Origami-inspired soft fluidic actuation for minimally invasive large-area electrocorticography.

Electrocorticography is an established neural interfacing technique wherein an array of electrodes enables large-area recording from the cortical surface. Electrocorticography is commonly used for seizure mapping however the implantation of large-area electrocorticography arrays is a highly invasive procedure, requiring a craniotomy larger than the implant area to place the device. In this work, flexible thin-film electrode arrays are combined with concepts from soft robotics, to realize a large-area electrocorticography device that can change shape via integrated fluidic actuators. We show that the 32-electrode device can be packaged using origami-inspired folding into a compressed state and implanted through a small burr-hole craniotomy, then expanded on the surface of the brain for large-area cortical coverage. The implantation, expansion, and recording functionality of the device is confirmed in-vitro and in porcine in-vivo models. The integration of shape actuation into neural implants provides a clinically viable pathway to realize large-area neural interfaces via minimally invasive surgical techniques.

A Review of Motor Brain-Computer Interfaces Using Intracranial Electroencephalography Based on Surface Electrodes and Depth Electrodes.

Brain-computer interfaces (BCIs) provide a communication interface between the brain and external devices and have the potential to restore communication and control in patients with neurological injury or disease. For the invasive BCIs, most studies recruited participants from hospitals requiring invasive device implantation. Three widely used clinical invasive devices that have the potential for BCIs applications include surface electrodes used in electrocorticography (ECoG) and depth electrodes used in Stereo-electroencephalography (SEEG) and deep brain stimulation (DBS). This review focused on BCIs research using surface (ECoG) and depth electrodes (including SEEG, and DBS electrodes) for movement decoding on human subjects. Unlike previous reviews, the findings presented here are from the perspective of the decoding target or task. In detail, five tasks will be considered, consisting of the kinematic decoding, kinetic decoding,identification of body parts, dexterous hand decoding, and motion intention decoding. The typical studies are surveyed and analyzed. The reviewed literature demonstrated a distributed motor-related network that spanned multiple brain regions. Comparison between surface and depth studies demonstrated that richer information can be obtained using surface electrodes. With regard to the decoding algorithms, deep learning exhibited superior performance using raw signals than traditional machine learning algorithms. Despite the promising achievement made by the open-loop BCIs, closed-loop BCIs with sensory feedback are still in their early stage, and the chronic implantation of both ECoG surface and depth electrodes has not been thoroughly evaluated.

Recording of single-unit activities with flexible micro-electrocorticographic array in rats for decoding of whole-body navigation.

Objective.Micro-electrocorticographic (µECoG) arrays are able to record neural activities from the cortical surface, without the need to penetrate the brain parenchyma. Owing in part to small electrode sizes, previous studies have demonstrated that single-unit spikes could be detected from the cortical surface, and likely from Layer I neurons of the neocortex. Here we tested the ability to useµECoG arrays to decode, in rats, body position during open field navigation, through isolated single-unit activities.Approach. µECoG arrays were chronically implanted onto primary motor cortex (M1) of Wistar rats, and neural recording was performed in awake, behaving rats in an open-field enclosure. The signals were band-pass filtered between 300-3000 Hz. Threshold-crossing spikes were identified and sorted into distinct units based on defined criteria including waveform morphology and refractory period. Body positions were derived from video recordings. We used gradient-boosting machine to predict body position based on previous 100 ms of spike data, and correlation analyses to elucidate the relationship between position and spike patterns.Main results.Single-unit spikes could be extracted during chronic recording fromµECoG, and spatial position could be decoded from these spikes with a mean absolute error of prediction of 0.135 and 0.090 in the x- and y- dimensions (of a normalized range from 0 to 1), and Pearson's r of 0.607 and 0.571, respectively.Significance. µECoG can detect single-unit activities that likely arise from superficial neurons in the cortex and is a promising alternative to intracortical arrays, with the added benefit of scalability to cover large cortical surface with minimal incremental risks. More studies should be performed in human related to its use as brain-machine interface.

