Background: Intracortical microstimulation (ICMS) is an emerging approach to restore sensation to people with neurological injury or disease. Biomimetic microstimulation, or stimulus trains that mimic neural activity in the brain through encoding of onset and offset transients, could improve the utility of ICMS for brain-computer interface (BCI) applications, but how biomimetic microstimulation affects neural activation is not understood. Current “biomimetic” ICMS trains aim to reproduce the strong onset and offset transients evoked in the brain by sensory input through dynamic modulation of stimulus parameters. Stimulus induced depression of neural activity (decreases in evoked intensity over time) is also a potential barrier to clinical implementation of sensory feedback, and dynamic microstimulation may reduce this effect. Objective: We evaluated how bio-inspired ICMS trains with dynamic modulation of amplitude and/or frequency change the calcium response, spatial distribution, and depression of neurons in the somatosensory and visual cortices. Methods: Calcium responses of neurons were measured in Layer 2/3 of visual and somatosensory cortices of anesthetized GCaMP6s mice in response to ICMS trains with fixed amplitude and frequency (Fixed) and three dynamic ICMS trains that increased the stimulation intensity during the onset and offset of stimulation by modulating the amplitude (DynAmp), frequency (DynFreq), or amplitude and frequency (DynBoth). ICMS was provided for either 1-s with 4-s breaks (Short) or for 30-s with 15-s breaks (Long). Results: DynAmp and DynBoth trains evoked distinct onset and offset transients in recruited neural populations, while DynFreq trains evoked population activity similar to Fixed trains. Individual neurons had heterogeneous responses primarily based on how quickly they depressed to ICMS, where neurons farther from the electrode depressed faster and a small subpopulation (1–5%) were modulated by DynFreq trains. Neurons that depressed to Short trains were also more likely to depress to Long trains, but Long trains induced more depression overall due to the increased stimulation length. Increasing the amplitude during the hold phase resulted in an increase in recruitment and intensity which resulted in more depression and reduced offset responses. Dynamic amplitude modulation reduced stimulation induced depression by 14.6 ± 0.3% for Short and 36.1 ± 0.6% for Long trains. Ideal observers were 0.031 ± 0.009 s faster for onset detection and 1.33 ± 0.21 s faster for offset detection with dynamic amplitude encoding. Conclusions: Dynamic amplitude modulation evokes distinct onset and offset transients, reduces depression of neural calcium activity, and decreases total charge injection for sensory feedback in BCIs by lowering recruitment of neurons during long maintained periods of ICMS. In contrast, dynamic frequency modulation evokes distinct onset and offset transients in a small subpopulation of neurons but also reduces depression in recruited neurons by reducing the rate of activation.
more »
« less
Responses of Cortical Neurons to Intracortical Microstimulation in Awake Primates
Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in awake nonhuman primates to stimulation, we recorded single-unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex (M1) of three macaque monkeys. Stimuli between 5 and 50 μA delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 ms. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition; high-frequency stimulation was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were often positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when using ICMS for scientific and clinical applications.
more » « less- NSF-PAR ID:
- 10406120
- Publisher / Repository:
- DOI PREFIX: 10.1523
- Date Published:
- Journal Name:
- eneuro
- Volume:
- 10
- Issue:
- 4
- ISSN:
- 2373-2822
- Page Range / eLocation ID:
- Article No. ENEURO.0336-22.2023
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
More Like this
-
-
more » « less
Abstract Neuronal ensembles are groups of neurons with correlated activity associated with sensory, motor, and behavioral functions. To explore how ensembles encode information, we investigated responses of visual cortical neurons in awake mice using volumetric two-photon calcium imaging during visual stimulation. We identified neuronal ensembles employing an unsupervised model-free algorithm and, besides neurons activated by the visual stimulus (termed “onsemble”), we also find neurons that are specifically inactivated (termed “offsemble”). Offsemble neurons showed faster calcium decay during stimuli, suggesting selective inhibition. In response to visual stimuli, each ensemble (onsemble+offsemble) exhibited small trial-to-trial variability, high orientation selectivity, and superior predictive accuracy for visual stimulus orientation, surpassing the sum of individual neuron activity. Thus, the combined selective activation and inactivation of cortical neurons enhances visual encoding as an emergent and distributed neural code.
