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Biology subjects

Shah, N. P.

Publications and source records attributed to Shah, N. P..

17 recordsLinked to original sources

Improved interpretability in LFADS models using a learned, context-dependent per-trial bias

The computation-through-dynamics perspective argues that biological neural circuits process information via the continuous evolution of their internal states. Inspired by this perspective, Latent Factor Activity using Dynamical systems (LFADS, [1]) identifies a generative model consistent with the neural activity recordings. LFADS models neural dynamics with a recurrent neural network (RNN) generator, which results in excellent fit to the data. However, it has been difficult to understand the dynamics of the LFADS generator. In this work, we show that this poor interpretability arises in part because the generator implements complex, multi-stable dynamics. We introduce a simple modification to LFADS that ameliorates issues with interpretability by providing an inferred per-trial bias (modeled as a constant input) to the RNN generator, enabling it to contextually adapt a simpler dynamical system to individual trials. In both simulated neural recordings from pendulum oscillations and real recordings during arm movements in nonhuman primates, we observed that the standard LFADS learned complex, multi-stable dynamics, whereas the modified LFADS learned easier-to-understand contextual dynamics. This enabled direct analysis of the generator, which reproduced at a single-trial level previous results shown only through more complex analyses at the trial average. Finally, we applied the per-trial inferred bias LFADS model to human intracortical brain computer interface recordings during attempted finger movements and speech. We show that modifying neural dynamics using linear operations of the per-trial bias addresses non-stationarity and identifies the extent of behavioral variability, problems known to plague BCI. We call our modification to LFADS as "contextual LFADS".

neuroscience↗

Gesture encoding in human left precentral gyrus neuronal ensembles

Understanding the cortical activity patterns driving dexterous upper limb motion has the potential to benefit a broad clinical population living with limited mobility through the development of novel brain-computer interface (BCI) technology. The present study examines the activity of ensembles of motor cortical neurons recorded using microelectrode arrays in the dominant hemisphere of two BrainGate clinical trial participants with cervical spinal cord injury as they attempted to perform a set of 48 different hand gestures. Although each participant displayed a unique organization of their respective neural latent spaces, it was possible to achieve classification accuracies of [~]70% for all 48 gestures (and [~]90% for sets of 10). Our results show that single unit ensemble activity recorded in a single hemisphere of human precentral gyrus has the potential to generate a wide range of gesture-related signals across both hands, providing an intuitive and diverse set of potential command signals for intracortical BCI use.

neuroscience↗

A flexible intracortical brain-computer interface for typing using finger movements

Keyboard typing with finger movements is a versatile digital interface for users with diverse skills, needs, and preferences. Currently, such an interface does not exist for people with paralysis. We developed an intracortical brain-computer interface (BCI) for typing with attempted flexion/extension movements of three finger groups on the right hand, or both hands, and demonstrated its flexibility in two dominant typing paradigms. The first paradigm is "point-and-click" typing, where a BCI user selects one key at a time using continuous real-time control, allowing selection of arbitrary sequences of symbols. During cued character selection with this paradigm, a human research participant with paralysis achieved 30-40 selections per minute with nearly 90% accuracy. The second paradigm is "keystroke" typing, where the BCI user selects each character by a discrete movement without real-time feedback, often giving a faster speed for natural language sentences. With 90 cued characters per minute, decoding attempted finger movements and correcting errors using a language model resulted in more than 90% accuracy. Notably, both paradigms matched the state-of-the-art for BCI performance and enabled further flexibility by the simultaneous selection of multiple characters as well as efficient decoder estimation across paradigms. Overall, the high-performance interface is a step towards the wider accessibility of BCI technology by addressing unmet user needs for flexibility.

neuroscience↗

A real-time, high-performance brain-computer interface for finger decoding and quadcopter control

