Electrocorticogram (ECoG): Engineering Approaches and Clinical Challenges for Translational Medicine

Electrocorticogram (ECoG) is an electrophysiological signal that results from the summation of neuronal activity near the cortical surface. To record ECoG signals, the scalp and skull are surgically opened and electrodes are placed on the cortical surface, either epidurally or subdurally. Owing to its improved spatiotemporal resolution and signal quality compared with electroencephalography, it is widely used to diagnose and treat neurological disorders in clinical settings for several decades, despite the invasiveness of ECoG. Recently, ECoG is applied in research to explore brain functions and connectivity, brain‐computer interfaces, and brain‐machine interfaces. In addition to the need for ECoG in neuroscience research, ECoG devices have advanced in terms of materials, fabrication, and function to overcome the limitations of commercially available ECoG arrays. Here, the conventional use of ECoG in clinical medicine, the new applications of ECoG in basic neuroscience research, and the future challenges in translating recent developments in ECoG devices for clinical use are described.


Introduction
An electrocorticogram (ECoG) is an electrical signal resulting from the summation of electrophysiological activities from multiple neurons residing near the cortical surface.ECoG signals can be detected from the cortical surface, either epidurally or to detect brain signals as accurately as intracortical recordings, [1,2] as well as to stimulate a specific brain region to treat neurological diseases. [3,4]n this review, we introduce the ECoG electrodes and procedures currently used in clinical environments and review recent technological developments toward emerging applications of ECoG beyond the current clinical use.Starting from the history of ECoG use in humans, the use of ECoG in clinics for diagnosis, treatment, analysis of brain functions, and brain-computer interfaces (BCI) or brain-machine interfaces (BMI) is discussed.Next, engineering efforts and approaches for developing novel ECoG tools for utilizing ECoG in translational research are introduced.Such novel devices enable the detection of higherresolution signals using ECoG with additional functionalities.The materials, fabrication methods, and additional functionalities used for micro-ECoG devices are highlighted.Finally, the existing challenges and directions for translating micro-ECoG electrodes into clinical applications are discussed.

Brief History of Electrophysiology and ECoG
In 1875, Caton reported measuring electric currents from two electrodes located on the surface of the gray matter and skull in experiments using rabbits and monkeys. [5]Beck et al., in 1890, showed the spontaneous and evoked electrical brain activity induced by sensory stimulation in dogs and rabbits. [6][9] In 1929, Berger reported the first noninvasive EEG recording in humans. [10]He described changes in the alpha and beta waves depending on whether the eyes were open or closed.In 1930, he performed the first direct recording of the cortical surface and white matter in humans. [11,12]ubsequently, Berger first recorded epileptiform activities from a human patient.In 1933, He reported in his report, "Über das Elektrenkephalogramm des Menschen", that he used EEG to record high voltage waves three times per second during seizures. [9]After Berger's report, Gibbs et al. (1935) demonstrated EEG epileptic patterns associated with different types of epilepsy-petit mal seizures and grand mal seizures; [13] later, they showed the possibility of the diagnosis of epilepsy and localization of seizure origin using brain activities. [14]Foerster not only confirmed Berger's results about epileptiform activities but also reported extremely low potential fluctuations in the region of tumor using an electrode placed on the exposed surface of the brain. [15][18] Hunter and Jasper suggested a method for recording EEG activity and seizure patterns simultaneously using an optical system consisting of mirrors and a camera. [19]In 1966, Goldensohn used closed-circuit television (CCTV) combined with the recording of EEG signals for the first time, [20] which became the current standard of invasive monitoring systems that simultaneously observe seizure patterns and epileptiform activities.

Recent ECoG Applications
The application of ECoG in human subjects has continued to grow since the 2000s as depicted in Figure 1a.Previously, electrocorticography using strips or grids of electrodes implanted in the subdural space was used to define the range of tumor resections for short-term intraoperative use [11,15] or to provide electrical stimulation for pain reduction in patients with intractable neuropathic pain. [21]In recent clinical fields, ECoG electrodes are generally implemented for invasive extra-operative monitoring as an implanted use in patients with drug-resistant epilepsy and are considered the gold standard for identifying precise seizure onset zones for resective surgery. [22,23]In addition, direct cortical stimulation using ECoG electrodes can provide information on the functional role of specific cortical sites and pathological responses such as afterdischarge.26] In modern clinical settings, ECoG has been primarily used in patients with epilepsy to detect epileptic zones before resective surgery.In addition to epilepsy, ECoG has shown potential for various clinical applications in the past, including tumor localization, pain reduction, Parkinson's disease, obsessive-compulsive disorder, and major depression (Figure 1b). [27]This growth is not limited to clinical use but has expanded significantly into various areas of neuroscience research.In certain cases, brain activities from these patients have been read out for neuroscience studies to explore sleep, pain, cognition, and memory functions and for BCI/BMI applications.Particularly, with the advancement of BCI and BMI technologies, ECoG's feasibility is increasing for rehabilitation purposes in patients with conditions like lockedin syndrome, amyotrophic lateral sclerosis, and spinal cord injury. [28]

