A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation.

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.

Intracortical microstimulation of human somatosensory cortex is sufficient to induce perceptual biases.

Time-order error, a psychophysical phenomenon in which the duration in between successive stimuli alters perception, has been studied for decades by neuroscientists and psychologists. To date, however, the locus of these effects is unknown. We use intracortical microstimulation of somatosensory cortex in humans as a tool to bypass initial stages of processing and restrict the possible locations that signals could be modified. We find that, using both amplitude discrimination and magnitude estimation paradigms, intracortical microstimulation reliably evoked time-order errors across all participants. Points of subjective equality were symmetrically shifted during amplitude discrimination experiments and the intensity of a successive stimulus was perceived as being more intense when compared to single stimulus trials in magnitude estimation experiments. The error was reduced for both paradigms at longer inter-stimulus intervals. These results show that direct activation of primary somatosensory cortex is sufficient to induce time-order errors.

Microstimulation of human somatosensory cortex evokes task-dependent, spatially patterned responses in motor cortex.

The primary motor (M1) and somatosensory (S1) cortices play critical roles in motor control but the signaling between these structures is poorly understood. To fill this gap, we recorded - in three participants in an ongoing human clinical trial (NCT01894802) for people with paralyzed hands - the responses evoked in the hand and arm representations of M1 during intracortical microstimulation (ICMS) in the hand representation of S1. We found that ICMS of S1 activated some M1 neurons at short, fixed latencies consistent with monosynaptic activation. Additionally, most of the ICMS-evoked responses in M1 were more variable in time, suggesting indirect effects of stimulation. The spatial pattern of M1 activation varied systematically: S1 electrodes that elicited percepts in a finger preferentially activated M1 neurons excited during that finger's movement. Moreover, the indirect effects of S1 ICMS on M1 were context dependent, such that the magnitude and even sign relative to baseline varied across tasks. We tested the implications of these effects for brain-control of a virtual hand, in which ICMS conveyed tactile feedback. While ICMS-evoked activation of M1 disrupted decoder performance, this disruption was minimized using biomimetic stimulation, which emphasizes contact transients at the onset and offset of grasp, and reduces sustained stimulation.

Tessellation of artificial touch via microstimulation of human somatosensory cortex.

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participant's hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multichannel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands.

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant's ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

Sensory computations in the cuneate nucleus of macaques.

Tactile nerve fibers fall into a few classes that can be readily distinguished based on their spatiotemporal response properties. Because nerve fibers reflect local skin deformations, they individually carry ambiguous signals about object features. In contrast, cortical neurons exhibit heterogeneous response properties that reflect computations applied to convergent input from multiple classes of afferents, which confer to them a selectivity for behaviorally relevant features of objects. The conventional view is that these complex response properties arise within the cortex itself, implying that sensory signals are not processed to any significant extent in the two intervening structures-the cuneate nucleus (CN) and the thalamus. To test this hypothesis, we recorded the responses evoked in the CN to a battery of stimuli that have been extensively used to characterize tactile coding in both the periphery and cortex, including skin indentations, vibrations, random dot patterns, and scanned edges. We found that CN responses are more similar to their cortical counterparts than they are to their inputs: CN neurons receive input from multiple classes of nerve fibers, they have spatially complex receptive fields, and they exhibit selectivity for object features. Contrary to consensus, then, the CN plays a key role in processing tactile information.

Chronic Use of a Sensitized Bionic Hand Does Not Remap the Sense of Touch.

Electrical stimulation of tactile nerve fibers that innervated an amputated hand results in vivid sensations experienced at a specific location on the phantom hand, a phenomenon that can be leveraged to convey tactile feedback through bionic hands. Ideally, electrically evoked sensations would be experienced on the appropriate part of the hand: touch with the bionic index fingertip, for example, would elicit a sensation experienced on the index fingertip. However, the perceived locations of sensations are determined by the idiosyncratic position of the stimulating electrode in the nerve and thus are difficult to predict or control. This problem could be circumvented if perceived sensations shifted over time to become consistent with the position of the sensor that triggers them. We show that, after long-term use of a neuromusculoskeletal prosthesis that featured a mismatch between the sensor location and the resulting tactile experience, the perceived location of the touch did not change.

Effect of scanning speed on texture-elicited vibrations.

To sense the texture of a surface, we run our fingers across it, which leads to the elicitation of skin vibrations that depend both on the surface and on exploratory parameters, particularly scanning speed. The transduction and processing of these vibrations mediate the ability to discern fine surface features. The objective of the present study is to characterize the effect of changes in scanning speed on texture-elicited vibrations to better understand how the exploratory movements shape the neuronal representation of texture. To this end, we scanned a variety of textures across the fingertip of human participants at a variety of speeds (10-160 mm s-1) while measuring the resulting vibrations using a laser Doppler vibrometer. First, we found that the intensity of the vibrations-as indexed by root-mean-square velocity-increases with speed but that the skin displacement remains constant. Second, we found that the frequency composition of the vibrations shifts systematically to higher frequencies with increases in scanning speed. Finally, we show that the speed-dependent shift in frequency composition accounts for the speed-dependent change in intensity.

