The Clinical Validation of Modulated Electro-Hyperthermia (mEHT).

The mEHT method uses tissues' thermal and bioelectromagnetic heterogeneity for the selective mechanisms. The success of the therapy for advanced, relapsed, and metastatic aggressive tumors can only be demonstrated by measuring survival time and quality of life (QoL). The complication is that mEHT-treated patients cannot be curatively treated any longer with "gold standards", where the permanent progression of the disease, the refractory, relapsing situation, the organ failure, the worsening of blood counts, etc., block them. Collecting a cohort of these patients is frequently impossible. Only an intent-to-treat (ITT) patient group was available. Due to the above limitations, many studies have single-arm data collection. The Phase III trial of advanced cervix tumors subgrouping of HIV-negative and -positive patients showed the stable efficacy of mEHT in all patients' subgroups. The single-arm represents lower-level evidence, which can be improved by comparing the survival data of various studies from different institutes. The Kaplan-Meier probability comparison had no significant differences, so pooled data were compared to other methods. Following this approach, we demonstrate the feasibility and superiority of mEHT in the cases of glioblastoma multiform, pancreas carcinomas, lung tumors, and colorectal tumors.

Biosignal processing methods to explore the effects of side-dominance on patterns of bi- and unilateral standing stability in healthy young adults.

We examined the effects of side-dominance on the laterality of standing stability using ground reaction force, motion capture (MoCap), and EMG data in healthy young adults. We recruited participants with strong right (n = 15) and left (n = 9) hand and leg dominance (side-dominance). They stood on one or two legs on a pair of synchronized force platforms for 50 s with 60 s rest between three randomized stance trials. In addition to 23 CoP-related variables, we also computed six MoCap variables representing each lower-limb joint motion time series. Moreover, 39 time- and frequency-domain features of EMG data from five muscles in three muscle groups were analyzed. Data from the multitude of biosignals converged and revealed concordant patterns: no differences occurred between left- and right-side dominant participants in kinetic, kinematic, or EMG outcomes during bipedal stance. Regarding single leg stance, larger knee but lower ankle joint kinematic values appeared in left vs right-sided participants during non-dominant stance. Left-vs right-sided participants also had lower medial gastrocnemius EMG activation during non-dominant stance. While right-side dominant participants always produced larger values for kinematic data of ankle joint and medial gastrocnemius EMG activation during non-dominant vs dominant unilateral stance, this pattern was the opposite for left-sided participants, showing larger values when standing on their dominant vs non-dominant leg, i.e., participants had a more stable balance when standing on their right leg. Our results suggest that side-dominance affects biomechanical and neuromuscular control strategies during unilateral standing.

Learning to Sort: Few-shot Spike Sorting with Adversarial Representation Learning.

Spike sorting has long been used to obtain activities of single neurons from multi-unit recordings by extracting spikes from continuous data and assigning them to putative neurons. A large body of spike sorting algorithms have been developed that typically project spikes into a low-dimensional feature space and cluster them through iterative computations. However, there is no reached consensus on the optimal feature space or the best way of segmenting spikes into clusters, which often leads to the requirement of human intervention. It is hence desirable to effectively and efficiently utilize human knowledge in spike sorting while keeping a minimum level of manual intervention. Furthermore, the iterative computations that are commonly involved during clustering are inherently slow and hinder real-time processing of large-scale recordings. In this paper, we propose a novel few-shot spike sorting paradigm that employs a deep adversarial representation neural network to learn from a handful of annotated spikes and robustly classify unseen spikes sharing similar properties to the labeled ones. Once trained, the deep neural network can implement a parametric function that encodes analytically the categorical distribution of spike clusters, which can be significantly accelerated by GPUs and support processing hundreds of thousands of recording channels in real time. The paradigm also includes a clustering routine termed DidacticSortto aid users for labeling spikes that will be used to train the deep neural network. We have validated the performance of the proposed paradigm with both synthetic and in vitro datasets.

Neural Interfaces for Intracortical Recording: Requirements, Fabrication Methods, and Characteristics.