Epilepsy Monitoring
The lifetime prevalence of epilepsy is known to be 7.60 per 1000 individuals worldwide. [29]Almost 1% of the world's population suffers from or has suffered from epilepsy.Approximately 25% of these patients have drug-resistant epilepsy, which occurs when an adequate trial of two anti-epileptic drugs (AEDs) fails to relieve seizures. [30,31]For those drug-intractable patients, surgical treatment is performed to achieve seizure relief by localization and removal of the seizure onset zone.ECoG electrodes are required for precise surgical procedures.
Before implantation of the ECoG electrodes for invasive monitoring, a noninvasive diagnosis is performed preoperatively. [32]o determine the laterality of the seizure onset zone, scalp EEG recordings are first conducted, along with video recordings to confirm the seizure patterns.To identify anatomical abnormalities or functional impairments associated with seizures, various imaging techniques are utilized, including magnetic resonance imaging (MRI) to assess structural abnormalities, positron emission tomography to evaluate glucose metabolism, and single photon emission computed tomography to assess regional cerebral blood flow.Sometimes biochemical abnormalities are evaluated with magnetic resonance spectroscopy.Magnetoencephalography, another noninvasive method for detecting brain activity, is useful in diagnosing neocortical epilepsy, where abnormalities are rarely found in structural images, and can provide important information to localize eloquent areas. [33]he Wada test (a sodium amobarbital intracarotid injection) and neuropsychological tests can be used to evaluate lateralization and quantitative functionalities such as attention, memory, language, and motor function. [34]n combination with neuroimaging or other diagnostic modalities, invasive monitoring is performed before surgical removal of the epileptogenic zone, distinguished from the eloquent area.In invasive EEG monitoring, brain activity is recorded for a certain period by implanting electrodes, such as grid or strip ECoG arrays or depth electrodes, onto the area presumed to be associated with a seizure origin using the aforementioned non-invasive modalities.Seizure origins can be determined by detecting the presence of spikes during interictal periods or determining the area where the change in brain activity first appears during the seizure (Figure 2a).
Through invasive ECoG studies in patients with epilepsy, it is confirmed that there is a significant association between a seizure-free outcome and resection areas showing a spreading ictal signal within 3 s, pathological low-frequency waves, or frequent interictal spikes. [35]In human patients and animal studies, high-frequency epileptic activity above 80 Hz has been recorded in epileptic tissues. [36,37]It is reported that the extracted feature from the phase locking value between the phase of high gamma activities (80-150 Hz) and the phase of lower frequency rhythms (4-30 Hz) is useful in finding the seizure onset zone. [38]

Study of Brain Mechanisms
In addition to epilepsy monitoring, ECoG has been used in clinical studies on sleep and consciousness.Slater et al. suggested a novel measure of local sleep while awake by detecting changes in local field potentials. [43]Alonso et al. proposed a method to quantify changes in neural activity to characterize the loss of consciousness by observing the enhanced stability of neural dynamics in an anesthetized state. [44] neuroscience, ECoG signals provide insights into the mechanisms of human cognitive processes.][47][48][49] Therefore, such focal activities represented by high gamma responses are considered to be significant and useful in cognitive neuroscience as well as in braincomputer interfacing. [50]rone et al. reported that an increase in gamma activity (>30 Hz) is induced by auditory perception. [46]Additionally, during auditory processing, corticocortical connections were suggested by the causal relationships of high gamma activity between areas in the early auditory pathways. [48]Ryun et al. showed that high gamma (50-140 Hz) power can be modulated by vibrotactile frequencies in the human primary and secondary somatosensory cortices (Figure 2b). [49]In the visual cortex, narrowband gamma activity was shown to differ depending on the properties of the stimuli, such as white noise or grating, but broadband gamma oscillations generally increased for all visual stimuli. [51]any studies have been conducted not only on sensory tasks, but also on cognitive experiments, such as memory, movement, and language.Lee et al. found that the cortical network in the alpha band (8-13 Hz) between the medial temporal and parietal lobes is associated with working memory. [52]The high gamma activity is spatially and temporally different depending on the movement type. [40,53,54]Moreover, in the motor imagery task, the spatial distribution of neural activity at high frequencies (76-100 Hz) and low frequencies (8-32 Hz) was similar to the activation pattern during actual motor movement (Figure 2c). [41]For the language task, Towle et al. showed that the gamma activity varies spatially depending on listening and speaking tasks.During speaking, compared to listening, activity in the frontal lobe increased while activity in the temporal lobe decreased. [55]Another study on cortical connectivity revealed that the role of Broca's area in language appears to formulate articulatory codes for speech pronunciation. [56] b) Time-frequency maps for various vibrotactile stimulus conditions in the primary somatosensory cortex (S1) and secondary somatosensory cortex (S2). [49]c) Power spectral density of cortical potentials for motor execution (left, red line), motor imagery (right, red line), and resting state (both, blue line) in the primary motor cortex. [41]d) Change in high gamma power during music listening relative to the baseline in the posterior superior temporal gyrus. [42]Reproduced with permission from publishers.

