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Background: tinnitus is a common and often debilitating condition with limited evidence-based treatment options. Deep brain stimulation (DBS) is an approved treatment modality for certain neurological conditions; its experimental use as a treatment modality for severe tinnitus is novel and beginning to show promise. This systematic review focuses on the current evidence for the safety and efficacy of DBS for treatment of refractory tinnitus. Methods: a systematic search in PubMed and EMBASE was performed to identify peer-reviewed studies on DBS of non-cortical structures for the primary indication of tinnitus treatment. Three studies were identified as meeting these criteria, one of which had two related sub-studies. Results: seven patients with available data who underwent DBS for tinnitus were identified. DBS targets included nucleus accumbens (NAc), ventral anterior limb of the internal capsule (vALIC), caudate nucleus, and the medial geniculate body (MGB) of the thalamus. All studies used the Tinnitus Functional Index (TFI) as a primary outcome measure. DBS of the caudate was most commonly reported (n = 5), with a mean TFI improvement of 23.3 points. Only one subject underwent DBS targeting the NAc/vALIC (extrapolated TFI improvement 46.8) and one subject underwent DBS targeting the MGB (TFI improvement 59 points). Conclusions: DBS is a promising treatment option for refractory subjective tinnitus, with early data, from small patient cohorts in multiple studies, suggesting its safety and efficacy. Further studies with a larger patient population are needed to support this safety and efficacy before implementing this treatment to daily practice. [ABSTRACT FROM AUTHOR]

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments. [ABSTRACT FROM AUTHOR]

Background: tinnitus is a common and often debilitating condition with limited evidence-based treatment options. Deep brain stimulation (DBS) is an approved treatment modality for certain neurological conditions; its experimental use as a treatment modality for severe tinnitus is novel and beginning to show promise. This systematic review focuses on the current evidence for the safety and efficacy of DBS for treatment of refractory tinnitus. Methods: a systematic search in PubMed and EMBASE was performed to identify peer-reviewed studies on DBS of non-cortical structures for the primary indication of tinnitus treatment. Three studies were identified as meeting these criteria, one of which had two related sub-studies. Results: seven patients with available data who underwent DBS for tinnitus were identified. DBS targets included nucleus accumbens (NAc), ventral anterior limb of the internal capsule (vALIC), caudate nucleus, and the medial geniculate body (MGB) of the thalamus. All studies used the Tinnitus Functional Index (TFI) as a primary outcome measure. DBS of the caudate was most commonly reported (n = 5), with a mean TFI improvement of 23.3 points. Only one subject underwent DBS targeting the NAc/vALIC (extrapolated TFI improvement 46.8) and one subject underwent DBS targeting the MGB (TFI improvement 59 points). Conclusions: DBS is a promising treatment option for refractory subjective tinnitus, with early data, from small patient cohorts in multiple studies, suggesting its safety and efficacy. Further studies with a larger patient population are needed to support this safety and efficacy before implementing this treatment to daily practice.

Implantable cell replacement therapies promise to completely restore the function of neural structures, possibly changing how we currently perceive the onset of neurodegenerative diseases. One of the major clinical hurdles for the routine implementation of stem cell therapies is poor cell retention and survival, demanding the need to better understand these mechanisms while providing precise and scalable approaches to monitor these cell-based therapies in both pre-clinical and clinical scenarios. This poses significant multidisciplinary challenges regarding planning, defining the methodology and requirements, prototyping and different stages of testing. Aiming toward an optogenetic neural stem cell implant controlled by a smart wireless electronic frontend, we show how an iterative development methodology coupled with a modular design philosophy can mitigate some of these challenges. In this study, we present a miniaturized, wireless-controlled, modular multisensor platform with fully interfaced electronics featuring three different modules: an impedance analyzer, a potentiostat and an optical stimulator. We show the application of the platform for electrical impedance spectroscopy-based cell monitoring, optical stimulation to induce dopamine release from optogenetically modified neurons and a potentiostat for cyclic voltammetry and amperometric detection of dopamine release. The multisensor platform is designed to be used as an opto-electric headstage for future in vivo animal experiments.