A scalable platform for acquisition of high-fidelity human intracranial EEG with minimal clinical burden.

Human neuroscience research has been significantly advanced by neuroelectrophysiological studies from people with refractory epilepsy-the only routine clinical intervention that acquires multi-day, multi-electrode human intracranial electroencephalography (iEEG). While a sampling rate below 2 kHz is sufficient for manual iEEG review by epileptologists, computational methods and research studies may benefit from higher resolution, which requires significant technical development. At adult and pediatric Stanford hospitals, research ports of commercial clinical acquisition systems were configured to collect 10 kHz iEEG of up to 256 electrodes simultaneously with the clinical data. The research digital stream was designed to be acquired post-digitization, resulting in no loss in clinical signal quality. This novel framework implements a near-invisible research platform to facilitate the secure, routine collection of high-resolution iEEG that minimizes research hardware footprint and clinical workflow interference. The addition of a pocket-sized router in the patient room enabled an encrypted tunnel to securely transmit research-quality iEEG across hospital networks to a research computer within the hospital server room, where data was coded, de-identified, and uploaded to cloud storage. Every eligible patient undergoing iEEG clinical evaluation at both hospitals since September 2017 has been recruited; participant recruitment is ongoing. Over 350+ terabytes (representing 1000+ days) of neuroelectrophysiology were recorded across 200+ participants of diverse demographics. To our knowledge, this is the first report of such a research integration within a hospital setting. It is a promising approach to promoting equitable participant enrollment and building comprehensive data repositories with consistent, high-fidelity specifications towards new discoveries in human neuroscience.

Voxeloc: A time-saving graphical user interface for localizing and visualizing stereo-EEG electrodes.

BACKGROUND: Thanks to its unrivalled spatial and temporal resolutions and signal-to-noise ratio, intracranial EEG (iEEG) is becoming a valuable tool in neuroscience research. To attribute functional properties to cortical tissue, it is paramount to be able to determine precisely the localization of each electrode with respect to a patient's brain anatomy. Several software packages or pipelines offer the possibility to localize manually or semi-automatically iEEG electrodes. However, their reliability and ease of use may leave to be desired. NEW METHOD: Voxeloc (voxel electrode locator) is a Matlab-based graphical user interface to localize and visualize stereo-EEG electrodes. Voxeloc adopts a semi-automated approach to determine the coordinates of each electrode contact, the user only needing to indicate the deep-most contact of each electrode shaft and another point more proximally. RESULTS: With a deliberately streamlined functionality and intuitive graphical user interface, the main advantages of Voxeloc are ease of use and inter-user reliability. Additionally, oblique slices along the shaft of each electrode can be generated to facilitate the precise localization of each contact. Voxeloc is open-source software and is compatible with the open iEEG-BIDS (Brain Imaging Data Structure) format. COMPARISON WITH EXISTING METHODS: Localizing full patients' iEEG implants was faster using Voxeloc than two comparable software packages, and the inter-user agreement was better. CONCLUSIONS: Voxeloc offers an easy-to-use and reliable tool to localize and visualize stereo-EEG electrodes. This will contribute to democratizing neuroscience research using iEEG.

Development of a novel, concentric micro-ECoG array enabling simultaneous detection of a single location by multiple electrode sizes.

