Werner K. Doyle

The human K-complex represents an isolated cortical down-state.

Down But Not Out The K-complex, a defining characteristic of slow wave sleep, is the largest spontaneously occurring component of the healthy human electroencephalogram (EEG) but little is known about its physiological characteristics in the human cortex. Cash et al. (p. 1084) investigated the intracortical origin of K-complexes in humans undergoing surgery for epileptic seizures. In simultaneous subdural EEG and intracortical multisite microelectrode recordings, K complexes represented cortical downstates reflecting a decrease in neural firing. These down-states are a fundamental mode of cortical operation that have been well studied in animals and may contribute to sleep preservation and memory consolidation. A characteristic electroencephalogram pattern seen during sleep is accompanied by a steep decline in neural activity. The electroencephalogram (EEG) is a mainstay of clinical neurology and is tightly correlated with brain function, but the specific currents generating human EEG elements remain poorly specified because of a lack of microphysiological recordings. The largest event in healthy human EEGs is the K-complex (KC), which occurs in slow-wave sleep. Here, we show that KCs are generated in widespread cortical areas by outward dendritic currents in the middle and upper cortical layers, accompanied by decreased broadband EEG power and decreased neuronal firing, which demonstrate a steep decline in network activity. Thus, KCs are isolated “down-states,” a fundamental cortico-thalamic processing mode already characterized in animals. This correspondence is compatible with proposed contributions of the KC to sleep preservation and memory consolidation.

NeuroGrid: recording action potentials from the surface of the brain

Recording from neural networks at the resolution of action potentials is critical for understanding how information is processed in the brain. Here, we address this challenge by developing an organic material–based, ultraconformable, biocompatible and scalable neural interface array (the ‘NeuroGrid’) that can record both local field potentials(LFPs) and action potentials from superficial cortical neurons without penetrating the brain surface. Spikes with features of interneurons and pyramidal cells were simultaneously acquired by multiple neighboring electrodes of the NeuroGrid, allowing for the isolation of putative single neurons in rats. Spiking activity demonstrated consistent phase modulation by ongoing brain oscillations and was stable in recordings exceeding 1 weeks duration. We also recorded LFP-modulated spiking activity intraoperatively in patients undergoing epilepsy surgery. The NeuroGrid constitutes an effective method for large-scale, stable recording of neuronal spikes in concert with local population synaptic activity, enhancing comprehension of neural processes across spatiotemporal scales and potentially facilitating diagnosis and therapy for brain disorders.

Vagus nerve stimulation in 436 consecutive patients with treatment-resistant epilepsy: Long-term outcomes and predictors of response

OBJECTIVE The goal of this study was to assess the efficacy and safety of vagus nerve stimulation in a consecutive series of adults and children with treatment-resistant epilepsy (TRE). METHODS In this retrospective review of a prospectively created database of 436 consecutive patients who underwent vagus nerve stimulator implantation for TRE between November 1997 and April 2008, there were 220 (50.5%) females and 216 (49.5%) males ranging in age from 1 to 76 years at the time of implantation (mean: 29.0 ± 16.5). Thirty-three patients (7.6%) in the primary implantation group had inadequate follow-up (<3 months from implantation) and three patients had early device removal because of infection and were excluded from seizure control outcome analyses. RESULTS Duration of vagus nerve stimulation treatment varied from 10 days to 11 years (mean: 4.94 years). Mean seizure frequency significantly improved following implantation (mean reduction: 55.8%, P<0.0001). Seizure control ≥ 90% was achieved in 90 patients (22.5%), ≥ 75% seizure control in 162 patients (40.5%), ≥ 50% improvement in 255 patients (63.75%), and <50% improvement in 145 patients (36.25%). Permanent injury to the vagus nerve occurred in 2.8% of patients. CONCLUSION Vagus nerve stimulation is a safe and effective palliative treatment option for focal and generalized TRE in adults and children. When used in conjunction with a multidisciplinary and multimodality treatment regimen including aggressive antiepileptic drug regimens and epilepsy surgery when appropriate, more than 60% of patients with TRE experienced at least a 50% reduction in seizure burden. Good results were seen in patients with non-U.S. Food and Drug Administration-approved indications. Prospective, randomized trials are needed for patients with generalized epilepsies and for younger children to potentially expand the number of patients who may benefit from this palliative treatment.