Lamina-specific population encoding of cutaneous signals in the spinal dorsal horn using multi-electrode arrays.

KEY POINTS: Traditional, widely used in vivo electrophysiological techniques for the investigation of spinal processing of somatosensory information fail to account for the diverse functions of each lamina. To overcome this oversimplification, we have used multi-electrode arrays, in vivo, to simultaneously record neuronal activity across all laminae of the spinal dorsal horn. Multi-electrode arrays are sensitive enough to detect lamina- and region-specific encoding of different subtypes of afferent fibres and to detect short-lived changes in synaptic plasticity as measured by the application of cutaneous electrical stimulation of varying intensity and frequency. Differential encoding of innocuous and noxious thermal and mechanical stimuli were also detected across the laminae with the technique, as were the effects of the application of capsaicin. This new approach to the study of the dorsal spinal cord produces significantly more information per experiment, permitting accelerated research whilst also permitting the effects of pharmacological tools to modulate network responses. ABSTRACT: The dorsal horn (DH) of the spinal cord is a complex laminar structure integrating peripheral signals into the central nervous system. Spinal somatosensory processing is commonly measured electrophysiologically in vivo by recording the activity of individual wide-dynamic-range neurons in the deep DH and extrapolating their behaviour to all cells in every lamina. This fails to account for the specialized processes that occur in each lamina and the considerable heterogeneity in cellular phenotype within and between laminae. Here we overcome this oversimplification by employing linear multi-electrode arrays (MEAs) in the DH of anaesthetized rats to simultaneously measure activity across all laminae. The MEAs, comprising 16 channels, were inserted into the lumbar dorsal horn and peripheral neurons activated electrically via transcutaneous electrodes and ethologically with von Frey hairs (vFHs) or an aluminium heating block. Ascending electrical stimuli showed fibre thresholds with distinct dorsoventral innervation profiles. Wind up was observed across the DH during the C-fibre and post-discharge latencies following 0.5 Hz stimulation. Intrathecal application of morphine (5 ng/50 µl) significantly reduced Aδ- and C-fibre-evoked activity in deep and superficial DH. Light vFHs (≤10 g) predominantly activated intermediate and deep laminae whereas noxious vFHs (26 g) also activated the superficial laminae. Noxious heat (55°C) induced significantly greater activity in the superficial and deep laminae than the innocuous control (30°C). The application of these arrays produced the first description of the processing of innocuous and noxious stimuli throughout the intact DH.

Cancer Chemotherapy in Early Life Significantly Alters the Maturation of Pain Processing.

Advances in pediatric cancer treatment have led to a ten year survival rate greater than 75%. Platinum-based chemotherapies (e.g. cisplatin) induce peripheral sensory neuropathy in adult and pediatric cancer patients. The period from birth through to adulthood represents a period of maturation within nociceptive systems. Here we investigated how cisplatin impacts upon postnatal maturation of nociceptive systems. Neonatal Wistar rats (Postnatal day (P) 7) were injected (i.p.) daily with either vehicle (PBS) or cisplatin (1mg/kg) for five consecutive days. Neither group developed mechanical or thermal hypersensitivity immediately during or after treatment. At P22 the cisplatin group developed mechanical (P < 0.05) and thermal (P < 0.0001) hypersensitivity versus vehicle group. Total DRG or dorsal horn neuronal number did not differ at P45, however there was an increase in intraepidermal nerve fiber density in cisplatin-treated animals at this age. The percentage of IB4+ve, CGRP+ve and NF200+ve DRG neurons was not different between groups at P45. There was an increase in TrkA+ve DRG neurons in the cisplatin group at P45, in addition to increased TrkA, NF200 and vGLUT2 immunoreactivity in the lumbar dorsal horn versus controls. These data highlight the impact pediatric cancer chemotherapy has upon the maturation of pain pathways and later life pain experience.

Age-dependent plasticity in endocannabinoid modulation of pain processing through postnatal development.

Significant age- and experience-dependent remodelling of spinal and supraspinal neural networks occur, resulting in altered pain responses in early life. In adults, endogenous opioid peptide and endocannabinoid (ECs) pain control systems exist which modify pain responses, but the role they play in acute responses to pain and postnatal neurodevelopment is unknown. Here, we have studied the changing role of the ECs in the brainstem nuclei essential for the control of nociception from birth to adulthood in both rats and humans. Using in vivo electrophysiology, we show that substantial functional changes occur in the effect of microinjection of ECs receptor agonists and antagonists in the periaqueductal grey (PAG) and rostroventral medulla (RVM), both of which play central roles in the supraspinal control of pain and the maintenance of chronic pain states in adulthood. We show that in immature PAG and RVM, the orphan receptor, GPR55, is able to mediate profound analgesia which is absent in adults. We show that tissue levels of endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol, within the PAG and RVM are developmentally regulated (using mass spectrometry). The expression patterns and levels of ECs enzymes and receptors were assessed using quantitative PCR and immunohistochemistry. In human brainstem, we show age-related alterations in the expression of key enzymes and receptors involved in ECs function using PCR and in situ hybridisation. These data reveal that significant changes on ECs that to this point have been unknown and which shed new light into the complex neurochemical changes that permit normal, mature responses to pain.