Brain-Computer/Machine Interface (BCI/BMI)
Based on the neuroscientific findings discussed in the previous section, studies utilizing ECoG for BCI (or BMI) applications have recently emerged.60] However, recent efforts have been made to use ECoG to decode brain activities for BCI purposes, demonstrating the feasibility of using ECoG in decoding movement or communication intentions.For instance, for motor BCI, Kang et al. suggested a method for expecting movement intention using the temporal dynamics of brain connectivity in the dorsolateral prefrontal and primary motor cortices. [61]Talakoub et al. predicted the trajectory of real arm movements with high performance. [62]Jang et al. demonstrated the successful prediction of imagined hand movement trajectories and suggested a more appropriate paradigm for higher decoding accuracy. [63]In addition, Lorach et al. iden-tified hip flexion using ECoG from the sensorimotor cortex to restore communication between the brain and spinal cord from patients with chronic tetraplegia. [64]Another study demonstrated the feasibility of decoding hand gestures with high accuracy from high-density ECoG signals in the sensorimotor cortex, highlighting the potential for developing a high-performance BCI using high-density ECoG. [54]or the auditory BCI system, Martin et al. demonstrated the feasibility of a music BCI system by suggesting an encoding model to predict the high gamma activity (70-150 Hz) from the auditory spectrogram during the music imagery task. [65]Anumanchipalli et al. succeeded in designing a speech decoder using cortical activity related to articulatory movement. [66]A recent study showed that direct cortical signals from high-density ECoG electrodes in the sensorimotor cortex could be used to decode words and sentences during overt and silent speech in real-time with high accuracy for a paralyzed participant to control communication BCI. [67,68]able 1.Commercial ECoG devices that have been used in human subjects.

Commercial ECoG Electrodes
Macro-sized ECoG electrode arrays have been commercialized and have been widely used in hospitals since the first Palm Desert Conference on the Treatment of Epilepsy in 1986. [69]Commercial ECoG arrays are generally used for the invasive monitoring of patients with epilepsy in clinical practice, mainly within 1-2 weeks, and are implanted for a maximum of 30 days (Table 1).In general, ECoG signals allow for the recording of extracellular field potentials and the study of the connectivity of brain regions, allowing us to understand various pathological responses and cognitive processes.In addition, ECoG electrodes have a high spatial resolution at the millimeter scale.In addition, since dozens to 200 electrodes are generally implanted for invasive monitoring, a relatively broad area of the cortex is covered.Moreover, electrical stimulation can be performed directly on a specific cortical area using ECoG electrodes. [70]ommercial ECoG arrays are mostly composed of a medical silicone substrate to minimize foreign body responses and have conductive parts such as electrodes, traces, and pads made of stainless steel or platinum to minimize chemical reactions with biological tissues.Platinum electrodes are preferred for their superior resistance to electrolysis and stable electrochemical properties, making them more suitable for long-term applications and consistent signal quality. [71]Conversely, stainless steel electrodes are more cost-effective, though they are less resistant to corrosion and may subsequently exhibit less stable electrical properties for chronic applications. [72]An ECoG array consists of a strip or a grid of electrodes (Figure 3).In general, a strip has 2-12 electrodes arranged in a line, and a grid has 8-64 electrodes arranged in a grid.The size of the metal electrodes ranges from 3 to 6 mm, and the size of the exposure is slightly smaller.It is estimated that ≈500 000 cells exist near an electrode or in the local area underneath it. [73]Generally, the electrode spacing ranges from 5 to 15 mm, and the thickness of the ECoG electrode arrays is usually 0.7 mm.The 8 × 8 grid covers a relatively wide cortical area of 80 × 80 mm 2 .The size and shape, such as the L-shape or T-shape, and the number of electrodes can be customized if needed.An electrode with a contact size ˂2 mm and an inter-electrode distance ˂5 mm is regarded as a high-density electrode.Such highdensity ECoG arrays can even detect high-frequency ripples of hundreds of hertz in addition to normal ECoG signals during seizures. [74]

