Intraoperative changes in the H-reflex pathway during deep brain stimulation surgery for Parkinson's disease: A potential biomarker for optimal electrode placement.

BACKGROUND: Deep Brain Stimulation (DBS) targeting the subthalamic nucleus (STN) and globus pallidus interna (GPi) is an effective treatment for cardinal motor symptoms and motor complications in Parkinson's Disease (PD). However, malpositioned DBS electrodes can result in suboptimal therapeutic response. OBJECTIVE: We explored whether recovery of the H-reflex-an easily measured electrophysiological analogue of the stretch reflex, known to be altered in PD-could serve as an adjunct biomarker of suboptimal versus optimal electrode position during STN- or GPi-DBS implantation. METHODS: Changes in soleus H-reflex recovery were investigated intraoperatively throughout awake DBS target refinement across 26 nuclei (14 STN). H-reflex recovery was evaluated during microelectrode recording (MER) and macrostimulation at multiple locations within and outside target nuclei, at varying stimulus intensities. RESULTS: Following MER, H-reflex recovery normalized (i.e., became less Parkinsonian) in 21/26 nuclei, and correlated with on-table motor improvement consistent with an insertional effect. During macrostimulation, H-reflex recovery was maximally normalized in 23/26 nuclei when current was applied at the location within the nucleus producing optimal motor benefit. At these optimal sites, H-reflex normalization was greatest at stimulation intensities generating maximum motor benefit free of stimulation-induced side effects, with subthreshold or suprathreshold intensities generating less dramatic normalization. CONCLUSION: H-reflex recovery is modulated by stimulation of the STN or GPi in patients with PD and varies depending on the location and intensity of stimulation within the target nucleus. H-reflex recovery shows potential as an easily-measured, objective, patient-specific, adjunct biomarker of suboptimal versus optimal electrode position during DBS surgery for PD.

Advances in Penetrating Multichannel Microelectrodes Based on the Utah Array Platform.

The Utah electrode array (UEA) and its many derivatives have become a gold standard for high-channel count bi-directional neural interfaces, in particular in human subject applications. The chapter provides a brief overview of leading electrode concepts and the context in which the UEA has to be understood. It goes on to discuss the key advances and developments of the UEA platform in the past 15 years, as well as novel wireless and system integration technologies that will merge into future generations of fully integrated devices. Aspects covered include novel device architectures that allow scaling of channel count and density of electrode contacts, material improvements to substrate, electrode contacts, and encapsulation. Further subjects are adaptations of the UEA platform to support IR and optogenetic simulation as well as an improved understanding of failure modes and methods to test and accelerate degradation in vitro such as to better predict device failure and lifetime in vivo.

hiPSCs Derived Cardiac Cells for Drug and Toxicity Screening and Disease Modeling: What Micro- Electrode-Array Analyses Can Tell Us.

Human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CM) have been intensively used in drug development and disease modeling. Since iPSC-cardiomyocyte (CM) was first generated, their characterization has become a major focus of research. Multi-/micro-electrode array (MEA) systems provide a non-invasive user-friendly platform for detailed electrophysiological analysis of iPSC cardiomyocytes including drug testing to identify potential targets and the assessment of proarrhythmic risk. Here, we provide a systematical overview about the physiological and technical background of micro-electrode array measurements of iPSC-CM. We introduce the similarities and differences between action- and field potential and the advantages and drawbacks of MEA technology. In addition, we present current studies focusing on proarrhythmic side effects of novel and established compounds combining MEA systems and iPSC-CM. MEA technology will help to open a new gateway for novel therapies in cardiovascular diseases while reducing animal experiments at the same time.

A review of acute responses, after-effects and chronic complications related to microneurography.

Microneurography, a technique used to detect postganglionic sympathetic nerve traffic in humans, is increasingly used to further the understanding of autonomic regulation in health and disease. The technique involves the transcutaneous insertion of a microelectrode into a peripheral nerve, following which, a variety of adverse acute responses; after-effect and chronic complications have been documented. Here, we comprehensively review the potential adverse outcomes of microneurography and provide updated quantifiable incidence rates of their occurrence within a general population. We also present recommendations for risk assessment and management of such outcomes, as well as recommendations to improve future reporting. This review aims to use objective evidence to improve the understanding of the rare, but present, adverse outcomes of microneurography.