Objective.Detection of the epileptogenic zone is critical, especially for patients with drug-resistant epilepsy. Accurately mapping cortical regions exhibiting high activity during spontaneous seizure events while detecting neural activity up to 500 Hz can assist clinicians' surgical decisions and improve patient outcomes.Approach.We designed, fabricated, and tested a novel hybrid, multi-scale micro-electrocorticography (micro-ECoG) array with a unique embedded configuration. This array was compared to a commercially available microelectrode array (Neuronexus) for recording neural activity in rodent sensory cortex elicited by somatosensory evoked potentials and pilocarpine-induced seizures.Main results.Evoked potentials and spatial maps recorded by the multi-scale array ('micros', 'mesos', and 'macros' refering to the relative electrode sizes, 40 micron, 1 mm, and 4 mm respectively) were comparable to the Neuronexus array. The SSEPs recorded with the micros had higher peak amplitudes and greater signal power than those recorded by the larger mesos and macro. Seizure onset events and high-frequency oscillations (∼450 Hz) were detected on the multi-scale, similar to the commercially available array. The micros had greater SNR than the mesos and macro over the 5-1000 Hz frequency range during seizure monitoring. During cortical stimulation experimentation, the mesos successfully elicited motor effects.Significance.Previous studies have compared macro- and microelectrodes for localizing seizure activity in adjacent regions. The multi-scale design validated here is the first to simultaneously measure macro- and microelectrode signals from the same overlapping cortical area. This enables direct comparison of microelectrode recordings to the macroelectrode recordings used in standard neurosurgical practice. Previous studies have also shown that cortical regions generating high-frequency oscillations are at an increased risk for becoming epileptogenic zones. More accurate mapping of these micro seizures may improve surgical outcomes for epilepsy patients.

Depth versus surface: A critical review of subdural and depth electrodes in intracranial electroencephalographic studies.

Intracranial electroencephalographic (IEEG) recording, using subdural electrodes (SDEs) and stereoelectroencephalography (SEEG), plays a pivotal role in localizing the epileptogenic zone (EZ). SDEs, employed for superficial cortical seizure foci localization, provide information on two-dimensional seizure onset and propagation. In contrast, SEEG, with its three-dimensional sampling, allows exploration of deep brain structures, sulcal folds, and bihemispheric networks. SEEG offers the advantages of fewer complications, better tolerability, and coverage of sulci. Although both modalities allow electrical stimulation, SDE mapping can tessellate cortical gyri, providing the opportunity for a tailored resection. With SEEG, both superficial gyri and deep sulci can be stimulated, and there is a lower risk of afterdischarges and stimulation-induced seizures. Most systematic reviews and meta-analyses have addressed the comparative effectiveness of SDEs and SEEG in localizing the EZ and achieving seizure freedom, although discrepancies persist in the literature. The combination of SDEs and SEEG could potentially overcome the limitations inherent to each technique individually, better delineating seizure foci. This review describes the strengths and limitations of SDE and SEEG recordings, highlighting their unique indications in seizure localization, as evidenced by recent publications. Addressing controversies in the perceived usefulness of the two techniques offers insights that can aid in selecting the most suitable IEEG in clinical practice.

Intraoperative ECoG in bottom-of-the-sulcus syndrome using a novel flexible strip electrode.

The recording of epileptiform discharges from bottom-of-sulcus focal cortical dysplasia (BOSD) is often difficult during intraoperative electrocorticography (ECoG) due to the deep localization. We describe the use in this scenario of a new-generation electrode strip with high flexibility, easily adapted to cortical gyri and sulci. A right-handed 20-year-old male with drug-resistant focal epilepsy due to BOSD of the inferior frontal gyrus and daily focal aware seizures was evaluated for epilepsy surgery. Based on electroclinical and neuroimaging results, a focal cortectomy guided by ECoG was proposed. ECoG recordings were performed with new-generation cortical strips (Wise Cortical Strip; WCS®) and standard cortical strips. ECoG, performed on the convexity of the frontal cortical surface, recorded only sporadic spikes with both types of strips. Then, after microsurgical trans-sulcal dissection, WCS was molded along the sulcal surface of the suspected BOSD based on 3D-imaging reconstruction, showing continuous/subcontinuous 3-4-Hz rhythmic spike activity from the deepest electrode. Registration after resection of the BOSD did not show any epileptiform activity. Pathology showed dysmorphic neurons and gliosis. No surgical complications occurred. The patient is seizure-free after 12 months. This single case experience shows that highly flexible electrode strips with adaptability to cortical gyrations can identify IEDs originating from deep location and could therefore be useful in cases of bottom of the sulcus dysplasia.