People with paralysis express unmet needs for peer support, leisure activities, and sporting activities. Many within the general population rely on social media and massively multiplayer video games to address these needs. We developed a high-performance finger brain-computer-interface system allowing continuous control of 3 independent finger groups with 2D thumb movements. The system was tested in a human research participant over sequential trials requiring fingers to reach and hold on targets, with an average acquisition rate of 76 targets/minute and completion time of 1.58 {+/-} 0.06 seconds. Performance compared favorably to previous animal studies, despite a 2-fold increase in the decoded degrees-of-freedom (DOF). Finger positions were then used for 4-DOF velocity control of a virtual quadcopter, demonstrating functionality over both fixed and random obstacle courses. This approach shows promise for controlling multiple-DOF end-effectors, such as robotic fingers or digital interfaces for work, entertainment, and socialization.

bioengineering↗

Decomposition of retinal ganglion cell electrical images for cell type and functional inference

ObjectiveIdentifying neuronal cell types and their biophysical properties based on their extracellular electrical features is a major challenge for experimental neuroscience and for the development of high-resolution brain-machine interfaces. One example is identification of retinal ganglion cell (RGC) types and their visual response properties, which is fundamental for developing future electronic implants that can restore vision. ApproachThe electrical image (EI) of a RGC, or the mean spatio-temporal voltage footprint of its recorded spikes on a high-density electrode array, contains substantial information about its anatomical, morphological, and functional properties. However, the analysis of these properties is complex because of the high-dimensional nature of the EI. We present a novel optimization-based algorithm to decompose electrical image into a low-dimensional, biophysically-based representation: the temporally-shifted superposition of three learned basis waveforms corresponding to spike waveforms produced in the somatic, dendritic and axonal cellular compartments. ResultsThe decomposition was evaluated using large-scale multi-electrode recordings from the macaque retina. The decomposition accurately localized the somatic and dendritic compartments of the cell. The imputed dendritic fields of RGCs correctly predicted the location and shape of their visual receptive fields. The inferred waveform amplitudes and shapes accurately identified the four major primate RGC types (ON and OFF midget and parasol cells) substantially more accurately than previous approaches. SignificanceThese findings contribute to more accurate inference of RGC types and their original light responses based purely on their electrical features, with potential implications for vision restoration technology.

neuroscience↗

Pseudo-linear Summation explains Neural Geometry of Multi-finger Movements in Human Premotor Cortex

How does the motor cortex combine simple movements (such as single finger flexion/extension) into complex movements (such hand gestures or playing piano)? Motor cortical activity was recorded using intracortical multi-electrode arrays in two people with tetraplegia as they attempted single, pairwise and higher order finger movements. Neural activity for simultaneous movements was largely aligned with linear summation of corresponding single finger movement activities, with two violations. First, the neural activity was normalized, preventing a large magnitude with an increasing number of moving fingers. Second, the neural tuning direction of weakly represented fingers (e.g. middle) changed significantly as a result of the movement of other fingers. These deviations from linearity resulted in non-linear methods outperforming linear methods for neural decoding. Overall, simultaneous finger movements are thus represented by the combination of individual finger movements by pseudo-linear summation.

neuroscience↗

Fixational Eye Movements Enhance the Precision of Visual Information Transmitted by the Primate Retina

Fixational eye movements alter the number and timing of spikes transmitted from the retina to the brain, but whether these changes enhance or degrade the retinal signal is unclear. To quantify this, we developed a Bayesian method for reconstructing natural images from the recorded spikes of hundreds of retinal ganglion cells (RGCs) in the macaque retina (male), combining a likelihood model for RGC light responses with the natural image prior implicitly embedded in an artificial neural network optimized for denoising. The method matched or surpassed the performance of previous reconstruction algorithms, and provides an interpretable framework for characterizing the retinal signal. Reconstructions were improved with artificial stimulus jitter that emulated fixational eye movements, even when the eye movement trajectory was assumed to be unknown and had to be inferred from retinal spikes. Reconstructions were degraded by small artificial perturbations of spike times, revealing more precise temporal encoding than suggested by previous studies. Finally, reconstructions were substantially degraded when derived from a model that ignored cell-to-cell interactions, indicating the importance of stimulusevoked correlations. Thus, fixational eye movements enhance the precision of the retinal representation.