Fundamental neuroscience research and high-performance neuro-prostheses require large-scale brain interfaces with ever-greater spatial resolution across a large cortex coverage, which cannot be achieved with current passive (micro) electrocorticography (ECoG) technologies. In this article, we present an active micro-electrocorticography ($\mu $ ECoG) implant system that circumvents these challenges while achieving significantly lower noise compared to other existing active $\mu $ ECoG arrays. The proposed brain implant system is composed of a flexible, actively multiplexed 256-electrode $\mu $ ECoG array and an incremental- $\Delta \Sigma $ readout integrated circuit (ROIC). The 1 cm $\times $ 1 cm $\mu $ ECoG array was fabricated in a 3- $\mu \text{m}$ IGZO thin-film transistor (TFT) technology on a 15- $\mu \text{m}$ flexible foil and coupled to a 1.25 mm $\times $ 1.25 mm CMOS ROIC fabricated in a 22-nm fully depleted silicon on insulator (FDSOI) process. Due to the 256:16 time-division multiplexing achieved in the electrode array, only 16 multiplexed channels are required in the ROIC to acquire signals from the 256 electrodes simultaneously. By combining TFT multiplexing with newly proposed bulk-DAC (BDAC) feedback in the readout channel, we can integrate and address 4 $\times $ more electrodes than other passive arrays, achieve >10 $\times $ less noise than existing active arrays, and obtain >2 $\times $ effective channel area reduction in the ROIC while maintaining comparable electrical performance over current state-of-the-art ($\mu $)ECoG readouts. [ABSTRACT FROM AUTHOR]

Hydrocephalus (HCP) is a neurological disease resulting from the disruption of the cerebrospinal fluid (CSF) drainage mechanism in the brain. Reliable draining of CSF is necessary to treat hydrocephalus. The current standard of care is an implantable shunt system. However, shunts have a high failure rate caused by mechanical malfunctions, obstructions, infection, blockage, breakage, and over or under drainage. Such shunt failures can be difficult to diagnose due to nonspecific systems and the lack of long-term implantable pressure sensors. Herein, we present the evaluation of a fully realized and passive implantable valve made of hydrogel to restore CSF draining operations within the cranium. The valves are designed to achieve a non-zero cracking pressure and no reverse flow leakage by using hydrogel swelling. The valves were evaluated in a realistic fluidic environment with ex vivo CSF and brain tissue. They display a successful operation across a range of conditions, with negligible reverse flow leakage. Additionally, a novel wireless pressure sensor was incorporated alongside the valve for in situ intracranial pressure measurement. The wireless pressure sensor successfully replicated standard measurements. Those evaluations show the reproducibility of the valve and sensor functions and support the system's potential as a chronic implant to replace standard shunt systems. [ABSTRACT FROM AUTHOR]

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant's track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3–6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration. [ABSTRACT FROM AUTHOR]

Technological advancements in electronics and micromachining now allow the development of discrete wireless brain implantable micro-devices. Applications of such devices include stimulation or sensing and could enable direct placement near regions of interest within the brain without the need for electrode leads or separate battery compartments that are at increased risk of breakage and infection. Clinical use of leadless brain implants is accompanied by novel risks, such as migration of the implant. Additionally, the encapsulation material of the implants plays an important role in mitigating unwanted tissue reactions. These risks have the potential to cause harm or reduce the service of life of the implant. In the present study, we have assessed post-implantation tissue reaction and migration of borosilicate glass-encapsulated micro-implants within the cortex of the brain. Twenty borosilicate glass-encapsulated devices (2 × 3.5 × 20 mm) were implanted into the parenchyma of 10 sheep for 6 months. Radiographs were taken directly post-surgery and at 3 and 6 months. Subsequently, sheep were euthanized, and GFAP and IBA-1 histological analysis was performed. The migration of the implants was tracked by reference to two stainless steel screws placed in the skull. We found no significant difference in fluoroscopy intensity of GFAP and a small difference in IBA-1 between implanted tissue and control. There was no glial scar formation found at the site of the implant’s track wall. Furthermore, we observed movement of up to 4.6 mm in a subset of implants in the first 3 months of implantation and no movement in any implant during the 3–6-month period of implantation. Subsequent histological analysis revealed no evidence of a migration track or tissue damage. We conclude that the implantation of this discrete micro-implant within the brain does not present additional risk due to migration.