Implantable neural interfaces for central nervous system research have been designed with wire, polymer, or micromachining technologies over the past 70 years. Research on biocompatible materials, ideal probe shapes, and insertion methods has resulted in building more and more capable neural interfaces. Although the trend is promising, the long-term reliability of such devices has not yet met the required criteria for chronic human application. The performance of neural interfaces in chronic settings often degrades due to foreign body response to the implant that is initiated by the surgical procedure, and related to the probe structure, and material properties used in fabricating the neural interface. In this review, we identify the key requirements for neural interfaces for intracortical recording, describe the three different types of probes-microwire, micromachined, and polymer-based probes; their materials, fabrication methods, and discuss their characteristics and related challenges.

Age dependency of trauma-induced neocortical epileptogenesis.

Trauma and brain infection are the primary sources of acquired epilepsy, which can occur at any age and may account for a high incidence of epilepsy in developing countries. We have explored the hypothesis that penetrating cortical wounds cause deafferentation of the neocortex, which triggers homeostatic plasticity and lead to epileptogenesis (Houweling etal., 2005). In partial deafferentation experiments of adult cats, acute seizures occurred in most preparations and chronic seizures occurred weeks to months after the operation in 65% of the animals (Nita etal., 2006,2007; Nita and Timofeev, 2007). Similar deafferentation of young cats (age 8-12 months) led to some acute seizures, but we never observed chronic seizure activity even though there was enhanced slow-wave activity in the partially deafferented hemisphere during quiet wakefulness. This suggests that despite a major trauma, the homeostatic plasticity in young animals was able to restore normal levels of cortical excitability, but in fully adult cats the mechanisms underlying homeostatic plasticity may lead to an unstable cortical state. To test this hypothesis we made an undercut in the cortex of an elderly cat. After several weeks this animal developed seizure activity. These observations may lead to an intervention after brain trauma that prevents epileptogenesis from occurring in adults.

Long-term synchronized electrophysiological and behavioral wireless monitoring of freely moving animals.

Parallel electrophysiological recording and behavioral monitoring of freely moving animals is essential for a better understanding of the neural mechanisms underlying behavior. In this paper we describe a novel wireless recording technique, which is capable of synchronously recording in vivo multichannel electrophysiological (LFP, MUA, EOG, EMG) and activity data (accelerometer, video) from freely moving cats. The method is based on the integration of commercially available components into a simple monitoring system and is complete with accelerometers and the needed signal processing tools. LFP activities of freely moving group-housed cats were recorded from multiple intracortical areas and from the hippocampus. EMG, EOG, accelerometer and video were simultaneously acquired with LFP activities 24-h a day for 3 months. These recordings confirm the possibility of using our wireless method for 24-h long-term monitoring of neurophysiological and behavioral data of freely moving experimental animals such as cats, ferrets, rabbits and other large animals.

Laminar analysis of slow wave activity in humans.

Brain electrical activity is largely composed of oscillations at characteristic frequencies. These rhythms are hierarchically organized and are thought to perform important pathological and physiological functions. The slow wave is a fundamental cortical rhythm that emerges in deep non-rapid eye movement sleep. In animals, the slow wave modulates delta, theta, spindle, alpha, beta, gamma and ripple oscillations, thus orchestrating brain electrical rhythms in sleep. While slow wave activity can enhance epileptic manifestations, it is also thought to underlie essential restorative processes and facilitate the consolidation of declarative memories. Animal studies show that slow wave activity is composed of rhythmically recurring phases of widespread, increased cortical cellular and synaptic activity, referred to as active- or up-state, followed by cellular and synaptic inactivation, referred to as silent- or down-state. However, its neural mechanisms in humans are poorly understood, since the traditional intracellular techniques used in animals are inappropriate for investigating the cellular and synaptic/transmembrane events in humans. To elucidate the intracortical neuronal mechanisms of slow wave activity in humans, novel, laminar multichannel microelectrodes were chronically implanted into the cortex of patients with drug-resistant focal epilepsy undergoing cortical mapping for seizure focus localization. Intracortical laminar local field potential gradient, multiple-unit and single-unit activities were recorded during slow wave sleep, related to simultaneous electrocorticography, and analysed with current source density and spectral methods. We found that slow wave activity in humans reflects a rhythmic oscillation between widespread cortical activation and silence. Cortical activation was demonstrated as increased wideband (0.3-200 Hz) spectral power including virtually all bands of cortical oscillations, increased multiple- and single-unit activity and powerful inward transmembrane currents, mainly localized to the supragranular layers. Neuronal firing in the up-state was sparse and the average discharge rate of single cells was less than expected from animal studies. Action potentials at up-state onset were synchronized within +/-10 ms across all cortical layers, suggesting that any layer could initiate firing at up-state onset. These findings provide strong direct experimental evidence that slow wave activity in humans is characterized by hyperpolarizing currents associated with suppressed cell firing, alternating with high levels of oscillatory synaptic/transmembrane activity associated with increased cell firing. Our results emphasize the major involvement of supragranular layers in the genesis of slow wave activity.

