Project description:BackgroundInvasive cortical stimulation (ICS) is a neuromodulation method in which electrodes are implanted on the cortex to deliver chronic stimulation. ICS has been used to treat neurological disorders such as neuropathic pain, epilepsy, movement disorders and tinnitus. Noninvasive neuromodulation methods such as transcranial magnetic stimulation and transcranial electrical stimulation (TES) show great promise in treating some neurological disorders and require no surgery. However, only acute stimulation can be delivered. Epicranial current stimulation (ECS) is a novel concept for delivering chronic neuromodulation through subcutaneous electrodes implanted on the skull. The use of concentric-ring ECS electrodes may allow spatially focused stimulation and offer a less invasive alternative to ICS.ObjectivesDemonstrate ECS proof-of-concept using concentric-ring electrodes in rats and then use a computational model to explore the feasibility and limitations of ECS in humans.MethodsECS concentric-ring electrodes were implanted in 6 rats and pulsatile stimulation delivered to the motor cortex. An MRI based electro-anatomical human head model was used to explore different ECS concentric-ring electrode designs and these were compared with ICS and TES.ResultsConcentric-ring ECS electrodes can selectively stimulate the rat motor cortex. The computational model showed that the concentric-ring ECS electrode design can be optimized to achieve focused cortical stimulation. In general, focality was less than ICS but greater than noninvasive transcranial current stimulation.ConclusionECS could be a promising minimally invasive alternative to ICS. Further work in large animal models and patients is needed to demonstrate feasibility and long-term stability.
Project description:Infrared neural stimulation is a promising tool for stimulating the brain because it can be used to excite with high spatial precision without the need of delivering or inserting any exogenous agent into the tissue. Very few studies have explored its use in the brain, as most investigations have focused on sensory or motor nerve stimulation. Using intravital calcium imaging with the genetically encoded calcium indicator GCaMP6f, here we show that the application of infrared neural stimulation induces intracellular calcium signals in Layer 2/3 neurons in mouse cortex in vivo. The number of neurons exhibiting infrared-induced calcium response as well as the amplitude of those signals are shown to be both increasing with the energy density applied. By studying as well the spatial extent of the stimulation, we show that reproducibility of the stimulation is achieved mainly in the central part of the infrared beam path. Stimulating in vivo at such a degree of precision and without any exogenous chromophores enables multiple applications, from mapping the brain's connectome to applications in systems neuroscience and the development of new therapeutic tools for investigating the pathological brain.
Project description:We have previously shown that INS-fMRI is a rapid method for mapping mesoscale brain networks in the macaque monkey brain. Focal stimulation of single cortical sites led to the activation of connected cortical locations, resulting in a global connectivity map. Here, we have extended this method for mapping brainwide networks following stimulation of single subcortical sites. As a testbed, we focused on the basal nucleus of the amygdala in the macaque monkey. We describe methods to target basal nucleus locations with submillimeter precision, pulse train stimulation methods, and statistical tests for assessing non-random nature of activations. Using these methods, we report that stimulation of precisely targeted loci in the basal nucleus produced sparse and specific activations in the brain. Activations were observed in the insular and sensory association cortices as well as activations in the cingulate cortex, consistent with known anatomical connections. What is new here is that the activations were focal and, in some cases, exhibited shifting topography with millimeter shifts in stimulation site. The precision of the method enables networks mapped from different nearby sites in the basal nucleus to be distinguished. While further investigation is needed to improve the sensitivity of this method, our analyses do support the reproducibility and non-random nature of some of the activations. We suggest that INS-fMRI is a promising method for mapping large-scale cortical and subcortical networks at high spatial resolution.
Project description:Infrared neural stimulation (INS) has been proposed as an alternative method to electrical stimulation because of its spatial selective stimulation. Independent of the mechanism for INS, to translate the method into a device it is important to determine the energy for stimulation required at the target structure. Custom-designed, flat and angle polished fibers, were used to deliver the photons. By rotating the angle polished fibers, the orientation of the radiation beam in the cochlea could be changed. INS-evoked compound action potentials and single unit responses in the central nucleus of the inferior colliculus (ICC) were recorded. X-ray computed tomography was used to determine the orientation of the optical fiber. Maximum responses were observed when the radiation beam was directed towards the spiral ganglion neurons (SGNs), whereas little responses were seen when the beam was directed towards the basilar membrane. The radiant exposure required at the SGNs to evoke compound action potentials (CAPs) or ICC responses was on average 18.9 ± 12.2 or 10.3 ± 4.9 mJ/cm(2), respectively. For cochlear INS it has been debated whether the radiation directly stimulates the SGNs or evokes a photoacoustic effect. The results support the view that a direct interaction between neurons and radiation dominates the response to INS.
Project description:Controlling neuronal activity using implantable neural interfaces constitutes an important tool to understand and develop novel strategies against brain diseases. Infrared neurostimulation is a promising alternative to optogenetics for controlling the neuronal circuitry with high spatial resolution. However, bi-directional interfaces capable of simultaneously delivering infrared light and recording electrical signals from the brain with minimal inflammation have not yet been reported. Here, we have developed a soft fibre-based device using high-performance polymers which are >100-fold softer than conventional silica glass used in standard optical fibres. The developed implant is capable of stimulating the brain activity in localized cortical domains by delivering laser pulses in the 2 μm spectral region while recording electrophysiological signals. Action and local field potentials were recorded in vivo from the motor cortex and hippocampus in acute and chronic settings, respectively. Immunohistochemical analysis of the brain tissue indicated insignificant inflammatory response to the infrared pulses while the signal-to-noise ratio of recordings still remained high. Our neural interface constitutes a step forward in expanding infrared neurostimulation as a versatile approach for fundamental research and clinically translatable therapies.
