The complexity of the nervous system invites continued research exploring ways to modulate function, repair damage, or integrate with signals. While each of these areas includes decades of research, there continues to be development of novel approaches and an increase of knowledge in each. The goal of the current Research Topic is to solicit original research articles that address one or more of these research areas. Articles in this topic may cover a variety of areas, ranging from neuromodulation using ultrasound to novel techniques for peripheral nerve repair to ways in which microelectrodes may be modified or treated in order to improve biocompatibility. Ideally, submissions will pair novel techniques with an evaluation of their biological impact.

West Virginia University

The University of Utah

University of Pittsburgh

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Frontiers in Neuroscience

Neural Technology

Frontiers in Human Neuroscience

Brain Imaging and Stimulation

Brain-Computer Interfaces

Biocompatibility of Implanted Devices, Modulation, and Repair in the Nervous System

Editorial: Biocompatibility of implanted devices, modulation, and repair in the nervous system

IntroductionAvailable evidence suggests that as we age, our brain and immune system undergo changes that increase our susceptibility to injury, inflammation, and neurodegeneration. Since a significant portion of the potential patients treated with a microelectrode-based implant may be older, it is important to understand the recording performance of such devices in an aged population.</sec>MethodsWe studied the chronic recording performance and the foreign body response (FBR) to a clinically used microelectrode array implanted in the cortex of 18-month-old Sprague Dawley rats.</sec>Results and discussionTo the best of our knowledge, this is the first preclinical study of its type in the older mammalian brain. Here, we show that single-unit recording performance was initially robust then gradually declined over a 12-week period, similar to what has been previously reported using younger adult rats and in clinical trials. In addition, we show that FBR biomarker distribution was similar to what has been previously described for younger adult rats implanted with multi-shank recording arrays in the motor cortex. Using a quantitative immunohistochemcal approach, we observed that the extent of astrogliosis and tissue loss near the recording zone was inversely related to recording performance. A comparison of recording performance with a younger cohort supports the notion that aging, in and of itself, is not a limiting factor for the clinical use of penetrating microelectrode recording arrays for the treatment of certain CNS disorders.</sec>

Introduction: Available evidence suggests that as we age, our brain and immune system undergo changes that increase our susceptibility to injury, inflammation, and neurodegeneration. Since a significant portion of the potential patients treated with a microelectrode-based implant may be older, it is important to understand the recording performance of such devices in an aged population.Methods: We studied the chronic recording performance and the foreign body response (FBR) to a clinically used microelectrode array implanted in the cortex of 18-month-old Sprague Dawley rats.Results and discussion: To the best of our knowledge, this is the first preclinical study of its type in the older mammalian brain. Here, we show that single-unit recording performance was initially robust then gradually declined over a 12-week period, similar to what has been previously reported using younger adult rats and in clinical trials. In addition, we show that FBR biomarker distribution was similar to what has been previously described for younger adult rats implanted with multi-shank recording arrays in the motor cortex. Using a quantitative immunohistochemcal approach, we observed that the extent of astrogliosis and tissue loss near the recording zone was inversely related to recording performance. A comparison of recording performance with a younger cohort supports the notion that aging, in and of itself, is not a limiting factor for the clinical use of penetrating microelectrode recording arrays for the treatment of certain CNS disorders.

Advanced age is not a barrier to chronic intracortical single-unit recording in rat cortex

Intracortical recordings can be used to voluntarily control external devices via brain-machine interfaces (BMI). Multiple factors, including the foreign body response (FBR), limit the stability of these neural signals over time. Current clinically approved devices consist of multi-electrode arrays with a single electrode site at the tip of each shank, confining the recording interface to a single layer of the cortex. Advancements in manufacturing technology have led to the development of high-density electrodes that can record from multiple layers. However, the long-term stability of neural recordings and the extent of neuronal cell loss around the electrode across different cortical depths have yet to be explored. To answer these questions, we recorded neural signals from rats chronically implanted with a silicon-substrate microelectrode array spanning the layers of the cortex. Our results show the long-term stability of intracortical recordings varies across cortical depth, with electrode sites around L4-L5 having the highest stability. Using machine learning guided segmentation, our novel histological technique, DeepHisto, revealed that the extent of neuronal cell loss varies across cortical layers, with L2/3 and L4 electrodes having the largest area of neuronal cell loss. These findings suggest that interfacing depth plays a major role in the FBR and long-term performance of intracortical neuroprostheses.