Evaluating the in vivo glial response to miniaturized parylene cortical probes coated with an ultra-fast degrading polymer to aid insertion.

OBJECTIVE: Despite the feasibility of short-term neural recordings using implantable microelectrodes, attaining reliable, chronic recordings remains a challenge. Most neural recording devices suffer from a long-term tissue response, including gliosis, at the device-tissue interface. It was hypothesized that smaller, more flexible intracortical probes would limit gliosis by providing a better mechanical match with surrounding tissue. APPROACH: This paper describes the in vivo evaluation of flexible parylene microprobes designed to improve the interface with the adjacent neural tissue to limit gliosis and thereby allow for improved recording longevity. The probes were coated with an ultrafast degrading tyrosine-derived polycarbonate (E5005(2K)) polymer that provides temporary mechanical support for device implantation, yet degrades within 2 h post-implantation. A parametric study of probes of varying dimensions and polymer coating thicknesses were implanted in rat brains. The glial tissue response and neuronal loss were assessed from 72 h to 24 weeks post-implantation via immunohistochemistry. MAIN RESULTS: Experimental results suggest that both probe and polymer coating sizes affect the extent of gliosis. When an appropriate sized coating dimension (100 µm × 100 µm) and small probe (30 µm × 5 µm) was implanted, a minimal post-implantation glial response was observed. No discernible gliosis was detected when compared to tissue where a sham control consisting of a solid degradable polymer shuttle of the same dimensions was inserted. A larger polymer coating (200 µm × 200 µm) device induced a more severe glial response at later time points, suggesting that the initial insertion trauma can affect gliosis even when the polymer shuttle degrades rapidly. A larger degree of gliosis was also observed when comparing a larger sized probe (80 µm × 5 µm) to a smaller probe (30 µm × 5 µm) using the same polymer coating size (100 µm × 100 µm). There was no significant neuronal loss around the implantation sites for most device candidates except the group with largest polymer coating and probe sizes. SIGNIFICANCE: These results suggest that: (1) the degree of mechanical trauma at device implantation and mechanical mismatches at the probe-tissue interface affect long term gliosis; (2) smaller, more flexible probes may minimize the glial response to provide improved tissue biocompatibility when used for chronic neural signal recording; and (3) some degree of glial scarring did not significantly affect neuronal distribution around the probe.

Cortical visual prostheses: from microstimulation to functional percept.

Cortical visual prostheses are intended to restore vision by targeted electrical stimulation of the visual cortex. The perception of spots of light, called phosphenes, resulting from microstimulation of the visual pathway, suggests the possibility of creating meaningful percept made of phosphenes. However, to date electrical stimulation of V1 has still not resulted in perception of phosphenated images that goes beyond punctate spots of light. In this review, we summarize the clinical and experimental progress that has been made in generating phosphenes and modulating their associated perceptual characteristics in human and macaque primary visual cortex (V1). We focus specifically on the effects of different microstimulation parameters on perception and we analyse key challenges facing the generation of meaningful artificial percepts. Finally, we propose solutions to these challenges based on the application of supervised learning of population codes for spatial stimulation of visual cortex.

Potential for thermal damage to the blood-brain barrier during craniotomy: implications for intracortical recording microelectrodes.

OBJECTIVE: Our objective was to determine how readily disruption of the blood-brain barrier (BBB) occurred as a result of bone drilling during a craniotomy to implant microelectrodes in rat cortex. While the phenomenon of heat production during bone drilling is well known, practices to evade damage to the underlying brain tissue are inconsistently practiced and reported in the literature. APPROACH: We conducted a review of the intracortical microelectrode literature to summarize typical approaches to mitigate drill heating during rodent craniotomies. Post mortem skull-surface and transient brain-surface temperatures were experimentally recorded using an infrared camera and thermocouple, respectively. A number of drilling conditions were tested, including varying drill speed and continuous versus intermittent contact. In vivo BBB permeability was assayed 1 h after the craniotomy procedure using Evans blue dye. MAIN RESULTS: Of the reviewed papers that mentioned methods to mitigate thermal damage during craniotomy, saline irrigation was the most frequently cited (in six of seven papers). In post mortem tissues, we observed increases in skull-surface temperature ranging from +3 °C to +21 °C, dependent on drill speed. In vivo, pulsed-drilling (2 s-on/2 s-off) and slow-drilling speeds (1000 r.p.m.) were the most effective methods we studied to mitigate heating effects from drilling, while inconclusive results were obtained with saline irrigation. SIGNIFICANCE: Neuroinflammation, initiated by damage to the BBB and perpetuated by the foreign body response, is thought to play a key role in premature failure of intracortical recording microelectrodes. This study demonstrates the extreme sensitivity of the BBB to overheating caused by bone drilling. To avoid damage to the BBB, the authors recommend that craniotomies be drilled with slow speeds and/or with intermittent drilling with complete removal of the drill from the skull during 'off' periods. While saline alone was ineffective at preventing overheating, its use is still recommended to remove bone dust from the surgical site and to augment other cooling methods.