Mechanical Mismatch
The substrate of commercial ECoG arrays is typically medical silicone, which is a soft elastomer.Even though the substrate material is soft, millimeter-thick substrates possess high bending stiffnesses.The electrodes are made of rigid stainless steel or platinum plates.Thus, the mechanical properties of commercial ECoG arrays are much stiffer than soft brain tissues.The stiffness of ECoG arrays encounters inherent problems during the implantation and recording of electrophysiological signals.Stiff ECoG arrays do not have good contact with curved and soft brain tissues.Consequently, it hinders high-quality ECoG recordings.In addition, risks including symptomatic extra-axial fluid collection may be reduced by reducing the stiffness of the electrode arrays. [75]However, the manufacturing method of commercial ECoG electrodes has limited the fabrication of soft ECoG arrays owing to the procedures used and the low yield in production.

Low Spatial Resolution
The spatial resolution of electrophysiological signals is determined by the electrode size and density.The millimeter-sized electrodes and electrode arrangement of commercial ECoG arrays limit the spatial resolution as they can record the population activities of neurons close to the electrodes.To achieve a higher spatial resolution, electrodes need to be fabricated on a submillimeter scale with high-density to capture the activity of a smaller population of neurons.

Limited Functionality
The additional functions of ECoG arrays can expand the potential for target-specific drug delivery, neural circuit mapping, and minimal surgical risk.Commercial ECoG arrays focus on measuring electrophysiological signals from the human brain.Therefore, commercial ECoG arrays are limited for use in small animals, such as mice, rats, or monkeys, where brain mechanisms can be explored more actively.In addition, investigating neural circuits by measuring only electrophysiological signals is challenging.For an in-depth understanding of neural circuit mechanisms, it is desirable to integrate ECoG arrays with systemic modalities such as microfluidic or optical components.Furthermore, commercial ECoG arrays implanted after cranial incision require a large exposure window of 28 ± 15 cm 2 on average, [81] which can cause adverse effects such as clinical infection, subdural hemorrhage, [82][83][84][85][86] cerebral edema, or aseptic meningitis.Minimally invasive surgical and systemic strategies are expected to reduce surgical side effects in patients. [86,87]

Development of Micro-ECoG Electrodes
Since its introduction by Jasper and Penfield in 1949, ECoG electrodes have been commonly used to directly measure neural activity on the cortical surface in the clinical and research fields. [88,89]Since the 2000s, microelectromechanical system technology has been actively adopted to fabricate ECoG electrodes, and subsequently, an understanding of brain activity at high spatial resolution has become possible (Figure 4a). [90]In particular, polymer materials have been used as substrate materials in the fabrication of ECoG electrodes (Figure 4b).Some soft ECoG electrodes can establish conformal contact between the electrode and brain tissue. [91,92]Recently, ECoG electrodes have also been integrated with various additional functionalities for the study of the complex mechanisms of the brain and the development of neurological disease treatment.For example, optical imaging and optogenetic stimulation have been integrated into ECoG electrodes for research purposes. [93,94]A drug-delivery function was added for direct and focal injection into the central nervous system. [95]Bioabsorbable materials and minimally invasive electrode array structures have been developed to reduce surgical risks. [91,96]