This article presents the integration of a 32-channel neuromodulation system on chip (SoC) that is developed for chronic implantation in humans. The application-specific integrated circuit (ASIC) offers low-noise recording, a state-of-the-art (SotA) neurostimulator capable of both current- and voltage-controlled stimulation with high-voltage compliance, on-chip 16-bit data digitization as well as safety features such as electrode impedance estimation and charge balancing. The chip communicates through two distinct SPI interfaces for independent command and data transfer. Thus, the developed system constitutes a fully digital, bidirectional 32-channel interface to the brain. [ABSTRACT FROM AUTHOR]

Modern neuromodulation systems typically provide a large number of recording and stimulation channels, which reduces the available power and area budget per channel. To maintain the necessary input-referred noise performance despite growingly rigorous area constraints, chopped neural front-ends are often the modality of choice, as chopper-stabilization allows to simultaneously improve (1/f) noise and area consumption. The resulting issue of a drastically reduced input impedance has been addressed in prior art by impedance boosters based on voltage buffers at the input. These buffers precharge the large input capacitors, reduce the charge drawn from the electrodes and effectively boost the input impedance. Offset on these buffers directly translates into charge-transfer to the electrodes, which can accelerate electrode aging. To tackle this issue, a voltage buffer with ultra-low time-averaged offset is proposed, which cancels offset by periodic reconfiguration, thereby minimizing unintended charge transfer. This article explains the background and circuit design in detail and presents measurement results of a prototype implemented in a 180 nm HV CMOS process. The measurements confirm that signal-independent, buffer offset induced charge transfer occurs and can be mitigated by the presented buffer reconfiguration without adversely affecting the operation of the input impedance booster. The presented neural recorder front-end achieves state of the art performance with an area consumption of 0.036 mm2, an input referred noise of 1.32 μVrms (1 to 200 Hz) and 3.36 μVrms (0.2 to 10 kHz), power consumption of 13.7 μW from 1.8 V supply, as well as CMRR and PSRR ≥ 83 dB at 50 Hz. [ABSTRACT FROM AUTHOR]

The presented 16-channel Δ-modulated neural analog-to-digital converter (ADC) exhibits tolerance to input dc offsets of any value, up to the supply voltage. It employs a dynamic differential-difference comparator architecture with a super-GΩ input impedance ensuring negligible gate-leakage current and well-matched differential inputs resulting in more than 78 dB of rejection of common-mode signals and artifacts. The all-digital nature of the presented Δ-ADC enables sampling of input signals at high oversampling ratios (OSRs) making the front-end immune to stimulation artifacts with differential amplitudes up to a limit that is scalable by the OSR (e.g., 10 mVPP at OSR = 10 k). Moreover, it allows the Δ-ADC to linearly scale down the power consumption required by the application’s recording bandwidth. The oversampled Δ-ADC achieves an effective number of bits (ENOB) of 9.7-bit and 2.6-μ VRMS integrated input-referred noise over 1 Hz to 500-Hz bandwidth. It uses no large passives or statically biased circuits, such as operational amplifiers (Opamps) saving both channel area (0.011 mm2) and power consumption (0.99 μW). Experimentally measured results validate the key features of the design and include in vivo recordings in freely moving guinea pigs. The fabricated prototype system-on-a-chip (SoC) hosts an array of 16-channel neural-ADC with in-channel digitally programmable high-compliance current-mode biphasic stimulators as well as wireless circuitry for data communication and power/command reception. [ABSTRACT FROM AUTHOR]

Hydrocephalus (HCP) is a neurological disease resulting from the disruption of the cerebrospinal fluid (CSF) drainage mechanism in the brain. Reliable draining of CSF is necessary to treat hydrocephalus. The current standard of care is an implantable shunt system. However, shunts have a high failure rate caused by mechanical malfunctions, obstructions, infection, blockage, breakage, and over or under drainage. Such shunt failures can be difficult to diagnose due to nonspecific systems and the lack of long-term implantable pressure sensors. Herein, we present the evaluation of a fully realized and passive implantable valve made of hydrogel to restore CSF draining operations within the cranium. The valves are designed to achieve a non-zero cracking pressure and no reverse flow leakage by using hydrogel swelling. The valves were evaluated in a realistic fluidic environment with ex vivo CSF and brain tissue. They display a successful operation across a range of conditions, with negligible reverse flow leakage. Additionally, a novel wireless pressure sensor was incorporated alongside the valve for in situ intracranial pressure measurement. The wireless pressure sensor successfully replicated standard measurements. Those evaluations show the reproducibility of the valve and sensor functions and support the system’s potential as a chronic implant to replace standard shunt systems.