-
more » « less
Abstract Neurons in sensory cortices are more naturally and deeply integrated than any current neural population recording tools (e.g. electrode arrays, fluorescence imaging). Two concepts facilitate efforts to observe population neural code with single-cell recordings. First, even the highest quality single-cell recording studies find a fraction of the stimulus information in high-dimensional population recordings. Finding any of this missing information provides proof of principle. Second, neurons and neural populations are understood as coupled nonlinear differential equations. Therefore, fitted ordinary differential equations provide a basis for single-trial single-cell stimulus decoding. We obtained intracellular recordings of fluctuating transmembrane current and potential in mouse visual cortex during stimulation with drifting gratings. We use mean deflection from baseline when comparing to prior single-cell studies because action potentials are too sparse and the deflection response to drifting grating stimuli (e.g. tuning curves) are well studied. Equation-based decoders allowed more precise single-trial stimulus discrimination than tuning-curve-base decoders. Performance varied across recorded signal types in a manner consistent with population recording studies and both classification bases evinced distinct stimulus-evoked phases of population dynamics, providing further corroboration. Naturally and deeply integrated observations of population dynamics would be invaluable. We offer proof of principle and a versatile framework.
-
more » « less
Abstract Objective . Intracortical microstimulation (ICMS) can be an effective method for restoring sensory perception in contemporary brain–machine interfaces. However, the mechanisms underlying better control of neuronal responses remain poorly understood, as well as the relationship between neuronal activity and other concomitant phenomena occurring around the stimulation site.Approach . Different microstimulation frequencies were investigatedin vivo on Thy1-GCaMP6s mice using widefield and two-photon imaging to evaluate the evoked excitatory neural responses across multiple spatial scales as well as the induced hemodynamic responses. Specifically, we quantified stimulation-induced neuronal activation and depression in the mouse visual cortex and measured hemodynamic oxyhemoglobin and deoxyhemoglobin signals using mesoscopic-scale widefield imaging.Main results . Our calcium imaging findings revealed a preference for lower-frequency stimulation in driving stronger neuronal activation. A depressive response following the neural activation preferred a slightly higher frequency stimulation compared to the activation. Hemodynamic signals exhibited a comparable spatial spread to neural calcium signals. Oxyhemoglobin concentration around the stimulation site remained elevated during the post-activation (depression) period. Somatic and neuropil calcium responses measured by two-photon microscopy showed similar dependence on stimulation parameters, although the magnitudes measured in soma was greater than in neuropil. Furthermore, higher-frequency stimulation induced a more pronounced activation in soma compared to neuropil, while depression was predominantly induced in soma irrespective of stimulation frequencies.Significance . These results suggest that the mechanism underlying depression differs from activation, requiring ample oxygen supply, and affecting neurons. Our findings provide a novel understanding of evoked excitatory neuronal activity induced by ICMS and offer insights into neuro-devices that utilize both activation and depression phenomena to achieve desired neural responses. -
Abstract Studies of sensory-evoked neuronal responses often focus on mean spike rates, with fluctuations treated as internally-generated noise. However, fluctuations of spontaneous activity, often organized as traveling waves, shape stimulus-evoked responses and perceptual sensitivity. The mechanisms underlying these waves are unknown. Further, it is unclear whether waves are consistent with the low rate and weakly correlated “asynchronous-irregular” dynamics observed in cortical recordings. Here, we describe a large-scale computational model with topographically-organized connectivity and conduction delays relevant to biological scales. We find that spontaneous traveling waves are a general property of these networks. The traveling waves that occur in the model are sparse, with only a small fraction of neurons participating in any individual wave. Consequently, they do not induce measurable spike correlations and remain consistent with locally asynchronous irregular states. Further, by modulating local network state, they can shape responses to incoming inputs as observed in vivo.more » « less