Improvement of Mechanical Properties
The substrates of ECoG electrodes are recommended to be made of soft polymeric materials to reduce the mechanical mismatch between the electrodes and the brain.Thus, biocompatible polymeric materials, such as plastics, elastic materials, and hydrogels, are used as substrates (Figure 5).The Young's moduli of plastic materials, [2,[97][98][99][100][101] elastic materials, [102][103][104] and hydrogels [92] are typically ≈10 GPa, ≈10 MPa, and ≈1 MPa, respectively.Therefore, to fabricate ECoG electrodes with mechanical properties similar to those of brain tissues, the substrate materials should be considered in terms of Young's moduli and their suitability for microfabrication (Table 2).Additionally, to represent the flexibility of thin film ECoG devices, the bending stiffness (e.g., flexural rigidity, K) is one of the important parameters to be considered. [105] The bending stiffness of the beam-structured electrode is determined as the bending force that is needed to achieve conformal contact with the curved cortex surface.Here, F is the applied force, d is the deflection, E is Young's moduli of substrate materials, I is the moment of inertia, and L is the length of the electrode.The cross-sectional shape of the ECoG electrode is normally rectangular shape.The formation of the moment of inertia is expressed as where w and h are the width and thickness of the electrode substrate, respectively.
If the ECoG electrode is assumed to be a wide rectangular sheet (h ≪ L), the bending stiffness of the beam-structured electrode can be expressed as [133] Parylene C [ 107,[134][135][136] PDMS [ 107,[137][138][139][140] PVA [141][142][143][144][145] Young's modulus (MPa) The device structure of thin film enhances flexibility and enables conformal contact with the curved surface such as the brain cortex. [106]Therefore, conductive components such as electrodes and conductive lines are required to form flexible structures using microfabrication techniques.Plastic materials have higher Young's moduli than elastic materials (elastomers) and hydrogels.These materials have been widely employed to fabricate ECoG electrodes owing to their convenience and compatibility with microfabrication techniques.Elastomers and hydrogels are excellent substrate materials in terms of mechanical properties similar to those of the brain tissue.However, these materials exhibit low suitability for microfabrication techniques.A lot of ECoG electrodes are fabricated based on diverse substrate materials and have been developed to achieve stable chronic recording from the brain cortex (Table 3).

Plastic Materials
Plastic materials possess relatively higher Young's moduli among the polymeric substrates of the ECoG arrays.To reduce the mechanical mismatch between biological tissues and plastic substrates, the substrate is fabricated with a thickness of down to tens of micrometers using chemical vapor deposition (CVD) or spincoating procedures.Polyimide (PI) has a coefficient of thermal expansion similar to that of silicon.Thus, it is compatible with most microfabrication techniques that are conducted on silicon wafers.The glass transition temperature is higher than the processing temperature during metal electrode fabrication.Owing to these characteristics, PI is widely utilized in the fabrication of microelectronics.Moreover, advantages such as superior corrosion resistance and thermoxidative stability are the reasons for PI being preferred as an insulation and passivation layer. [107][110][111][112] Parylene C, a plastic material named polyparaxylene C, exhibits desirable characteristics for implantation in terms of chemical inertness, ion/moisture barrier function, optical transparency, and medical-grade biocompatibility (U.S. Pharmacopeia (USP) class VI approved by Food and Drug Administration (FDA)).Parylene C can be conformally and uniformly deposited as a substrate or as an insulation material for implantable devices.However, the CVD-based deposition limits the thickness of deposited parylene C. Parylene C also exhibits high compatibility with microfabrication techniques except for the procedures that are conducted at high temperatures due to its glass transition temperature of 80-100 °C.115][116][117][118]

Elastic Materials
Elastic materials are soft, stretchable polymers that do not undergo plastic deformation.Polydimethylsiloxane (PDMS) is a popular elastic material with the advantages of optical transparency, biocompatibility, and resistance to biodegradation.In particular, PDMS is a material approved to be USP class VI and has mechanical properties (Young's modulus close to 1 MPa) similar to those of biological tissues (Young's modulus of the brain ≈100 kPa). [119]However, this softness compromises the compatibility with microfabrication techniques owing to the large difference in the thermal expansion coefficient between the metals and PDMS.Recently, a fabrication method for stable metal patterns on a soft PDMS substrate was established using an intermediate parylene C layer, [120] which improved the compatibility of PDMS with microfabrication techniques. [121,122]125]

Hydrogel
Hydrogels have excellent mechanical properties similar to those of biological tissues and have attracted broad attention as biomaterials for applications such as electronic skins [126] or bioelectronics. [127]Hydrogels possess additional advantages such as transparency, biofluid permeability, and adhesion to biologi-cal tissues.Electrical functions can be integrated by mixing hydrogels with conductive nanowires or nanocomposites.However, hydrogel-based substrates are incompatible with general microfabrication techniques because of the changes in their mechanical properties, such as volume expansion and decreased Young's moduli, upon water absorption.Thus, alternative methods are required to integrate conductive patterns onto hydrogel substrates.Recently, polyvinyl alcohol (PVA) hydrogel substrate-based ECoG electrodes have been developed to enhance the conformal contact with the brain surface and simultaneously record ECoG signals during fMRI. [128]ecent studies report that conductive patterns based on hydrogels were fabricated by mixing PVA with Ag/Au nano core-shell nanowires [129] and polystyrene sulfonate (PEDOT:PSS) [130] to enhance the long-term stability of ECoG electrodes in aqueous environments.They recorded ECoG signals from the cerebral cortices of marmosets and mouse brain slices.