Interictal spikes with and without high-frequency oscillation have different single-neuron correlates.

Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these 'HFO-IEDs' at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from 'non-HFO-IEDs'. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit's firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit's firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.

MEG detection of high frequency oscillations and intracranial-EEG validation in pediatric epilepsy surgery.

OBJECTIVE: To assess the feasibility of automatically detecting high frequency oscillations (HFOs) in magnetoencephalography (MEG) recordings in a group of ten paediatric epilepsy surgery patients who had undergone intracranial electroencephalography (iEEG). METHODS: A beamforming source-analysis method was used to construct virtual sensors and an automatic algorithm was applied to detect HFOs (80-250 Hz). We evaluated the concordance of MEG findings with the sources of iEEG HFOs, the clinically defined seizure onset zone (SOZ), the location of resected brain structures, and with post-operative outcome. RESULTS: In 8/9 patients there was good concordance between the sources of MEG HFOs and iEEG HFOs and the SOZ. Significantly more HFOs were detected in iEEG relative to MEG t(71) = 2.85, p < .05. There was good concordance between sources of MEG HFOs and the resected area in patients with good and poor outcome, however HFOs were also detected outside of the resected area in patients with poor outcome. CONCLUSION: Our findings demonstrate the feasibility of automatically detecting HFOs non-invasively in MEG recordings in paediatric patients, and confirm compatibility of results with invasive recordings. SIGNIFICANCE: This approach provides support for the non-invasive detection of HFOs to aid surgical planning and potentially reduce the need for invasive monitoring, which is pertinent to paediatric patients.

Intracranial correlates of small sharp spikes.

OBJECTIVE: To identify cortical correlates of scalp small sharp spikes (SSS) using simultaneous scalp and intracranial EEG recordings. METHODS: Patients were retrospectively evaluated based on a database of intracranial long-term recordings at the Epilepsy Center Freiburg. Inclusion criteria were: simultaneous recordings with intracranial and scalp EEGs and the presence of at least five unequivocal SSS in the scalp EEG. Intracranial recordings were analyzed regarding the co-occurring intracranial potentials during scalp SSS. RESULTS: 33 patients, aged 9-60y, 17 females, fulfilled the above-mentioned criteria. Almost all patients had intracranial SSS correlates in the form of spike/polyspike-waves in the temporal lobe, predominantly in the hippocampus (24/28), less frequently involving the amygdala (5/29), temporal basal (3/18), lateral neocortical (4/32), entorhinal cortices (1/12), and the parietal lobe (2/13). Amplitudes of intrahippocampal spikes or polyspikes co-occurring with SSS were significantly higher than intracranial discharges without scalp correlates. In 45% of patients, intracranial spikes accompanying SSS were located within the seizure onset zone (SOZ). CONCLUSIONS: Our results strongly support an epileptic origin of SSS and provide evidence about their heterogenous generators. SIGNIFICANCE: This study suggests that SSS cannot with certainty be classified as "benign" but rather considered as one of the EEG manifestations of focal epilepsy.

MRI-Compatible and Conformal Electrocorticography Grids for Translational Research.

Intraoperative electrocorticography (ECoG) captures neural information from the surface of the cerebral cortex during surgeries such as resections for intractable epilepsy and tumors. Current clinical ECoG grids come in evenly spaced, millimeter-sized electrodes embedded in silicone rubber. Their mechanical rigidity and fixed electrode spatial resolution are common shortcomings reported by the surgical teams. Here, advances in soft neurotechnology are leveraged to manufacture conformable subdural, thin-film ECoG grids, and evaluate their suitability for translational research. Soft grids with 0.2 to 10 mm electrode pitch and diameter are embedded in 150 µm silicone membranes. The soft grids are compatible with surgical handling and can be folded to safely interface hidden cerebral surface such as the Sylvian fold in human cadaveric models. It is found that the thin-film conductor grids do not generate diagnostic-impeding imaging artefacts (<1 mm) nor adverse local heating within a standard 3T clinical magnetic resonance imaging scanner. Next, the ability of the soft grids to record subdural neural activity in minipigs acutely and two weeks postimplantation is validated. Taken together, these results suggest a promising future alternative to current stiff electrodes and may enable the future adoption of soft ECoG grids in translational research and ultimately in clinical settings.