The Use of Dexmedetomidine Infusion for Awake Craniotomy

Anesthesia for intracranial procedures requiring patient cooperation presents a challenge to the anesthesiologist. Drugs administered during the procedure should provide an adequate level of sedation and analgesia for bone flap removal, but must not interfere with functional testing and electrocorticography. In this case report, we describe the use of dexmedetomidine in combination with nitrous oxide and sevoflurane for bone flap removal and dexmedetomidine alone for brain mapping of the cortical speech area. Dexmedetomidine is a highly specific a2adrenoreceptor agonist with sedative, analgesic, and anesthetic-sparing effects (1,2). It does not suppress ventilation. Small-dose infusion of this drug in healthy volunteers provided sedation that could be easily reversed with verbal stimuli (3). We anticipated that the patient treated with dexmedetomidine would be sedated and comfortable but easily arousable to tolerate a prolonged awake craniotomy.

Awake craniotomy with dexmedetomidine in pediatric patients.

&NA; We present our experience with the use of dexmedetomidine, an &agr;2 agonist, in two children undergoing awake craniotomy. General anesthesia with the laryngeal mask airway was used for parts of the procedure not requiring patient cooperation to reduce the duration of wakefulness and abolish the discomfort of surgical stimulation. Dexmedetomidine was used as a primary anesthetic for brain mapping of the cortical speech area. The asleep‐awake‐sleep technique provided adequate sedation and analgesia throughout the surgery and allowed the patient to complete the necessary neuropsychological tests. To our knowledge, ours is the first description of the use of dexmedetomidine in pediatric neurosurgery.

Sensory-motor transformations for speech occur bilaterally

Historically, the study of speech processing has emphasized a strong link between auditory perceptual input and motor production output. A kind of ‘parity’ is essential, as both perception- and production-based representations must form a unified interface to facilitate access to higher-order language processes such as syntax and semantics, believed to be computed in the dominant, typically left hemisphere. Although various theories have been proposed to unite perception and production, the underlying neural mechanisms are unclear. Early models of speech and language processing proposed that perceptual processing occurred in the left posterior superior temporal gyrus (Wernicke’s area) and motor production processes occurred in the left inferior frontal gyrus (Broca’s area). Sensory activity was proposed to link to production activity through connecting fibre tracts, forming the left lateralized speech sensory–motor system. Although recent evidence indicates that speech perception occurs bilaterally, prevailing models maintain that the speech sensory–motor system is left lateralized and facilitates the transformation from sensory-based auditory representations to motor-based production representations. However, evidence for the lateralized computation of sensory–motor speech transformations is indirect and primarily comes from stroke patients that have speech repetition deficits (conduction aphasia) and studies using covert speech and haemodynamic functional imaging. Whether the speech sensory–motor system is lateralized, like higher-order language processes, or bilateral, like speech perception, is controversial. Here we use direct neural recordings in subjects performing sensory–motor tasks involving overt speech production to show that sensory–motor transformations occur bilaterally. We demonstrate that electrodes over bilateral inferior frontal, inferior parietal, superior temporal, premotor and somatosensory cortices exhibit robust sensory–motor neural responses during both perception and production in an overt word-repetition task. Using a non-word transformation task, we show that bilateral sensory–motor responses can perform transformations between speech-perception- and speech-production-based representations. These results establish a bilateral sublexical speech sensory–motor system.

Heterogeneous neuronal firing patterns during interictal epileptiform discharges in the human cortex

Epileptic cortex is characterized by paroxysmal electrical discharges. Analysis of these interictal discharges typically manifests as spike-wave complexes on electroencephalography, and plays a critical role in diagnosing and treating epilepsy. Despite their fundamental importance, little is known about the neurophysiological mechanisms generating these events in human focal epilepsy. Using three different systems of microelectrodes, we recorded local field potentials and single-unit action potentials during interictal discharges in patients with medically intractable focal epilepsy undergoing diagnostic workup for localization of seizure foci. We studied 336 single units in 20 patients. Ten different cortical areas and the hippocampus, including regions both inside and outside the seizure focus, were sampled. In three of these patients, high density microelectrode arrays simultaneously recorded between 43 and 166 single units from a small (4 mm x 4 mm) patch of cortex. We examined how the firing rates of individual neurons changed during interictal discharges by determining whether the firing rate during the event was the same, above or below a median baseline firing rate estimated from interictal discharge-free periods (Kruskal-Wallis one-way analysis, P<0.05). Only 48% of the recorded units showed such a modulation in firing rate within 500 ms of the discharge. Units modulated during the discharge exhibited significantly higher baseline firing and bursting rates than unmodulated units. As expected, many units (27% of the modulated population) showed an increase in firing rate during the fast segment of the discharge (+ or - 35 ms from the peak of the discharge), while 50% showed a decrease during the slow wave. Notably, in direct contrast to predictions based on models of a pure paroxysmal depolarizing shift, 7.7% of modulated units recorded in or near the seizure focus showed a decrease in activity well ahead (0-300 ms) of the discharge onset, while 12.2% of units increased in activity in this period. No such pre-discharge changes were seen in regions well outside the seizure focus. In many recordings there was also a decrease in broadband field potential activity during this same pre-discharge period. The different patterns of interictal discharge-modulated firing were classified into more than 15 different categories. This heterogeneity in single unit activity was present within small cortical regions as well as inside and outside the seizure onset zone, suggesting that interictal epileptiform activity in patients with epilepsy is not a simple paroxysm of hypersynchronous excitatory activity, but rather represents an interplay of multiple distinct neuronal types within complex neuronal networks.