Improvement of Spatial Resolution
Efforts to communicate with the brain have encouraged the use of high spatiotemporal resolution to record neural activity with spike-level accuracy in both BCI/BMI research and clinical seizure tracking (Figure 6).Physiological signals from micro-ECoG (μECoG) arrays can improve our understanding of physiological and pathological mechanisms with higher resolutions. [70] micro-ECoG array with a sampling rate of 20-30 kHz was shown to record brain activity in a wide frequency band, up to single-unit activities. [2,116]Accordingly, to decode brain functions such as perception, sensation, and movement, microelectrodes with a small size under 100 × 100 μm 2 and high density are preferred to detect the activity of individual neurons.As an example, Buzsaki's group fabricated a micro-ECoG array, named "NeuroGrid," with a 10 μm-diameter and 23 μm-spacing of electrodes. [116]NeuroGrid demonstrated the acquisition of action potential waveforms from superficial cortical neurons with high spatiotemporal resolution. [2]oreover, if micro-ECoG electrodes are used in clinical fields, precise seizure tracking can be achieved by accurately detecting ictal onset areas and identifying epileptic pathways in the core and penumbra areas.In addition, ECoG signals with high spatiotemporal resolution can improve the controllability of BCI/BMI.Dayeh's group developed 2048 ECoG electrodes named "PtNRGrids" to spatially confirm epileptic discharge spreads from a patient. [118]Also, they recorded complex spatiotemporal activities from the somatosensory and motor cortices of awake humans, associated with the vibration of fingers and grasping task, respectively.
Micro-ECoG arrays have been fabricated using microfabrication techniques to achieve high spatial resolution (Figure 7a).Microfabrication techniques enable not only the deposition and patterning of metal thin films down to the submicrometer scale but also the coating and etching of various organic/inorganic materials.Therefore, it provides choices for the material selection in the fabrication of ECoG electrodes.Recently, laser machining, inkjet printing, and 3D printing have been used to rapidly and conveniently develop ECoG electrodes (Figure 7b-d). [102,149,156,157]lthough conventional microfabrication techniques can The schematic shows the characteristics of ECoG and micro-ECoG.The ictal onset zone is the specific area where a seizure starts.The core surrounding the ictal onset zone can be defined by detecting brain activities using a micro-ECoG array with higher spatial resolution than an ECoG array.The penumbra, defined by using an ECoG array, refers to the surrounding area including the central core of a seizure zone.55] implement metal electrodes in tens of micrometers, it has disadvantages such as complex manufacturing procedures, and ineffectiveness in time and cost (Figure 7e).Other methods of laser machining, inkjet printing, and 3D printing have advantages such as simple fabrication procedures, but they imply relatively low resolution of electrode patterns and limited rials to be employed.Therefore, it is necessary to understand the available electrode materials based on the fabrication method.Consequently, a suitable fabrication strategy for ECoG electrodes is required for specific clinical applications and neuroscientific research.

Laser Machining
The fabrication procedures of ECoG electrodes through laser machining are similar to those of microfabrication, except for the patterning of the metal film and/or array outline.This method is relatively convenient and fast since laser cutting is used instead of a photolithography-dry/wet etching-cleaning cycle.A Pt or PtIr foil is laminated onto the substrate and patterned to create electrodes with a resolution of several hundreds of micrometers using an ND:YDG laser. [103,176]However, laser machining has several challenges, such as low cutting resolution caused by damage from laser ablation and limited employable materials.Thus, this method limits the fabrication of micro-ECoG electrodes to resolutions of several micrometers.

Inkjet Printing
Inkjet printing has been developed using drop-on-demand patterning technology to directly disperse conductive materials on a scale of tens of micrometers.This maskless patterning method has the advantages of low cost and short throughput in manufacturing.However, solvent-or water-soluble materials, such as Ag ink and PEDOT:PSS, which can be ejected through an inkjet nozzle, are necessary for the fabrication of microelectrodes. [148,158]ecently, inkjet printing-based electrodes with a diameter of 30 μm were fabricated, so that they could have a resolution sufficient for single-cell recording. [157]

Integration of Additional Functions
Previously, the role of micro-ECoG arrays was limited to measuring electrophysiological signals or modulating neural activities.However, recent results from neuroscience research and clinical applications have shown that multifaceted studies are required for an in-depth understanding of higher-order brain functions and a promising approach to treating neurological diseases.Thus, micro-ECoG arrays have been integrated with various functions, including drug delivery, optical stimulation, fluorescence imaging, minimally invasive implantation, and bioabsorbable materials (Figure 8).ECoG arrays with additional functions are being developed to be more biocompatible in biological environments, deeply understand brain mechanisms, and meet clinical requirements.