An electronic neuromorphic system for real-time detection of high frequency oscillations (HFO) in intracranial EEG.

The analysis of biomedical signals for clinical studies and therapeutic applications can benefit from embedded devices that can process these signals locally and in real-time. An example is the analysis of intracranial EEG (iEEG) from epilepsy patients for the detection of High Frequency Oscillations (HFO), which are a biomarker for epileptogenic brain tissue. Mixed-signal neuromorphic circuits offer the possibility of building compact and low-power neural network processing systems that can analyze data on-line in real-time. Here we present a neuromorphic system that combines a neural recording headstage with a spiking neural network (SNN) processing core on the same die for processing iEEG, and show how it can reliably detect HFO, thereby achieving state-of-the-art accuracy, sensitivity, and specificity. This is a first feasibility study towards identifying relevant features in iEEG in real-time using mixed-signal neuromorphic computing technologies.

Global and Parallel Cortical Processing Based on Auditory Gamma Oscillatory Responses in Humans.

Gamma oscillations are physiological phenomena that reflect perception and cognition, and involve parvalbumin-positive γ-aminobutyric acid-ergic interneuron function. The auditory steady-state response (ASSR) is the most robust index for gamma oscillations, and it is impaired in patients with neuropsychiatric disorders such as schizophrenia and autism. Although ASSR reduction is known to vary in terms of frequency and time, the neural mechanisms are poorly understood. We obtained high-density electrocorticography recordings from a wide area of the cortex in 8 patients with refractory epilepsy. In an ASSR paradigm, click sounds were presented at frequencies of 20, 30, 40, 60, 80, 120, and 160 Hz. We performed time-frequency analyses and analyzed intertrial coherence, event-related spectral perturbation, and high-gamma oscillations. We demonstrate that the ASSR is globally distributed among the temporal, parietal, and frontal cortices. The ASSR was composed of time-dependent neural subcircuits differing in frequency tuning. Importantly, the frequency tuning characteristics of the late-latency ASSR varied between the temporal/frontal and parietal cortex, suggestive of differentiation along parallel auditory pathways. This large-scale survey of the cortical ASSR could serve as a foundation for future studies of the ASSR in patients with neuropsychiatric disorders.

Imaging of focal seizures with Electrical Impedance Tomography and depth electrodes in real time.

Intracranial EEG is the current gold standard technique for localizing seizures for surgery, but it can be insensitive to tangential dipole or distant sources. Electrical Impedance Tomography (EIT) offers a novel method to improve coverage and seizure onset localization. The feasibility of EIT has been previously assessed in a computer simulation, which revealed an improved accuracy of seizure detection with EIT compared to intracranial EEG. In this study, slow impedance changes, evoked by cell swelling occurring over seconds, were reconstructed in real time by frequency division multiplexing EIT using depth and subdural electrodes in a swine model of epilepsy. EIT allowed to generate repetitive images of ictal events at similar time course to fMRI but without its significant limitations. EIT was recorded with a system consisting of 32 parallel current sources and 64 voltage recorders. Seizures triggered with intracranial injection of benzylpenicillin (BPN) in five pigs caused a repetitive peak impedance increase of 3.4 ± 1.5 mV and 9.5 ± 3% (N =205 seizures); the impedance signal change was seen already after a single, first seizure. EIT enabled reconstruction of the seizure onset 9 ± 1.5 mm from the BPN cannula and 7.5 ± 1.1 mm from the closest SEEG contact (p<0.05, n =37 focal seizures in three pigs) and it could address problems with sampling error in intracranial EEG. The amplitude of the impedance change correlated with the spread of the seizure on the SEEG (p <<0.001, n =37). The results presented here suggest that combining a parallel EIT system with intracranial EEG monitoring has a potential to improve the diagnostic yield in epileptic patients and become a vital tool in improving our understanding of epilepsy.