neuroscience↗

A critical role for PLCG1 in RAS activation by BCR-ABL1 and FLT3-ITD

Myeloid leukemias are frequently associated with pathologically activating mutations in tyrosine kinases [BCR-ABL1 in chronic myeloid leukemia (CML); FLT3 juxtamembrane internal tandem duplication (ITD) mutations, FLT3 and KIT activation loop mutations in acute myeloid leukemia (AML)]. Mutations in these kinases activate RAS, which initiates multiple downstream signaling pathways that regulate cell proliferation, differentiation, and apoptosis. The mechanisms whereby RAS is activated by these kinases is incompletely understood, and a better understanding of the molecular mediators involved in RAS activation may uncover new therapeutic strategies. Here we identify a biologically and therapeutically important novel mechanism whereby BCR-ABL1 and FLT3-ITD activate the critical downstream effector RAS in part through phospholipase C gamma-1 (PLCG1). PLCG1 knockout decreases proliferation of CML and FLT3-ITD-expressing AML cells, reduces RAS nucleotide exchange factor activity, and increases sensitivity of CML cells to BCR-ABL1 tyrosine kinase inhibitors (TKIs). Collectively, these studies suggest that PLCG1 inhibition may augment clinical responses to BCR-ABL1 and FLT3 TKIs in CML and AML.

cancer biology↗

Precise control of neural activity using temporally dithered and spatially multiplexed electrical stimulation

Neural implants have the potential to restore lost sensory function by electrically evoking the complex naturalistic activity patterns of neural populations. However, it can be difficult to predict and control evoked neural responses to simultaneous multi-electrode stimulation due to nonlinearity of the responses. We present a solution to this problem and demonstrate its utility in the context of a bi-directional retinal implant for restoring vision. A dynamically optimized stimulation approach encodes incoming visual stimuli into a rapid, greedily chosen, temporally dithered and spatially multiplexed sequence of simple stimulation patterns. Stimuli are selected to optimize the reconstruction of the visual stimulus from the evoked responses. Temporal dithering exploits the slow time scales of downstream neural processing, and spatial multiplexing exploits the independence of responses generated by distant electrodes. The approach was evaluated using an experimental laboratory prototype of a retinal implant: large-scale, high-resolution multi-electrode stimulation and recording of macaque and rat retinal ganglion cells ex vivo. The dynamically optimized stimulation approach substantially enhanced performance compared to existing approaches based on static mapping between visual stimulus intensity and current amplitude. The modular framework enabled parallel extensions to naturalistic viewing conditions, incorporation of perceptual similarity measures, and efficient implementation for an implantable device. A direct closed-loop test of the approach supported its potential use in vision restoration. Impact StatementA novel method of electrical stimulation to precisely control neural activity for sensory restoration exhibits improvements in visual stimulus reconstruction, enables efficient hardware design, and extends to naturalistic conditions.

neuroscience↗

Inferring light responses of primate retinal ganglion cells using intrinsic electrical signatures

Reproducing high-acuity vision with an epiretinal implant will likely require inferring the natural light responses of diverse RGC types in the implanted retina, without measuring them directly. Here we demonstrate an approach that exploits intrinsic electrical features of primate RGCs. First, ON-parasol and OFF-parasol RGCs were identified with 95% accuracy using electrical features. Then, the somatic electrical footprint, predicted cell type, and average linear-nonlinear-Poisson model parameters of each cell type were used to infer a light response model for each cell. Across five retinas, these models achieved an average correlation with measured firing rates of 0.49 for white noise visual stimuli and 0.50 for natural scenes stimuli, compared to 0.65 and 0.58 respectively for models fitted to recorded light responses, an upper bound. This finding, and linear decoding of images from predicted RGC activity, suggested that the inference approach may be useful for high-fidelity sight restoration.