Near-field inductively coupled wireless power transfer (WPT) system has been extensively utilized for brain implant applications. Still, the efficient and reliable delivery of power is challenging as the received power varies due to different variabilities between the transmitter (TX) and the receiver (RX) coils. A closed-loop adaptive control system utilizing load shift keying, designed in the 0.5 µm standard CMOS process for providing the required power to the implant load compensating for these discrepancies is proposed in this paper. Both the proposed TX and the RX coils are fabricated using FR4 substrate having the dimensions of 10 × 10 mm and 5 × 5 mm, respectively. By changing the supply voltage of the power amplifier, this adaptive closed-loop system regulates the transmitted power to deliver 5.83 mW of power to the load, which is the approximate mid-point of the threshold window. The system achieves power transfer efficiencies of 9% and 8% at 8 mm distance through the air and the tissue media, respectively. Preliminary results show that the miniaturized WPT module with the feedback-loop achieves 8% and 3% of efficiency improvement for 8 mm distance between the TX and the RX coils, compared to the open-loop counterparts. [ABSTRACT FROM AUTHOR]

When designing electrodes and probes for brain–machine interfaces, one of the challenges faced involves minimizing the brain-tissue response, which would otherwise create an environment that is detrimental for the accurate functioning of such probes. Following the implantation process, the brain reacts with a sterile inflammation response and resulting astrocytic glial scar formation, potentially resulting in neuronal cell loss around the implantation site. Such alterations in the naïve brain tissue can hinder both the quality of neuronal recordings, and the efficacy of deep-brain stimulation. In this study, we chronically implanted a glass-supported polyimide microelectrode in the dorsolateral striatum of Sprague–Dawley rats. The effect of high-frequency stimulation (HFS) was investigated using c-fos immunoreactivity techniques. GFAP and ED1 immunohistochemistry were used to analyze the brain-tissue response. No changes in c-fos expression were found for either the acute or chronic stimulus groups; although a c-fos expression was found along the length of the implantation trajectory, following chronic implantation of our stiffened polyimide microelectrode. Furthermore, we also observed the formation of a glial scar around the microelectrode, with an accompanying low number of inflammation cells. Histological and statistical analysis of NeuN-positive cells did not demonstrate a pronounced “kill zone” with accompanying neuronal cell death around the implantation site, neither on the polymer side, nor on the glass side of the PI-glass probe.

Closed-loop neuromodulation for the treatment of neurological disorders requires monitoring of the brain activity uninterruptedly even during neurostimulation. This article presents a bidirectional 32-channel CMOS neural interface that can record neural activity during stimulation. Each channel consists of a dc-coupled $\Delta ^{2} \Sigma $ -modulated analog-to-digital converter (neural-ADC), which records slow potentials (< 0.1 Hz) while accommodating rail-to-rail dc offset using a spectrum-shaping front-end. This front-end equalizes the neural signal spectrum before signal quantization, which reduces the energy consumption and silicon area. Upon detection of a large artifact by an in-channel event-triggered digital block, the modulator feedback DAC tracks the artifact with step sizes incrementing in a radix-2 exponential form, preventing the neural-ADC from saturation. Upon tracking the artifact, the multi-bit DAC step size is reduced to zoom into the input neural signal at the highest recording resolution. The modulator’s multi-bit DAC is reused in a time-shared fashion as a current-mode stimulator with no area overhead. The $\Delta ^{2} \Sigma $ -ADC consumes 1.7 $\mu \text{W}$ from 0.6-V/1.2-V digital/analog supplies and time-shares the modulator’s feedback DAC as the multi-bit current-mode stimulator operating at 3.3 V. The ADC occupies a silicon area of 0.023 mm2 in the 130-nm CMOS and achieves a signal-to-noise-and-distortion ratio (SNDR) of 70 dB over the 500-Hz bandwidth and an equivalent noise efficiency factor (NEF) of 2.86 without a stand-alone front-end amplifier. The 32-channel bidirectionally interfacing prototype is validated in the in vivo whole brain of a rodent. [ABSTRACT FROM AUTHOR]