Multimodal in vivo recording using transparent graphene microelectrodes illuminates spatiotemporal seizure dynamics at the microscale.

Neurological disorders such as epilepsy arise from disrupted brain networks. Our capacity to treat these disorders is limited by our inability to map these networks at sufficient temporal and spatial scales to target interventions. Current best techniques either sample broad areas at low temporal resolution (e.g. calcium imaging) or record from discrete regions at high temporal resolution (e.g. electrophysiology). This limitation hampers our ability to understand and intervene in aberrations of network dynamics. Here we present a technique to map the onset and spatiotemporal spread of acute epileptic seizures in vivo by simultaneously recording high bandwidth microelectrocorticography and calcium fluorescence using transparent graphene microelectrode arrays. We integrate dynamic data features from both modalities using non-negative matrix factorization to identify sequential spatiotemporal patterns of seizure onset and evolution, revealing how the temporal progression of ictal electrophysiology is linked to the spatial evolution of the recruited seizure core. This integrated analysis of multimodal data reveals otherwise hidden state transitions in the spatial and temporal progression of acute seizures. The techniques demonstrated here may enable future targeted therapeutic interventions and novel spatially embedded models of local circuit dynamics during seizure onset and evolution.

Neuro-inflammatory Sequelae of Minimal Trauma in the Non-traumatized Human Brain: A Microdialysis Study.

Cytokine measurement directly from the brain parenchyma by means of microdialysis has documented the activation of certain procedures in vivo, after brain trauma in humans. However, the intercalation of the micro-catheter insertion with the phenomena triggered by the head trauma renders the assessment of the findings problematic. The present study attempts to elucidate the pure effect of minimal trauma, represented by the insertion of the micro-catheter, on the non-traumatized human brain. Microdialysis catheters were implanted in 12 patients with drug-resistant epilepsy, and subjected to invasive electroencephalography with intracranial electrodes. Samples were collected during the first 5 days of monitoring. The dialysate was analyzed using bead flow cytometry, and the concentrations of interleukin (IL)-1, IL-6, IL-8, IL-10, IL-12, and tumor necrosis factor-α (TNF-α) were measured. The levels of IL-1 and IL-8 were found to be raised until 48 h post-implantation, and thereafter they reached a plateau of presumably baseline values. The temporal profile of the IL-6 variation was different, with the increase being much more prolonged, as its concentration had not returned to baseline levels at the fifth day post-insertion. TNF-α was found to be significantly raised only 2 h after implantation. IL-10 and IL-12 did not have any significant response to micro-trauma. These findings imply that the reaction of the neuro-inflammatory mechanisms of the brain exist even after minimal trauma, and is unexpectedly intense for IL-6. Questions may arise regarding the objectivity of findings attributed by some studies to inflammatory perturbation after head injury.

Responsive Neurostimulation as a Novel Palliative Option in Epilepsy Surgery.