Intracortical recordings can be used to voluntarily control external devices via brain-machine interfaces (BMI). Multiple factors, including the foreign body response (FBR), limit the stability of these neural signals over time. Current clinically approved devices consist of multi-electrode arrays with a single electrode site at the tip of each shank, confining the recording interface to a single layer of the cortex. Advancements in manufacturing technology have led to the development of high-density electrodes that can record from multiple layers. However, the long-term stability of neural recordings and the extent of neuronal cell loss around the electrode across different cortical depths have yet to be explored. To answer these questions, we recorded neural signals from rats chronically implanted with a silicon-substrate microelectrode array spanning the layers of the cortex. Our results show the long-term stability of intracortical recordings varies across cortical depth, with electrode sites around L4-L5 having the highest stability. Using machine learning guided segmentation, our novel histological technique, DeepHisto, revealed that the extent of neuronal cell loss varies across cortical layers, with L2/3 and L4 electrodes having the largest area of neuronal cell loss. These findings suggest that interfacing depth plays a major role in the FBR and long-term performance of intracortical neuroprostheses.

Layer-dependent stability of intracortical recordings and neuronal cell loss

The retinal structural changes after subretinal implantation of three-dimensional (3D) microelectrodes were investigated in a mini pig. Three types of electrode were implanted into the subretinal spaces of nine mini pigs: 75-μm-high 3D electrodes on a 200-μm-thick right-angled polydimethylsiloxane (PDMS) substrate (group 1); a 140-μm-thick sloped PDMS substrate without electrodes (group 2); and a 140-μm-thick sloped PDMS substrate with 20-μm-high 3D electrodes (group 3). One mini pig was used as a control. Spectral domain–optical coherence tomography (SD–OCT) images were obtained at baseline and 2, 6, and 12 weeks post-surgery. Retinal specimens were immunostained using a tissue-clearing method 3 months post-implantation. The 75-μm-high 3D electrodes progressively penetrated the inner nuclear layer (INL) and touched the inner plexiform layer (IPL) 2 weeks post-surgery. At 6 weeks post-operatively, the electrodes were in contact with the nerve-fiber layer, accompanied by a severe fibrous reaction. In the other groups, the implants remained in place without subretinal migration. Immunostaining showed that retinal ganglion and bipolar cells were preserved without fibrosis over the retinal implants in groups 2 and 3 during the 12-week implantation period. In summary, SD–OCT and immunohistology results showed differences in the extent of reactions, such as fibrosis over the implants and penetration of the electrodes into the inner retinal layer depending on different types of electrodes. A sloped substrate performed better than a right-angled substrate in terms of retinal preservation over the implanted electrodes. The 20-μm-high electrodes showed better structural compatibility than the 75-μm-high 3D electrodes. There was no significant difference between the results of sloped implants without electrodes and 20-μm-high 3D electrodes, indicating that the latter had no adverse effects on retinal tissue.

