Objective. Intracortical microstimulation of the primary somatosensory cortex (S1) has shown great progress in restoring touch sensations to patients with paralysis. Stimulation parameters such as amplitude, phase duration, and frequency can influence the quality of the evoked percept as well as the amount of charge necessary to elicit a response. Previous studies in V1 and auditory cortices have shown that the behavioral responses to stimulation amplitude and phase duration change across cortical depth. However, this depth-dependent response has yet to be investigated in S1. Similarly, to our knowledge, the response to microstimulation frequency across cortical depth remains unexplored. Approach. To assess these questions, we implanted rats in S1 with a microelectrode with electrode-sites spanning all layers of the cortex. A conditioned avoidance behavioral paradigm was used to measure detection thresholds and responses to phase duration and frequency across cortical depth. Main results. Analogous to other cortical areas, the sensitivity to charge and strength–duration chronaxies in S1 varied across cortical layers. Likewise, the sensitivity to microstimulation frequency was layer dependent. Significance. These findings suggest that cortical depth can play an important role in the fine-tuning of stimulation parameters and in the design of intracortical neuroprostheses for clinical applications.

Although the basal ganglia have been implicated in a growing list of human behaviors, they include some of the least understood nuclei in the brain. For several decades studies have employed numerous methodologies to uncover evidence pointing to the basal ganglia as a hub of both motor and non-motor function. Recently, new electrophysiological characterization of the basal ganglia in humans has become possible through direct access to these deep structures as part of routine neurosurgery. Electrophysiological approaches for identifying non-motor function have the potential to unlock a deeper understanding of pathways that may inform clinical interventions and particularly neuromodulation. Various electrophysiological modalities can also be combined to reveal functional connections between the basal ganglia and traditional structures throughout the neocortex that have been linked to non-motor behavior. Several reviews have previously summarized evidence for non-motor function in the basal ganglia stemming from behavioral, clinical, computational, imaging, and non-primate animal studies; in this review, instead we turn to electrophysiological studies of non-human primates and humans. We begin by introducing common electrophysiological methodologies for basal ganglia investigation, and then we discuss studies across numerous non-motor domains–emotion, response inhibition, conflict, decision-making, error-detection and surprise, reward processing, language, and time processing. We discuss the limitations of current approaches and highlight the current state of the information.

Intracortical microstimulation (ICMS) of the somatosensory cortex (S1) can restore sensory function in patients with paralysis. Studies assessing the stability of ICMS have reported heterogeneous responses across electrodes and over time, potentially hindering the implementation and translatability of these technologies. The foreign body response (FBR) and the encapsulating glial scar have been associated with a decay in chronic performance of implanted electrodes. Moreover, the morphology, intrinsic properties, and function of cells vary across cortical layers, each potentially affecting the sensitivity to ICMS as well as the degree of the FBR across cortical depth. However, layer-by-layer comparisons of the long-term stability of ICMS as well as the extent of the astrocytic glial scar change across cortical layers have not been well explored. Here, we implanted silicon microelectrodes with electrode sites spanning all the layers of S1 in rats. Using a behavioral paradigm, we obtained ICMS detection thresholds from all cortical layers for up to 40 weeks. Our results showed that the sensitivity and long-term performance of ICMS is indeed layer dependent. Overall, detection thresholds decreased during the first 7 weeks post-implantation (WPI). This was followed by a period in which thresholds remained stable or increased depending on the interfacing layer: thresholds in L1 and L6 exhibited the most consistent increases over time, while those in L4 and L5 remained the most stable. Furthermore, histological investigation of the tissue surrounding the electrode showed a biological response of microglia and macrophages which peaked at L1, while the area of the astrocytic glial scar peaked at L2/3. Interestingly, the biological response of these FBR markers is less exacerbated at L4 and L5, suggesting a potential link between the FBR and the long-term stability of ICMS. These findings suggest that interfacing depth can play an important role in the design of chronically stable implantable microelectrodes.

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Intracortical microstimulation (ICMS) has shown promise in restoring quality of life to patients suffering from paralysis, specifically when used in the primary somatosensory cortex (S1). However, these benefits can be hampered by long-term degradation of electrode performance due to the brain’s foreign body response. Advances in microfabrication techniques have allowed for the development of neuroprostheses with subcellular electrodes, which are characterized by greater versatility and a less detrimental immune response during chronic use. These probes are hypothesized to enable more selective, higher-resolution stimulation of cortical tissue with long-term implants. However, microstimulation using physiologically relevant charges with these smaller-scale devices can damage electrode sites and reduce the efficacy of the overall device. Studies have shown promise in bypassing this limitation by spreading the stimulation charge between multiple channels in an implanted electrode array, but to our knowledge the usefulness of this strategy in laminar arrays with electrode sites spanning each layer of the cortex remains unexplored. To investigate the efficacy of simultaneous multi-channel ICMS in electrode arrays with stimulation sites spanning cortical depth, we implanted laminar electrode arrays in the primary somatosensory cortex of rats trained in a behavioral avoidance paradigm. By measuring detection thresholds, we were able to quantify improvements in ICMS performance using a simultaneous multi-channel stimulation paradigm. The charge required per site to elicit detection thresholds was halved when stimulating from two adjacent electrode sites, although the overall charge used by the implant was increased. This reduction in threshold charge was more pronounced when stimulating with more than two channels and lessened with greater distance between stimulating channels. Our findings suggest that these improvements are based on the synchronicity and polarity of each stimulus, leading us to conclude that these improvements in stimulation efficiency per electrode are due to charge summation as opposed to a summation of neural responses to stimulation. Additionally, the per-site charge reductions are seen regardless of the cortical depth of each utilized channel. This evocation of physiological detection thresholds with lower stimulation currents per electrode site has implications for the feasibility of stimulation regimes in future advanced neuroprosthetic devices, which could benefit from reducing the charge output per site.

Highlights: • Electrical microstimulation to modulate neural activity has emerged as a critical tool in brain research, neurotherapeutics, and bidirectional neuroprostheses. • Recent successes in sensory, motor, auditory, visual, and cognitive neuroprostheses demonstrate a need for more focal micro-neuromodulation technologies. • Advances in electronics, optics, and magnetics are leading towards stable, high spatialresolution interfaces. • Advances in neuroprosthetic technologies may one day enable single neuron, whole-brain micro-neuromodulation.

The pancreas is a visceral organ with exocrine functions for digestion and endocrine functions for maintenance of blood glucose homeostasis. In pancreatic diseases such as Type 1 diabetes, islets of the endocrine pancreas become dysfunctional and normal regulation of blood glucose concentration ceases. In healthy individuals, parasympathetic signaling to islets via the vagus nerve, triggers release of insulin from pancreatic β-cells and glucagon from α-cells. Using electrical stimulation to augment parasympathetic signaling may provide a way to control pancreatic endocrine functions and ultimately control blood glucose. Historical data suggest that cervical vagus nerve stimulation recruits many visceral organ systems. Simultaneous modulation of liver and digestive function along with pancreatic function provides differential signals that work to both raise and lower blood glucose. Targeted pancreatic vagus nerve stimulation may provide a solution to minimizing off-target effects through careful electrode placement just prior to pancreatic insertion.

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