Patients with drug-resistant focal onset epilepsy are not always suitable candidates for resective surgery, a definitive intervention to control their seizures. The alternative surgical treatment for these patients in Japan has been vagus nerve stimulation (VNS). Besides VNS, epileptologists in the United States can choose a novel palliative option called responsive neurostimulation (RNS), a closed-loop neuromodulation system approved by the US Food and Drug Administration in 2013. The RNS System continuously monitors neural electroencephalography (EEG) activity at the possible seizure onset zone (SOZ) where electrodes are placed and responds with electrical stimulation when a pre-defined epileptic activity is detected. The controlled clinical trials in the United States have demonstrated long-term utility and safety of the RNS System. Seizure reduction rates have continued to improve over time, reaching 75% over 9 years of treatment. The incidence of implant-site infection, the most frequent device-related adverse event, is similar to those of other neuromodulation devices. The RNS System has shown favorable efficacy for both mesial temporal lobe epilepsy (TLE) and neocortical epilepsy of the eloquent cortex. Another unique advantage of the RNS System is its ability to provide chronic monitoring of ambulatory electrocorticography (ECoG). Valuable information obtained from ECoG monitoring provides a better understanding of the state of epilepsy in each patient and improves clinical management. This article reviews the developmental history, structure, and clinical utility of the RNS System, and discusses its indications as a novel palliative option for drug-resistant epilepsy.

Multimodal Detection for Cryptogenic Epileptic Seizures Based on Combined Micro Sensors.

The cryptogenic epilepsy of the neocortex is a disease in which the seizure is accompanied by intense cerebral nerve electrical activities but the lesions are not observed. It is difficult to locate disease foci. Electrocorticography (ECoG) is one of the gold standards in seizure focus localization. This method detects electrical signals, and its limitations are inadequate resolution which is only 10 mm and lack of depth information. In order to solve these problems, our new method with implantable micro ultrasound transducer (MUT) and photoplethysmogram (PPG) device detects blood changes to achieve higher resolution and provide depth information. The basis of this method is the neurovascular coupling mechanism, which shows that intense neural activity leads to sufficient cerebral blood volume (CBV). The neurovascular coupling mechanism established the relationship between epileptic electrical signals and CBV. The existence of mechanism enables us to apply our new methods on the basis of ECoG. Phantom experiments and in vivo experiments were designed to verify the proposed method. The first phantom experiments designed a phantom with two channels at different depths, and the MUT was used to detect the depth where the blood concentration changed. The results showed that the MUT detected the blood concentration change at the depth of 12 mm, which is the position of the second channel. In the second phantom experiments where a PPG device and MUT were used to monitor the change of blood concentration in a thick tube, the results showed that the trend of superficial blood concentration change provided by the PPG device is the same as that provided by the MUT within the depth of 2.5 mm. Finally, in the verification of in vivo experiments, the blood concentration changes on the surface recorded by the PPG device and the changes at a certain depth recorded by the MUT all matched the seizure status shown by ECoG. These results confirmed the effectiveness of the combined micro sensors.

Polyherbal Formulation Enhancing Cerebral Slow Waves in Sleeping Rats.

Polyherbal medicines are composed of multiple herbs and have traditionally been used in East Asian countries for the remedy of physiological symptoms. Although the effects of polyherbal formulations have been investigated at the molecular and behavioral levels, less is known about whether and how medicinal herbs affect the central nervous system in terms of neurophysiology. We introduced a novel blended herbal formulation that consisted of 35% linden, 21% mulberry, 20% lavandin, 20% butterfly pea, and 4% tulsi. After intraperitoneal administration of this formulation or saline, we simultaneously recorded epidural electrocorticograms (ECoGs) from the olfactory bulb (OB), primary somatosensory cortex (S1), and primary motor cortex (M1), along with electromyograms (EMGs) and electrocardiograms (ECGs), of rats exploring an open field arena. Using the EMGs and OB ECoGs, we segmented the behavioral states of rats into active awake, quiet awake, and sleeping states. Compared to saline, herbal medicine significantly shortened the total sleep time. Moreover, we converted the ECoG signal into a frequency domain using a fast Fourier transform (FFT) and calculated the powers at various ECoG oscillation frequencies. In the sleeping state, a slow component (0.5-3 Hz) of S1 ECoGs was significantly enhanced following the administration of the formulation, which suggests a region- and frequency-specific modulation of extracellular field oscillations by the polyherbal medicine.