neuroscience↗

Efficient Inference of Sensitivity to Electrical Stimulation from Intrinsic Electrical Properties of Primate Retinal Ganglion Cells

High-fidelity electronic implants can in principle restore the function of neural circuits by precisely activating neurons via extracellular stimulation. However, direct characterization of the individual electrical responses of a large population of target neurons, in order to precisely control their activity, is often difficult or impossible. A potential solution is to leverage biophysical principles to infer sensitivity to electrical stimulation from features of spontaneous electrical activity, which can be recorded relatively easily. Here, this approach is developed and its potential value for vision restoration is tested quantitatively using large-scale high-density stimulation and recording from primate retinal ganglion cells (RGCs) ex vivo. Electrodes recording larger spikes from a given cell exhibited lower stimulation thresholds, with distinct trends for somas and axons, across cell types, retinas, and eccentricities. Thresholds for somatic stimulation increased with distance from the axon initial segment. The dependence of spike probability on injected current was inversely related to threshold, and was substantially steeper for axonal than somatic compartments, which could be identified by recorded electrical signatures. Dendritic stimulation was largely ineffective for eliciting spikes. These findings were quantitatively reproduced with biophysical simulations, and confirmed in tests on human RGCs. The inference of stimulation sensitivity from recorded electrical features was tested in simulated visual reconstruction, and revealed that the approach could significantly improve the function of future high-fidelity retinal implants.

neuroscience↗

Focal Electrical Stimulation of Human Retinal Ganglion Cells

Vision restoration with retinal implants that electrically stimulate retinal ganglion cells (RGCs), which transmit visual information to the brain, is limited by indiscriminate activation of many cells and cell types. Recent work in isolated macaque retina has demonstrated that direct electrical stimulation of RGCs can be performed with single-cell, single-spike resolution. However, the fidelity of epiretinal stimulation has not been examined in the human retina. Here, electrical activation of the major RGC types was examined using large-scale, multi-electrode recording and stimulation in the human retina ex vivo and compared directly to results from macaque. Targeted activation with single-cell, single-spike resolution was often possible without activating overlying axon bundles, at low stimulation current levels similar to those in macaque. Distinct cell types could be identified and targeted based on their distinct electrical signatures. Simulation based on these measurements revealed that a novel, dynamic stimulation approach would produce a nearly optimal evoked visual signal. These results indicate that high-fidelity control of spiking in human RGCs is achievable with extracellular stimulation and that the macaque retina is an accurate model for vision restoration with epiretinal implants.

neuroscience↗

Functional Organization of Midget and Parasol Ganglion Cells in the Human Retina

The functional organization of diverse retinal ganglion cell (RGC) types, which shapes the visual signal transmitted to the brain, has been examined in many species. The unique spatial, temporal, and chromatic properties of the numerically dominant RGC types in macaque monkey retina are presumed to most accurately model human vision. However, the functional similarity between RGCs in macaques and humans has only begun to be tested, and recent work suggests possible differences. Here, the properties of the numerically dominant human RGC types were examined using large-scale multi-electrode recordings with fine-grained visual stimulation in isolated retina, and compared to results from dozens of recordings from macaque retina using the same experimental methods and conditions. The properties of four major human RGC types -- ON-parasol, OFF-parasol, ON-midget, and OFF-midget -- closely paralleled those of the same macaque RGC types, including the spatial and temporal light sensitivity, precisely coordinated mosaic organization of receptive fields, ON-OFF asymmetries, spatial response nonlinearity, and sampling of photoreceptor inputs over space. Putative smooth monostratified cells and polyaxonal amacrine cells were also identified based on similarities to cell types previously identified in macaque retina. The results suggest that recently proposed differences between human and macaque RGCs probably reflect experimental differences, and that the macaque model provides an accurate picture of human RGC function.