Drug Delivery
ECoG electrodes have been integrated with drug delivery functions for precise and target-specific drug infusion.In a study by Minev et al., a microfluidic channel passively delivered drugs via ECoG arrays are integrated with a) microfluidic channels for drug delivery, [95] b) light emitting component for optogenetic modulation, [129] c) transparent substrate/electrode for optical monitoring, [178] d) expandable structure for minimal invasiveness, [179] e) biodegradable materials for bioabsorbability. [130]Reproduced with permission from publishers.mechanical movement to eliminate the side effects of serotonergic agents on the autonomic system. [95]A flexible drug delivery microdevice (f-DDM) released an antiepileptic drug (AED) with a controllable amount and multiple drugs for the precise control of seizures. [180]Especially, an electrophoretic ion pump was included to resolve the issues of clogging and reflux, thereby enhancing drug delivery performance. [181]In another study, bioresorbable silk fibroin was used to deliver phenobarbital, an AED.As a result, the suppression of epileptic seizures was observed with the dissolution of silk fibroin. [110]These studies were conducted to enhance the performance of drug delivery in precision medicine.

Optogenetic Modulation
Optogenetic modulation is a prospective method for investigating the functional connectivity of neural circuits with a high spatiotemporal resolution.Using this method, a circuit connection with specific cell-type activity can be identified.The stimulation artifact, which is usually seen in electrical stimulation, is eliminated; therefore, the optogenetic method has a definite advantage in neuromodulation studies. [182]For stimulation and recording in the same brain area, the electrodes and substrate of a micro-ECoG device need to be composed of transparent materials.Accordingly, transparent ECoG arrays fabricated using various electrode materials such as ITO, graphene, carbon nanotubes, metal nanowires, or PEDOT:PSS have been developed. [115,172,183,184]An ECoG array including a transparent ITO electrode was integrated with the micro-LED array for optical modulation and simultaneous recording of induced signals in the visual cortex. [185]Embed-ded micro-LED arrays can simultaneously achieve optical stimulation in multiple areas of the cortex.

Optical Monitoring
Integrating an optical window and transparent ECoG array can facilitate simultaneous optical imaging and electrophysiological signal recording.Simultaneous detection using both modalities allows multifaceted studies of neural circuits.Au nanospheres were used as the transparent electrode material and exhibited an average transmittance of over 65% at 300-1100 nm light wavelength. [186]In this study, the cell morphology was successfully captured through an Au nanosphere electrode by phasecontrast imaging.In addition, graphene-based ECoG electrodes with a transmittance of over 90% were fabricated to acquire spatiotemporal neural fluorescence responses. [175]A multilayerassembled ECoG array with PEDOT:PSS, ITO, and Ag, resulting in a transmittance of 89% at 550 nm, was developed to conduct electrical and optical multimodal recording. [187]

Minimal Invasiveness
The implantation of ECoG electrodes generally requires a larger opening of the skull than the lesion site, accompanying patient risks, such as a high probability of infection and brain swelling.Therefore, several solutions have been devised to reduce the size of the trephination hole but keep the contact area of ECoG arrays as needed.An expandable ECoG array, composed of an elastic PDMS substrate, was suggested to implant in the gap between the skull and cortex through a smaller trephination hole than the cortical area to cover, by expanding the array inside the gap. [179]nother ECoG electrode integrated with a neodymium magnet was developed, and the placement of the device at a desired location inside the skull was demonstrated. [81]After positioning the device, the magnet utilized as the carrier was released from the device and extracted through the hole in the skull.Recently, a soft robotic electrode, which can be expanded and cover a large area of cortical surface by hydraulic injection, demonstrated minimally invasive cortical surgery for applications of neurological disorders. [188]

Bioabsorbability
Bioresorbable ECoG electrodes can reduce the postoperative risk of surgical extraction of the device after a certain period of time.Polycaprolactone (PCL)-and PCL/ poly(lactic-co-glycolic acid) (PLGA)-based electrode substrates were fully fabricated by inkjet printing, and bioabsorbability was confirmed in accelerated aging environments for up to 70 h. [157]This result is projected for a degradable period of two years in vivo, confirming the slow degradation of the implanted devices.In addition, the PLLA/PCL substrate and molybden (Mo)-based ECoG array were fabricated through microfabrication techniques and dissolved in 37 °C phosphate buffered saline solution for 30 days.The ECoG array detected the onset of epileptic seizures. [96]Moreover, the biodegradable Si nanomembranes (Si NMs)-based ECoG arrays achieved chronic recordings of seizure-like spiking activity for 30 days. [151]