Project description:Regaining the function of an impaired limb is highly desirable in paralyzed individuals. One possible avenue to achieve this goal is to bridge the interrupted pathway between preserved neural structures and muscles using a brain-computer interface. Here, we demonstrate that monkeys with subcortical stroke were able to learn to use an artificial cortico-muscular connection (ACMC), which transforms cortical activity into electrical stimulation to the hand muscles, to regain volitional control of a paralysed hand. The ACMC induced an adaptive change of cortical activities throughout an extensive cortical area. In a targeted manner, modulating high-gamma activity became localized around an arbitrarily-selected cortical site controlling stimulation to the muscles. This adaptive change could be reset and localized rapidly to a new cortical site. Thus, the ACMC imparts new function for muscle control to connected cortical sites and triggers cortical adaptation to regain impaired motor function after stroke.
Project description:Infrared neural stimulation (INS) is a neurostimulation modality that uses pulsed infrared light to evoke artifact-free, spatially precise neural activity with a noncontact interface; however, the technique has not been demonstrated in humans. The objective of this study is to demonstrate the safety and efficacy of INS in humans in vivo. The feasibility of INS in humans was assessed in patients ([Formula: see text]) undergoing selective dorsal root rhizotomy, where hyperactive dorsal roots, identified for transection, were stimulated in vivo with INS on two to three sites per nerve with electromyogram recordings acquired throughout the stimulation. The stimulated dorsal root was removed and histology was performed to determine thermal damage thresholds of INS. Threshold activation of human dorsal rootlets occurred in 63% of nerves for radiant exposures between 0.53 and [Formula: see text]. In all cases, only one or two monitored muscle groups were activated from INS stimulation of a hyperactive spinal root identified by electrical stimulation. Thermal damage was first noted at [Formula: see text] and a [Formula: see text] safety ratio was identified. These findings demonstrate the success of INS as a fresh approach for activating human nerves in vivo and providing the necessary safety data needed to pursue clinically driven therapeutic and diagnostic applications of INS in humans.
Project description:Over the past decade, optical methods have emerged for modulating brain functions as an alternative to electrical stimulation. Among various optical techniques, infrared neural stimulation has been effective via a thermal mechanism enabling focused and noninvasive stimulation without any genetic manipulation, but it results in bulk heating of neural tissue. Recently, it has been shown that neural cells can be activated more efficiently by pulsed near-infrared (NIR) light delivered to gold nanorods (GNRs) near the neural cells. Despite its potential, however, the biophysical mechanism underlying this GNR-enhanced NIR stimulation has not been clearly explained yet. Here, we propose an integrative and quantitative model to elucidate the mechanism by modeling heat generated from interaction between NIR light and GNRs, the temperature-dependent ion channels (transient receptor potential vanilloid 1; TRPV1) in the neuronal membrane, and a heat-induced capacitive current through the membrane. Our results show that NIR pulses induce abrupt temperature elevation near the neuronal membrane and lead to both the TRPV1-channel and capacitive currents. Both current sources synergistically increase the membrane potential and elicit an action potential, and which mechanism is dominant depends on conditions such as the laser pulse duration and TRPV1 channel density. Although the TRPV1 mechanism dominates in most cases we tested, the capacitive current makes a larger contribution when a very short laser pulse is illuminated on neural cells with relatively low TRPV1 channel densities.
Project description:Transcutaneous spinal cord stimulation (tSCS) has the potential to promote improved sensorimotor rehabilitation by modulating the circuitry of the spinal cord non-invasively. Little is currently known about how cervical or lumbar tSCS influences the excitability of spinal and corticospinal networks, or whether the synergistic effects of multi-segmental tSCS occur between remote segments of the spinal cord. The aim of this review is to describe the emergence and development of tSCS as a novel method to modulate the spinal cord, while highlighting the effectiveness of tSCS in improving sensorimotor recovery after spinal cord injury. This review underscores the ability of single-site tSCS to alter excitability across multiple segments of the spinal cord, while multiple sites of tSCS converge to facilitate spinal reflex and corticospinal networks. Finally, the potential and current limitations for engaging cervical and lumbar spinal cord networks through tSCS to enhance the effectiveness of rehabilitation interventions are discussed. Further mechanistic work is needed in order to optimize targeted rehabilitation strategies and improve clinical outcomes.
Project description:Significance: We present a new optical method for modulating cortical activity in multiple locations and across multiple time points with high spatial and temporal precision. Our method uses infrared light and does not require dyes or transgenic modifications. It is compatible with a number of other stimulation and recording techniques. Aim: Infrared neural stimulation (INS) has been largely confined to single point stimuli. In this study, we expand upon this approach and develop a rapidly switched fiber array capable of generation of stimulus patterns. Our prototype is capable of stimulating at nine separate locations but is easily scalable. Approach: Our device is made of commercially available components: a solid-state infrared laser, a piezoelectric fiber coupled optical switch, and 200-μm diameter optical fibers. We validate it using intrinsic optical signal imaging of INS responses in macaque and squirrel monkey sensory cortical areas. Results: We demonstrate that our switched array can consistently generate responses in primate cortex, consistent with earlier single channel INS investigations. Conclusions: Our device can successfully target the cortical surface, either at one specific region or multiple points spread out across different areas. It is compatible with a host of other imaging and stimulation modalities.