The retinal structural changes after subretinal implantation of three-dimensional (3D) microelectrodes were investigated in a mini pig. Three types of electrode were implanted into the subretinal spaces of nine mini pigs: 75-&#x3bc;m-high 3D electrodes on a 200-&#x3bc;m-thick right-angled polydimethylsiloxane (PDMS) substrate (group 1); a 140-&#x3bc;m-thick sloped PDMS substrate without electrodes (group 2); and a 140-&#x3bc;m-thick sloped PDMS substrate with 20-&#x3bc;m-high 3D electrodes (group 3). One mini pig was used as a control. Spectral domain&#x2013;optical coherence tomography (SD&#x2013;OCT) images were obtained at baseline and 2, 6, and 12 weeks post-surgery. Retinal specimens were immunostained using a tissue-clearing method 3 months post-implantation. The 75-&#x3bc;m-high 3D electrodes progressively penetrated the inner nuclear layer (INL) and touched the inner plexiform layer (IPL) 2 weeks post-surgery. At 6 weeks post-operatively, the electrodes were in contact with the nerve-fiber layer, accompanied by a severe fibrous reaction. In the other groups, the implants remained in place without subretinal migration. Immunostaining showed that retinal ganglion and bipolar cells were preserved without fibrosis over the retinal implants in groups 2 and 3 during the 12-week implantation period. In summary, SD&#x2013;OCT and immunohistology results showed differences in the extent of reactions, such as fibrosis over the implants and penetration of the electrodes into the inner retinal layer depending on different types of electrodes. A sloped substrate performed better than a right-angled substrate in terms of retinal preservation over the implanted electrodes. The 20-&#x3bc;m-high electrodes showed better structural compatibility than the 75-&#x3bc;m-high 3D electrodes. There was no significant difference between the results of sloped implants without electrodes and 20-&#x3bc;m-high 3D electrodes, indicating that the latter had no adverse effects on retinal tissue.

Structural changes in the retina after implantation of subretinal three-dimensional implants in mini pigs

AimElectrodes that provide brain to machine or computer interfacing must survive the lifetime of the person to be considered an acceptable prosthetic. The electrodes may be external such as with electroencephalographic (EEG), internal extracortical such as electrocorticographic (ECoG) or intracortical.</sec>MethodsMost intracortical electrodes are placed close to the neuropil being recorded and do not survive years of recording. However, the Neurotrophic Electrode is placed within the cortex and the neuropil grows inside and through the hollow tip of the electrode and is thus trapped inside. Highly flexible coiled lead wires minimize the strain on the electrode tip. Histological analysis includes immunohistochemical detection of neurofilaments and the absence of gliosis.</sec>ResultsThis configuration led to a decade long recording in this locked-in person. At year nine, the neural activity underwent conditioning experiments indicating that the neural activity was functional and not noise. This paper presents data on the histological analysis of the tissue inside the electrode tip after 13 years of implantation.</sec>ConclusionThis paper is a singular example of histological analysis after a decade of recording. The histological analysis laid out herein is strong evidence that the brain can grow neurites into the electrode tip and record for a decade. This is profoundly important in the field of brain to machine or computer interfacing by implying that long term electrodes should incorporate some means of growing the neuropil into the electrode rather than placing the electrode into the neuropil.</sec>

Aim: Electrodes that provide brain to machine or computer interfacing must survive the lifetime of the person to be considered an acceptable prosthetic. The electrodes may be external such as with electroencephalographic (EEG), internal extracortical such as electrocorticographic (ECoG) or intracortical.Methods: Most intracortical electrodes are placed close to the neuropil being recorded and do not survive years of recording. However, the Neurotrophic Electrode is placed within the cortex and the neuropil grows inside and through the hollow tip of the electrode and is thus trapped inside. Highly flexible coiled lead wires minimize the strain on the electrode tip. Histological analysis includes immunohistochemical detection of neurofilaments and the absence of gliosis.Results: This configuration led to a decade long recording in this locked-in person. At year nine, the neural activity underwent conditioning experiments indicating that the neural activity was functional and not noise. This paper presents data on the histological analysis of the tissue inside the electrode tip after 13 years of implantation.Conclusion: This paper is a singular example of histological analysis after a decade of recording. The histological analysis laid out herein is strong evidence that the brain can grow neurites into the electrode tip and record for a decade. This is profoundly important in the field of brain to machine or computer interfacing by implying that long term electrodes should incorporate some means of growing the neuropil into the electrode rather than placing the electrode into the neuropil.