When designing electrodes and probes for brain–machine interfaces, one of the challenges faced involves minimizing the brain-tissue response, which would otherwise create an environment that is detrimental for the accurate functioning of such probes. Following the implantation process, the brain reacts with a sterile inflammation response and resulting astrocytic glial scar formation, potentially resulting in neuronal cell loss around the implantation site. Such alterations in the naïve brain tissue can hinder both the quality of neuronal recordings, and the efficacy of deep-brain stimulation. In this study, we chronically implanted a glass-supported polyimide microelectrode in the dorsolateral striatum of Sprague–Dawley rats. The effect of high-frequency stimulation (HFS) was investigated using c-fos immunoreactivity techniques. GFAP and ED1 immunohistochemistry were used to analyze the brain-tissue response. No changes in c-fos expression were found for either the acute or chronic stimulus groups; although a c-fos expression was found along the length of the implantation trajectory, following chronic implantation of our stiffened polyimide microelectrode. Furthermore, we also observed the formation of a glial scar around the microelectrode, with an accompanying low number of inflammation cells. Histological and statistical analysis of NeuN-positive cells did not demonstrate a pronounced "kill zone" with accompanying neuronal cell death around the implantation site, neither on the polymer side, nor on the glass side of the PI-glass probe. [ABSTRACT FROM AUTHOR]

Highlights • SECOND is a Matlab-based program that quantifies immunohistochemistry data. • Region of interest (ROI), contrast adjustment, and exclusion data is input by users. • Mean intensity (and other metrics) as a function of distance from the ROI is output. • The user interface provides intuitive tools, allowing for a rapid learning curve. • The primary benefit of SECOND is its efficiency and portability to other groups. Abstract Background Brain-implanted devices, including intracortical microelectrodes, are used in neuroscience applications ranging from research to rehabilitation and beyond. Significant efforts are focused on developing new device designs and insertion strategies that mitigate initial trauma and subsequent neuroinflammation that occurs as a result of implantation. A frequently published metric is the neuroinflammatory response quantified as a function of distance from the interface edge, using fluorescent immunohistochemical markers. New method Here, we sought to develop a graphical user interface software in Matlab to provide an objective, repeatable, and easy-to-use method for analyzing fluorescence immunohistochemistry images of neuroinflammation. The user interface allows for efficient batch-processing and review of images, and incorporates zoom and contrast features to improve the accuracy of identifying the 'region of interest' (ROI). Results The software was validated against previously published results and demonstrated equivalent scientific conclusions. Furthermore, a comparison between novice and expert users demonstrated consistency across levels of training and a rapid learning-curve. Comparison with existing method(s) Existing methods published in the intracortical microelectrode literature include a wide variety of procedures within ImageJ and Matlab. However, specific procedural details are often lacking. Conclusions The distribution of the methodology may promote efficiency and reproducibility across the field seeking to characterize the tissue response to implanted neural interfaces. It may also serve as a template for researchers seeking to perform other types of histological quantification as a function of distance from an ROI. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a long-term future scenario model of the brain implant industry that can be used for the industrial policy and corporate strategy. There are many discussions about the possibility of the brain science industry as a future core industry, but researches on specific industrial development policies and corporate strategy fields are very lacking. This is because this field has not yet accumulated the necessary information to create industrial growth policies or corporate strategies. In order to overcome these limitations, this study developed future scenarios using the system dynamics model for the brain implant industry and proposed a strategy suitable for each scenario. This study can be used as the main data for the policy development of the brain science industry and the strategy development in individual companies. There is a need to study the signal that can identify the future scenario of global market development in the future. [ABSTRACT FROM AUTHOR]

First, existing commercially available open-loop and closed-loop implantable neurostimulators are reviewed and compared in terms of their targeted application, physical size, system-level features, and performance as a medical device. Next, signal processing algorithms as the primary strength point of the closed-loop neurostimulators are reviewed, and various design and implementation requirements and trade-offs are discussed in details along with quantitative examples. The review results in a set of guidelines for algorithm selection and evaluation. Second, the implementation of an inductively-powered seizure-predicting microsystem for monitoring and treatment of intractable epilepsy is presented. The miniaturized system is comprised of two miniboards and a power receiver coil. The first board hosts a 24-channel neurostimulator system on chip [15] fabricated in a 0.13\;\mu \textm CMOS technology and performs neural recording, on-chip digital signal processing, and electrical stimulation. The second board communicates recorded brain signals as well as signal processing results wirelessly. The multilayer flexible coil receives inductively-transmitted power. The system is sized at 2 $\times$ 2 \times$ 0.7 \text{cm}^3 and weighs 6 g. The approach is validated in the control of chronic seizures in vivo in freely moving rats. [ABSTRACT FROM PUBLISHER]