Inhibition of the cluster of differentiation 14 innate immunity pathway with IAXO-101 improves chronic microelectrode performance.

OBJECTIVE: Neuroinflammatory mechanisms are hypothesized to contribute to intracortical microelectrode failures. The cluster of differentiation 14 (CD14) molecule is an innate immunity receptor involved in the recognition of pathogens and tissue damage to promote inflammation. The goal of the study was to investigate the effect of CD14 inhibition on intracortical microelectrode recording performance and tissue integration. APPROACH: Mice implanted with intracortical microelectrodes in the motor cortex underwent electrophysiological characterization for 16 weeks, followed by endpoint histology. Three conditions were examined: (1) wildtype control mice, (2) knockout mice lacking CD14, and (3) wildtype control mice administered a small molecule inhibitor to CD14 called IAXO-101. MAIN RESULTS: The CD14 knockout mice exhibited acute but not chronic improvements in intracortical microelectrode performance without significant differences in endpoint histology. Mice receiving IAXO-101 exhibited significant improvements in recording performance over the entire 16 week duration without significant differences in endpoint histology. SIGNIFICANCE: Full removal of CD14 is beneficial at acute time ranges, but limited CD14 signaling is beneficial at chronic time ranges. Innate immunity receptor inhibition strategies have the potential to improve long-term intracortical microelectrode performance.

Thinking Small: Progress on Microscale Neurostimulation Technology.

OBJECTIVES: Neural stimulation is well-accepted as an effective therapy for a wide range of neurological disorders. While the scale of clinical devices is relatively large, translational, and pilot clinical applications are underway for microelectrode-based systems. Microelectrodes have the advantage of stimulating a relatively small tissue volume which may improve selectivity of therapeutic stimuli. Current microelectrode technology is associated with chronic tissue response which limits utility of these devices for neural recording and stimulation. One approach for addressing the tissue response problem may be to reduce physical dimensions of the device. "Thinking small" is a trend for the electronics industry, and for implantable neural interfaces, the result may be a device that can evade the foreign body response. MATERIALS AND METHODS: This review paper surveys our current understanding pertaining to the relationship between implant size and tissue response and the state-of-the-art in ultrasmall microelectrodes. A comprehensive literature search was performed using PubMed, Web of Science (Clarivate Analytics), and Google Scholar. RESULTS: The literature review shows recent efforts to create microelectrodes that are extremely thin appear to reduce or even eliminate the chronic tissue response. With high charge capacity coatings, ultramicroelectrodes fabricated from emerging polymers, and amorphous silicon carbide appear promising for neurostimulation applications. CONCLUSION: We envision the emergence of robust and manufacturable ultramicroelectrodes that leverage advanced materials where the small cross-sectional geometry enables compliance within tissue. Nevertheless, future testing under in vivo conditions is particularly important for assessing the stability of thin film devices under chronic stimulation.

A novel flexible cuff-like microelectrode for dual purpose, acute and chronic electrical interfacing with the mouse cervical vagus nerve.