neuroscience↗

Reconstruction of natural images from responses of primate retinal ganglion cells

The visual message conveyed by a retinal ganglion cell (RGC) is often summarized by its spatial receptive field, but in principle also depends on the responses of other RGCs and natural image statistics. This possibility was explored by linear reconstruction of natural images from responses of the four numerically-dominant macaque RGC types. Reconstructions were highly consistent across retinas. The optimal reconstruction filter for each RGC - its visual message - reflected natural image statistics, and resembled the receptive field only when nearby, same-type cells were included. ON and OFF cells conveyed largely independent, complementary representations, and parasol and midget cells conveyed distinct and expected features. Correlated activity and nonlinearities had statistically significant but minor effects on reconstruction. Simulated reconstructions, using linear-nonlinear cascade models of RGC light responses that incorporated measured spatial properties and nonlinearities, produced similar results. Spatiotemporal reconstructions exhibited similar spatial properties, suggesting that the results are relevant for natural vision.

neuroscience↗

Unusual physiological properties of two ganglion cell types in primate retina

The visual functions of the diverse retinal ganglion cell types in the primate retina, and the parallel visual pathways they initiate, remain poorly understood. Here, the unusual physiological and computational properties of the ON and OFF smooth monostratified (SM) ganglion cells are explored. Large-scale multi-electrode recordings from 48 macaque retinas revealed that these cells exhibited strikingly irregular receptive field structure composed of spatially segregated hotspots, quite different from the receptive fields of previously described retinal ganglion cell types. The ON and OFF SM cells are paired cell types, but OFF SM cells exhibited stronger hotspot structure than ON cells. Targeted visual stimulation and computational inference demonstrate strong nonlinear subunit properties of each hotspot that contributed to the signaling properties of SM cells. Analysis of shared inputs to neighboring SM cells indicated that each hotspot could not be explained by an individual presynaptic input. Surprisingly, visual stimulation of different hotspots produced subtly different spatiotemporal spike waveforms in the same SM cell, consistent with a dendritic contribution to hotspot structure. These findings point to a previously unreported nonlinear mechanism in the output of the primate retina that contributes to signaling spatial information.

neuroscience↗

Inference of Nonlinear Spatial Subunits by Spike-Triggered Clustering in Primate Retina

Integration of rectified synaptic inputs is a widespread nonlinear motif in sensory neuroscience. We present a novel method for maximum likelihood estimation of nonlinear subunits by soft-clustering spike-triggered stimuli. Subunits estimated from parasol ganglion cells recorded in macaque retina partitioned the receptive field into compact regions, likely representing bipolar cell inputs. Joint clustering with multiple RGCs revealed shared subunits in neighboring cells, producing a parsimonious population model. Closed-loop subunit validation was then performed by projecting white noise into the null space of the linear receptive field. Responses to these null stimuli were more accurately explained by a model with multiple subunits, and were stronger in OFF cells than ON cells. Presentation of natural stimuli containing jittering edges and textures also revealed greater response prediction accuracy with the subunit model. Finally, the generality of the approach was demonstrated by application to V1 data.

neuroscience↗

Learning a neural response metric for retinal prosthesis

Retinal prostheses for treating incurable blindness are designed to electrically stimulate surviving retinal neurons, causing them to send artificial visual signals to the brain. However, electrical stimulation generally cannot precisely reproduce typical patterns of neural activity in the retina. Therefore, an electrical stimulus must be selected so as to produce a neural response as close as possible to the desired response. This requires a technique for computing the distance between a desired response and an achievable response that is meaningful in terms of the visual signal being conveyed. We propose a method to learn a metric on neural responses directly from recorded light responses of a population of retinal ganglion cells (RGCs) in the primate retina. The learned metric produces a measure of similarity of RGC population responses that accurately reflects the similarity of visual inputs. Using data from electrical stimulation experiments, we demonstrate that the learned metric could produce improvements in the performance of a retinal prosthesis.

neuroscience↗