. When significant trends are evaluated as a whole, it appears that the aging process appears to more substantively alter thalamocortical interactions leading to an increase in cortical inefficiency. Despite this, we find that higher gamma rhythms appear to be more anatomically constrained with age, while lower frequency rhythms appear to broaden in cortical involvement as time progresses. From an independent signal standpoint, this would favor high gamma rhythms' utilization as a separable signal that could be maintained chronically.

Nonuniform high-gamma (60-500 Hz) power changes dissociate cognitive task and anatomy in human cortex.

High-gamma-band (>60 Hz) power changes in cortical electrophysiology are a reliable indicator of focal, event-related cortical activity. Despite discoveries of oscillatory subthreshold and synchronous suprathreshold activity at the cellular level, there is an increasingly popular view that high-gamma-band amplitude changes recorded from cellular ensembles are the result of asynchronous firing activity that yields wideband and uniform power increases. Others have demonstrated independence of power changes in the low- and high-gamma bands, but to date, no studies have shown evidence of any such independence above 60 Hz. Based on nonuniformities in time-frequency analyses of electrocorticographic (ECoG) signals, we hypothesized that induced high-gamma-band (60-500 Hz) power changes are more heterogeneous than currently understood. Using single-word repetition tasks in six human subjects, we showed that functional responsiveness of different ECoG high-gamma sub-bands can discriminate cognitive task (e.g., hearing, reading, speaking) and cortical locations. Power changes in these sub-bands of the high-gamma range are consistently present within single trials and have statistically different time courses within the trial structure. Moreover, when consolidated across all subjects within three task-relevant anatomic regions (sensorimotor, Broca's area, and superior temporal gyrus), these behavior- and location-dependent power changes evidenced nonuniform trends across the population. Together, the independence and nonuniformity of power changes across a broad range of frequencies suggest that a new approach to evaluating high-gamma-band cortical activity is necessary. These findings show that in addition to time and location, frequency is another fundamental dimension of high-gamma dynamics.

Stable and dynamic cortical electrophysiology of induction and emergence with propofol anesthesia.

The mechanism(s) by which anesthetics reversibly suppress consciousness are incompletely understood. Previous functional imaging studies demonstrated dynamic changes in thalamic and cortical metabolic activity, as well as the maintained presence of metabolically defined functional networks despite the loss of consciousness. However, the invasive electrophysiology associated with these observations has yet to be studied. By recording electrical activity directly from the cortical surface, electrocorticography (ECoG) provides a powerful method to integrate spatial, temporal, and spectral features of cortical electrophysiology not possible with noninvasive approaches. In this study, we report a unique comprehensive recording of invasive human cortical physiology during both induction and emergence from propofol anesthesia. Propofol-induced transitions in and out of consciousness (defined here as responsiveness) were characterized by maintained large-scale functional networks defined by correlated fluctuations of the slow cortical potential (<0.5 Hz) over the somatomotor cortex, present even in the deeply anesthetized state of burst suppression. Similarly, phase-power coupling between θ- and γ-range frequencies persisted throughout the induction and emergence from anesthesia. Superimposed on this preserved functional architecture were alterations in frequency band power, variance, covariance, and phase-power interactions that were distinct to different frequency ranges and occurred in separable phases. These data support that dynamic alterations in cortical and thalamocortical circuit activity occur in the context of a larger stable architecture that is maintained despite anesthetic-induced alterations in consciousness.

Electrocorticographic frequency alteration mapping for extraoperative localization of speech cortex.

OBJECTIVE: Electrocortical stimulation (ECS) has long been established for delineating eloquent cortex in extraoperative mapping. However, ECS is still coarse and inefficient in delineating regions of functional cortex and can be hampered by afterdischarges. Given these constraints, an adjunct approach to defining motor cortex is the use of electrocorticographic (ECoG) signal changes associated with active regions of cortex. The broad range of frequency oscillations are categorized into 2 main groups with respect to sensorimotor cortex: low-frequency bands (LFBs) and high-frequency bands (HFBs). The LFBs tend to show a power reduction, whereas the HFBs show power increases with cortical activation. These power changes associated with activated cortex could potentially provide a powerful tool in delineating areas of speech cortex. We explore ECoG signal alterations as they occur with activated region of speech cortex and its potential in clinical brain mapping applications. METHODS: We evaluated 7 patients who underwent invasive monitoring for seizure localization. Each had extraoperative ECS mapping to identify speech cortex. Additionally, all subjects performed overt speech tasks with an auditory or a visual cue to identify associated frequency power changes in regard to location and degree of concordance with ECS results. RESULTS: Electrocorticographic frequency alteration mapping (EFAM) had an 83.9% sensitivity and a 40.4% specificity in identifying any language site when considering both frequency bands and both stimulus cues. Electrocorticographic frequency alteration mapping was more sensitive in identifying the Wernicke area (100%) than the Broca area (72.2%). The HFB is uniquely suited to identifying the Wernicke area, whereas a combination of the HFB and LFB is important for Broca localization. CONCLUSION: The concordance between stimulation and spectral power changes demonstrates the possible utility of EFAM as an adjunct method to improve the efficiency and resolution of identifying speech cortex.