OBJECTIVE: Neural reflexes regulate immune responses and homeostasis. Advances in bioelectronic medicine indicate that electrical stimulation of the vagus nerve can be used to treat inflammatory disease, yet the understanding of neural signals that regulate inflammation is incomplete. Current interfaces with the vagus nerve do not permit effective chronic stimulation or recording in mouse models, which is vital to studying the molecular and neurophysiological mechanisms that control inflammation homeostasis in health and disease. We developed an implantable, dual purpose, multi-channel, flexible 'microelectrode' array, for recording and stimulation of the mouse vagus nerve. APPROACH: The array was microfabricated on an 8 µm layer of highly biocompatible parylene configured with 16 sites. The microelectrode was evaluated by studying the recording and stimulation performance. Mice were chronically implanted with devices for up to 12 weeks. MAIN RESULTS: Using the microelectrode in vivo, high fidelity signals were recorded during physiological challenges (e.g potassium chloride and interleukin-1ß), and electrical stimulation of the vagus nerve produced the expected significant reduction of blood levels of tumor necrosis factor (TNF) in endotoxemia. Inflammatory cell infiltration at the microelectrode 12 weeks of implantation was limited according to radial distribution analysis of inflammatory cells. SIGNIFICANCE: This novel device provides an important step towards a viable chronic interface for cervical vagus nerve stimulation and recording in mice.

Progress in artificial vision through suprachoroidal retinal implants.

Retinal implants have proven their ability to restore visual sensation to people with degenerative retinopathy, characterized by photoreceptor cell death and the retina's inability to sense light. Retinal bionics operate by electrically stimulating the surviving neurons in the retina, thus triggering the transfer of visual sensory information to the brain. Suprachoroidal implants were first investigated in Australia in the 1950s. In this approach, the neuromodulation hardware is positioned between the sclera and the choroid, thus providing significant surgical and safety benefits for patients, with the potential to maintain residual vision combined with the artificial input from the device. Here we review the latest advances and state of the art devices for suprachoroidal prostheses, highlight future technologies and discuss challenges and perspectives towards improved rehabilitation of vision.

The Insertion of Electrodes in the Brain for Electrophysiological Recording or Chronic Stimulation Is Not Associated With Any Biochemically Detectable Neuronal Injury.

OBJECTIVE: The aim of this study was to evaluate the degree of brain tissue injury that could be potentially induced by the introduction of a) microrecording electrodes, b) macrostimulation electrodes, or c) chronic stimulation electrodes. We aimed to evaluate whether the use of five simultaneous microrecording tracks is associated with any brain injury not detectable by conventional imaging such as CT or MRI. MATERIALS AND METHODS: The study included 61 patients who underwent surgery for implantation of 121 DBS leads. In all cases, five simultaneous tracts were utilized for microelectrode recordings. All patients underwent measurements of serum S-100b at specific time points as follows: a) prior to the operation, and b) intraoperatively at specific stages of the procedure: 1) after opening the burr hole, 2) after the insertion of microrecording electrodes, 3) during macrostimulation, 4) at the end of the operation, and 5) on the first postoperative day. RESULTS: The levels of serum S-100B protein remained within the normal range during the entire period of investigation in all patients with the exception of two cases. In both patients, the procedure was complicated by intraparenchymal hemorrhage visible in neuro-imaging. The first patient developed a small intraparenchymal hemorrhage, visible on the postoperative MRI, with no neurological deficit. The second patient experienced a focal epileptic seizure after the insertion of the right DBS chronic lead and the postoperative CT scan revealed a right frontal lobe hemorrhage. CONCLUSION: These results strongly indicate that the insertion of either multiple recording electrodes or the implantation of chronic electrodes in DBS does not increase the risk of brain hemorrhage or of other intracranial complications, and furthermore it does not cause any biochemically detectable brain tissue damage.

Analysis of Al2O3-parylene C bilayer coatings and impact of microelectrode topography on long term stability of implantable neural arrays.