Multistage epilepsy surgery: safety, efficacy, and utility of a novel approach in pediatric extratemporal epilepsy.

OBJECTIVE To evaluate the safety, efficacy, and utility of a novel surgical strategy consisting of multiple (more than two) operative stages performed during the same hospital admission with subdural grid and strip electrodes in selected pediatric extratemporal epilepsy. METHODS Subdural grid and strip electrodes were used for multistage chronic electroencephalographic monitoring in 15 pediatric patients (age, <19 yr) with refractory localization-related epilepsy and poor surgical prognostic factors. Initial resective surgery and/or multiple subpial transections were performed, followed by further monitoring and additional resection and/or multiple subpial transections. RESULTS Mean patient age was 9.7 years. Mean duration of total invasive monitoring was 10.5 days (range, 8-14 d). The first monitoring period averaged 6.5 days, and the second averaged 3.9 days. Additional surgery was performed in 13 of 15 patients. Two patients who did not undergo additional surgery had a Class I outcome. Rationales for reinvestigation included incomplete localization, multifocality, and proximity to eloquent cortex. Complications were minimal, including two transfusions. There were no cases of wound infection, cerebral edema, hemorrhage, or major permanent neurological deficit. Minimum duration of follow-up was 31 months. Outcomes were 60% Engel Class I (9 of 15 patients), 27% Class III (4 of 15 patients), and 13% Class IV (2 of 15 patients). CONCLUSION In a very select group of pediatric patients with poor surgical prognostic factors, the multistage approach can be beneficial. After failed epilepsy surgery, subsequent reoperation with additional intracranial investigation traditionally is used when a single residual focus is suspected. Our results, however, support the contention that multistage epilepsy surgery is safe, effective, and useful in a challenging and select pediatric population with extratemporal medically refractory epilepsy.

Pediatric Language Mapping: Sensitivity of Neurostimulation and Wada Testing in Epilepsy Surgery

Summary:  Purpose: Functional mapping of eloquent cortex with electrical neurostimulation is used both intra‐ and extraoperatively to tailor resections. In pediatric patients, however, functional mapping studies frequently fail to localize language. Wada testing has also been reported to be less sensitive in children.

Subfascial Implantation of Intrathecal Baclofen Pumps in Children: Technical Note

OBJECTIVEIndwelling intrathecal drug delivery systems are becoming increasingly important as a method of neuromodulation within the nervous system. In particular, intrathecal baclofen therapy has shown efficacy and safety in the management of spasticity and dystonia in children. The most common complications leading to explantation of the pumps are skin breakdown and infection at the pump implantation site. The pediatric population poses particular challenges with regard to these complications because appropriate candidates for intrathecal baclofen therapy are often undernourished and thus have a dearth of soft tissue mass to cover a subcutaneously implanted baclofen pump. We report a technique of subfascial implantation that provides greater soft tissue coverage of the pump, thereby reducing the potential for skin breakdown and improving the cosmetic appearance of the implantation site. METHODSEighteen consecutively treated children (average age, 8 yr, 7 mo) with spasticity and/or dystonia underwent subfascial implantation of a baclofen pump. These children’s mean weight of 42.9 lb is less than the expected weight for a group of children in this age group, ranging from 4 years, 8 months, to 15 years, 7 months. In all patients, the pump was inserted into a pocket surgically constructed between the rectus abdominus and the external oblique muscles and the respective anterior fascial layers. RESULTSAt an average follow-up of 13.7 months, no infection or skin breakdown had occurred at the pump surgical site in any of the 18 patients. CONCLUSIONAt this early follow-up, the subfascial implantation technique was associated with a reduced rate of local wound and pump infections and provided optimal cosmetic results as compared with that observed in retrospective cases.