Challenges and Prospects
As discussed in this review, medical and neuroscientific research on ECoG has expanded remarkably since 2010.The majority of EcoG usage is still observed in clinical monitoring and diagnosis; however, its use in neuroscientific discovery and technological development, such as in BCI/BMI, is rapidly increasing.Along with these trends, micro-ECoG devices and flexible and/or soft ECoG devices have been actively developed with improved biocompatibility, higher spatial resolution, and additional functionalities owing to the advancements in materials and fabrication technologies.These new developments are currently used in animal models in combination with neuroscientific studies.This needs to be translated into clinics to advance clinical ECoG toward more personalized and customized treatments and next-generation precision medicine, such as electroceuticals.The main aim of micro-ECoG devices is the achievement of advanced healthcare for patients with neurological diseases and the advancement of neural interfaces with reliable long-term performance.Moreover, the devices aim to provide minimal invasiveness for severely paralyzed patients with impaired physical functions due to spinal cord injury, amyotrophic lateral sclerosis, or locked-in syndrome, as well as for patients with cognitive impairment.Finally, in parallel with the efforts to develop new technologies, efforts to obtain approval from the regulatory entity in each country should be present simultaneously to realize the translation of promising new technologies.

Figure 1 .
Figure 1.Trends of publications regarding electrocorticography. a) The number of publications searched using the term "electrocorticography" is represented by blue bars, and using the terms "electrocorticography" and "human" is represented by magenta bars.b) The number of publications on human research is categorized into two fields of medicine (blue bar) and neuroscience (magenta bar).All data are based on Scopus.

Figure 2 .
Figure 2. Examples of human ECoG studies in medicine and neuroscience fields.a) Representative ictal discharges across multiple electrodes (top) and dynamic voltage topographic maps on the cortical surface at the time points I to IV (bottom).[39]b) Time-frequency maps for various vibrotactile stimulus conditions in the primary somatosensory cortex (S1) and secondary somatosensory cortex (S2).[49]c) Power spectral density of cortical potentials for motor execution (left, red line), motor imagery (right, red line), and resting state (both, blue line) in the primary motor cortex.[41]d) Change in high gamma power during music listening relative to the baseline in the posterior superior temporal gyrus.[42]Reproduced with permission from publishers.

Figure 3 .
Figure 3. Examples of commercial ECoG electrodes used in the clinical field according to manufacturers.a) g.tec Medical Engineering GmbH, b) PMT Corporation,and c) Ad-Tech Medical Instrument Corporation, respectively.An electrode array with multiple rows and columns is referred to as a grid-type electrode, while an electrode array with a single row is referred to as a stripe-type electrode.

Figure 4 .
Figure 4. Trends of publications regarding ECoG electrodes from 1970 to 2021.a) The blue column indicates publication trends using the term "ECoG electrode", among which studies searched using the terms "micro" and "ECoG electrode" are shown in magenta, and b) studies searched using the terms "flexible" or "soft" together with "ECoG electrode" are shown in green.All data are based on Scopus.

Figure 5 .
Figure 5. Representative substrate materials for ECoG electrodes.a) Young's modulus of the brain tissue to materials used in ECoG electrodes.b) Optical images of substrate materials such as hydrogel (b-1), polydimethylsiloxane (PDMS) (b-2), medical-grade silicone used for commercial ECoG electrodes (b-3), and parylene C (b-4) when placed on the model of the human brain; (top) aerial-and (bottom) side views.The red dotted lines indicate the outline of the curved brain surface.The green dotted lines indicate the outline of each substrate material placed on the curved brain surface.The gap between the brain surface and the substrate is marked by black arrows.

Figure 6 .
Figure 6.Comparison between macro-and micro-ECoG array (ECoG versus micro-ECoG).The schematic shows the characteristics of ECoG and micro-ECoG.The ictal onset zone is the specific area where a seizure starts.The core surrounding the ictal onset zone can be defined by detecting brain activities using a micro-ECoG array with higher spatial resolution than an ECoG array.The penumbra, defined by using an ECoG array, refers to the surrounding area including the central core of a seizure zone.Intense and synchronized brain activities are observed in the seizure core, while low-level and desynchronized firings are observed in the penumbra.[153][154][155]

Table 2 .
Properties of the common materials used to build ECoG electrode arrays.
Food and Drug Administration.USP calss VI indicates there are no harmful reactions or long-term bodily effects caused by chemicals.FDA approval means that the hydrogel is permitted for clinical use.

Table 3 .
Summary of the developed ECoG electrodes for in-vivo recording studies.