OBJECTIVE: Performance of many dielectric coatings for neural electrodes degrades over time, contributing to loss of neural signals and evoked percepts. Studies using planar test substrates have found that a novel bilayer coating of atomic-layer deposited (ALD) Al2O3 and parylene C is a promising candidate for neural electrode applications, exhibiting superior stability to parylene C alone. However, initial results from bilayer encapsulation testing on non-planar devices have been less positive. Our aim was to evaluate ALD Al2O3-parylene C coatings using novel test paradigms, to rigorously evaluate dielectric coatings for neural electrode applications by incorporating neural electrode topography into test structure design. APPROACH: Five test devices incorporated three distinct topographical features common to neural electrodes, derived from the utah electrode array (UEA). Devices with bilayer (52 nm Al2O3 + 6 µm parylene C) were evaluated against parylene C controls (N ⩾ 6 per device type). Devices were aged in phosphate buffered saline at 67 °C for up to 311 d, and monitored through: (1) leakage current to evaluate encapsulation lifetimes (>1 nA during 5VDC bias indicated failure), and (2) wideband (1-105 Hz) impedance. MAIN RESULTS: Mean-times-to-failure (MTTFs) ranged from 12 to 506 d for bilayer-coated devices, versus 10 to >2310 d for controls. Statistical testing (log-rank test, α = 0.05) of failure rates gave mixed results but favored the control condition. After failure, impedance loss for bilayer devices continued for months and manifested across the entire spectrum, whereas the effect was self-limiting after several days, and restricted to frequencies <100 Hz for controls. These results correlated well with observations of UEAs encapsulated with bilayer and control films. SIGNIFICANCE: We observed encapsulation failure modes and behaviors comparable to neural electrode performance which were undetected in studies with planar test devices. We found the impact of parylene C defects to be exacerbated by ALD Al2O3, and conclude that inferior bilayer performance arises from degradation of ALD Al2O3 when directly exposed to saline. This is an important consideration, given that neural electrodes with bilayer coatings are expected to have ALD Al2O3 exposed at dielectric boundaries that delineate electrode sites. Process improvements and use of different inorganic coatings to decrease dissolution in physiological fluids may improve performance. Testing frameworks which take neural electrode complexities into account will be well suited to reliably evaluate such encapsulation schemes.

Microelectronics, bioinformatics and neurocomputation for massive neuronal recordings in brain circuits with large scale multielectrode array probes.

Deciphering neural network function in health and disease requires recording from many active neurons simultaneously. Developing approaches to increase their numbers is a major neurotechnological challenge. Parallel to recent advances in optical Ca(2+) imaging, an emerging approach consists in adopting complementary-metal-oxide-semiconductor (CMOS) technology to realize MultiElectrode Array (MEA) devices. By implementing signal conditioning and multiplexing circuits, these devices allow nowadays to record from several thousands of single neurons at sub-millisecond temporal resolution. At the same time, these recordings generate very large data streams which become challenging to analyze. Here, at first we shortly review the major approaches developed for data management and analysis for conventional, low-resolution MEAs. We highlight how conventional computational tools cannot be easily up-scaled to very large electrode array recordings, and custom bioinformatics tools are an emerging need in this field. We then introduce a novel approach adapted for the acquisition, compression and analysis of extracellular signals acquired simultaneously from 4096 electrodes with CMOS MEAs. Finally, as a case study, we describe how this novel large scale recording platform was used to record and analyze extracellular spikes from the ganglion cell layer in the wholemount retina at pan-retinal scale following patterned light stimulation.

Current trends in nanomaterial embedded field effect transistor-based biosensor.

Recently, as metal-, polymer-, and carbon-based biocompatible nanomaterials have been increasingly incorporated into biosensing applications, with various nanostructures having been used to increase the efficacy and sensitivity of most of the detecting devices, including field effect transistor (FET)-based devices. These nanomaterial-based methods also became the ideal for the amalgamation of biomolecules, especially for the fabrication of ultrasensitive, low-cost, and robust FET-based biosensors; these are categorically very successful at binding the target specified entities in the confined gated micro-region for high functionality. Furthermore, the contemplation of nanomaterial-based FET biosensors to various applications encompasses the desire for detection of many targets with high selectivity, and specificity. We assess how such devices have empowered the achievement of elevated biosensor performance in terms of high sensitivity, selectivity and low detection limits. We review the recent literature here to illustrate the diversity of FET-based biosensors, based on various kinds of nanomaterials in different applications and sum up that graphene or its assisted composite based FET devices are comparatively more efficient and sensitive with highest signal to noise ratio. Lastly, the future prospects and limitations of the field are also discussed.

Advances in functional electrical stimulation (FES).

This review discusses the advancements that are needed to enhance the effects of electrical stimulation for restoring or assisting movement in humans with an injury/disease of the central nervous system. A complex model of the effects of electrical stimulation of peripheral systems is presented. The model indicates that both the motor and sensory systems are activated by electrical stimulation. We propose that a hierarchical hybrid controller may be suitable for functional electrical stimulation (FES) because this type of controller acts as a structural mimetic of its biological counterpart. Specific attention is given to the neural systems at the periphery with respect to the required electrodes and stimulators. Furthermore, we note that FES with surface electrodes is preferred for the therapy, although there is a definite advantage associated with implantable technology for life-long use. The last section of the review discusses the potential need to combine FES and robotic systems to provide assistance in some cases.