Short and long term biocompatibility of NeuroProbes silicon probes.

Brain implants provide exceptional tools to understand and restore cerebral functions. The utility of these devices depends crucially on their biocompatibility and long term viability. We addressed these points by implanting non-functional, NeuroProbes silicon probes, without or with hyaluronic acid (Hya), dextran (Dex), dexamethasone (DexM), Hya+DexM coating, into rat neocortex. Light and transmission electron microscopy were used to investigate neuronal survival and glial response. The surface of explanted probes was examined in the scanning electron microscope. We show that blood vessel disruption during implantation could induce considerable tissue damage. If, however, probes could be inserted without major bleeding, light microscopical evidence of damage to surrounding neocortical tissue was much reduced. At distances less than 100 microm from the probe track a considerable neuron loss ( approximately 40%) occurred at short survival times, while the neuronal numbers recovered close to control levels at longer survival. Slight gliosis was observed at both short and long term survivals. Electron microscopy showed neuronal cell bodies and synapses close (<10 microm) to the probe track when bleeding could be avoided. The explanted probes were usually partly covered by tissue residue containing cells with different morphology. Our data suggest that NeuroProbes silicon probes are highly biocompatible. If major blood vessel disruption can be avoided, the low neuronal cell loss and gliosis should provide good recording and stimulating results with future functional probes. We found that different bioactive molecule coatings had small differential effects on neural cell numbers and gliosis, with optimal results achieved using the DexM coated probes.

Properties of in vivo interictal spike generation in the human subiculum.

A large proportion of hippocampal afferents and efferents are relayed through the subiculum. It is also thought to be a key structure in the generation and maintenance of epileptic activity; rhythmic interictal-like discharges were recorded in previous studies of subicular slices excised from temporal lobe epilepsy patients. In order to investigate if and how the subiculum is involved in the generation of epileptic discharges in vivo, subicular and lateral temporal lobe electrical activity were recorded under anesthesia in 11 drug-resistant epilepsy patients undergoing temporal lobectomy. Based on laminar field potential gradient, current source density, multiple unit activity (MUA) and spectral analyses, two types of interictal spikes were distinguished in the subiculum. The more frequently occurring spike started with an initial excitatory current (current source density sink) in the pyramidal cell layer associated with increased MUA in the same location, followed by later inhibitory currents (current source density source) and decreased MUA. In the other spike type, the initial excitation was confined to the apical dendritic region and it was associated with a less-prominent increase in MUA. Interictal spikes were highly synchronized at spatially distinct locations of the subiculum. Laminar data showed that the peak of the initial excitation occurred within 0-4 ms at subicular sites separated by 6 mm at the anterior-posterior axis. In addition, initial spike peak amplitudes were highly correlated in most recordings. A subset of subicular and temporal lobe spikes were also highly synchronous, in one case the subicular spikes reliably preceded the temporal lobe discharges. Our results indicate that multiple spike generator mechanisms exist in the human epileptic subiculum suggesting a complex network interplay between medial and lateral temporal structures during interictal epileptic activity. The observed widespread intra-subicular synchrony may reflect both of its intrinsic and extrinsically triggered activity supporting the hypothesis that subiculum may also play an active role in the distribution of epileptiform activity to other brain regions. Limited data suggest that subiculum might even play a pacemaker role in the generation of paroxysmal discharges.