Long-term changes in the material properties of brain tissue at the implant-tissue interface.

OBJECTIVE: Brain tissue undergoes dramatic molecular and cellular remodeling at the implant-tissue interface that evolves over a period of weeks after implantation. The biomechanical impact of such remodeling on the interface remains unknown. In this study, we aim to assess the changes in the mechanical properties of the brain-electrode interface after chronic implantation of a microelectrode. APPROACH: Microelectrodes were implanted in the rodent cortex at a depth of 1 mm for different durations-1 day (n = 4), 10-14 days (n = 4), 4 weeks (n = 4) and 6-8 weeks (n = 7). After the initial duration of implantation, the microelectrodes were moved an additional 1 mm downward at a constant speed of 10 µm s(-1). Forces experienced by the microelectrode were measured during movement and after termination of movement. The biomechanical properties of the interfacial brain tissue were assessed from measured force-displacement curves using two separate models-a two-parameter Mooney-Rivlin hyperelastic model and a viscoelastic model with a second-order Prony series. MAIN RESULTS: Estimated shear moduli using a second-order viscoelastic model increased from 0.5-2.6 kPa (day 1 of implantation) to 25.7-59.3 kPa (after 4 weeks of implantation) and subsequently decreased to 0.8-7.9 kPa after 6-8 weeks of implantation in 6 of the 7 animals. The estimated elastic modulus increased from 4.1-7.8 kPa on the day of implantation to 24-44.9 kPa after 4 weeks. The elastic modulus was estimated to be 6.8-33.3 kPa in 6 of the 7 animals after 6-8 weeks of implantation. The above estimates suggest that the brain tissue surrounding the microelectrode evolves from a stiff matrix with maximal shear and elastic modulus after 4 weeks of implantation into a composite of two different layers with different mechanical properties-a stiff compact inner layer surrounded by softer brain tissue that is biomechanically similar to brain tissue-during the first week of implantation. Tissue micromotion-induced stresses on the microelectrode constituted 12-55% of the steady-state stresses on the microelectrode on the day of implantation (n = 4), 2-21% of the steady-state stresses after 4 weeks of implantation (n = 4), and 4-10% of the steady-state stresses after 6-8 weeks of implantation (n = 7). SIGNIFICANCE: Understanding biomechanical behavior at the brain-microelectrode interface is necessary for the long-term success of implantable neuroprosthetics and microelectrode arrays. Such quantitative physical characterization of the dynamic changes in the electrode-tissue interface will (a) drive the design and development of more mechanically optimal, chronic brain implants, and (b) lead to new insights into key cellular and molecular events such as neuronal adhesion, migration and function in the immediate vicinity of the brain implant.

Neural stimulation for visual rehabilitation: advances and challenges.

Blindness affects tens of million people worldwide and its prevalence constantly increases along with population aging. In some pathologies leading to vision loss, prosthetic approaches are currently the only hope for the patient to recover some visual perception. Here, we review the latest advances in visual prosthetic strategies with their respective strength and weakness. The principle is to electrically stimulate neurons along the visual pathway. Ocular approaches target the remaining retinal cells whereas brain stimulation aims at stimulating higher visual structures directly. Even though ocular approaches are less invasive and easier to implement, brain stimulation can be applied to diseases where the connection between the retina and the brain is lost such as in glaucoma and could therefore benefit to patients with different pathologies. Today, numbers of groups are investigating these strategies and the first devices start being commercialized. However, critical bottlenecks still impair our scientific efforts towards efficient visual implants. These challenges include electrode miniaturization, material optimization, multiplexing of stimulation channels and encoding of visual information into electrical stimuli.

Advances in patch clamp technique: towards higher quality and quantity.

The patch clamp technique, developed in late 1970s, started a new period of experimental cardiac electrophysiology enabling measurement of ionic currents on isolated cardiomyocytes down to the level of single channels. Since that time, the technique has been substantially improved by development of several upgraded modifications providing so far unavailable data (e.g. action potential clamp, dynamic clamp, high-resolution scanning patch clamp), or facilitating the patch clamp technique by increasing its efficiency (planar patch clamp, automated patch clamp). The current review summarizes the leading new patch clamp based techniques used in cardiac cellular electrophysiology, their principles and prominent related papers.