Regulation of arousal and performance of a healthy non-human primate using closed-loop central thalamic deep brain stimulation.

Application of closed-loop approaches in systems neuroscience and brain-computer interfaces holds great promise for revolutionizing our understanding of the brain and for developing novel neuromodulation strategies to restore lost function. The anterior forebrain mesocircuit (AFM) of the mammalian brain is hypothesized to underlie arousal regulation of the cortex and striatum, and support cognitive functions during wakefulness. Dysfunction of arousal regulation is hypothesized to contribute to cognitive dysfunctions in various neurological disorders, and most prominently in patients following traumatic brain injury (TBI). Several clinical studies have explored the use of daily central thalamic deep brain stimulation (CT-DBS) within the AFM to restore consciousness and executive attention in TBI patients. In this study, we explored the use of closed-loop CT-DBS in order to episodically regulate arousal of the AFM of a healthy non-human primate (NHP) with the goal of restoring behavioral performance. We used pupillometry and near real-time analysis of ECoG signals to episodically initiate closed-loop CT-DBS and here we report on our ability to enhance arousal and restore the animal's performance. The initial computer based approach was then experimentally validated using a customized clinical-grade DBS device, the DyNeuMo-X, a bi-directional research platform used for rapidly testing closed-loop DBS. The successful implementation of the DyNeuMo-X in a healthy NHP supports ongoing clinical trials employing the internal DyNeuMo system (NCT05437393, NCT05197816) and our goal of developing and accelerating the deployment of novel neuromodulation approaches to treat cognitive dysfunction in patients with structural brain injuries and other etiologies.

Geometry of spiking patterns in early visual cortex: a topological data analytic approach.

In the brain, spiking patterns live in a high-dimensional space of neurons and time. Thus, determining the intrinsic structure of this space presents a theoretical and experimental challenge. To address this challenge, we introduce a new framework for applying topological data analysis (TDA) to spike train data and use it to determine the geometry of spiking patterns in the visual cortex. Key to our approach is a parametrized family of distances based on the timing of spikes that quantifies the dissimilarity between neuronal responses. We applied TDA to visually driven single-unit and multiple single-unit spiking activity in macaque V1 and V2. TDA across timescales reveals a common geometry for spiking patterns in V1 and V2 which, among simple models, is most similar to that of a low-dimensional space endowed with Euclidean or hyperbolic geometry with modest curvature. Remarkably, the inferred geometry depends on timescale and is clearest for the timescales that are important for encoding contrast, orientation and spatial correlations.

Predicting task performance from biomarkers of mental fatigue in global brain activity.

Objective.Detection and early prediction of mental fatigue (i.e. shifts in vigilance), could be used to adapt neuromodulation strategies to effectively treat patients suffering from brain injury and other indications with prominent chronic mental fatigue.Approach.In this study, we analyzed electrocorticography (ECoG) signals chronically recorded from two healthy non-human primates (NHP) as they performed a sustained attention task over extended periods of time. We employed a set of spectrotemporal and connectivity biomarkers of the ECoG signals to identify periods of mental fatigue and a gradient boosting classifier to predict performance, up to several seconds prior to the behavioral response.Main results.Wavelet entropy and the instantaneous amplitude and frequency were among the best single features across sessions in both NHPs. The classification performance using higher order spectral-temporal (HOST) features was significantly higher than that of conventional spectral power features in both NHPs. Across the 99 sessions analyzed, average F1 scores of 77.5% ± 8.2% and 91.2% ± 3.6%, and accuracy of 79.5% ± 8.9% and 87.6% ± 3.9% for the classifier were obtained for each animal, respectively.Significance.Our results here demonstrate the feasibility of predicting performance and detecting periods of mental fatigue by analyzing ECoG signals, and that this general approach, in principle, could be used for closed-loop control of neuromodulation strategies.

Robust modulation of arousal regulation, performance, and frontostriatal activity through central thalamic deep brain stimulation in healthy nonhuman primates.

The central thalamus (CT) is a key component of the brain-wide network underlying arousal regulation and sensory-motor integration during wakefulness in the mammalian brain. Dysfunction of the CT, typically a result of severe brain injury (SBI), leads to long-lasting impairments in arousal regulation and subsequent deficits in cognition. Central thalamic deep brain stimulation (CT-DBS) is proposed as a therapy to reestablish and maintain arousal regulation to improve cognition in select SBI patients. However, a mechanistic understanding of CT-DBS and an optimal method of implementing this promising therapy are unknown. Here we demonstrate in two healthy nonhuman primates (NHPs), Macaca mulatta, that location-specific CT-DBS improves performance in visuomotor tasks and is associated with physiological effects consistent with enhancement of endogenous arousal. Specifically, CT-DBS within the lateral wing of the central lateral nucleus and the surrounding medial dorsal thalamic tegmental tract (DTTm) produces a rapid and robust modulation of performance and arousal, as measured by neuronal activity in the frontal cortex and striatum. Notably, the most robust and reliable behavioral and physiological responses resulted when we implemented a novel method of CT-DBS that orients and shapes the electric field within the DTTm using spatially separated DBS leads. Collectively, our results demonstrate that selective activation within the DTTm of the CT robustly regulates endogenous arousal and enhances cognitive performance in the intact NHP; these findings provide insights into the mechanism of CT-DBS and further support the development of CT-DBS as a therapy for reestablishing arousal regulation to support cognition in SBI patients.

Responses to orientation discontinuities in V1 and V2: physiological dissociations and functional implications.

Segmenting the visual image into objects is a crucial stage of visual processing. Object boundaries are typically associated with differences in luminance, but discontinuities in texture also play an important role. We showed previously that a subpopulation of neurons in V2 in anesthetized macaques responds to orientation discontinuities parallel to their receptive field orientation. Such single-cell responses could be a neurophysiological correlate of texture boundary detection. Neurons in V1, on the other hand, are known to have contextual response modulations such as iso-orientation surround suppression, which also produce responses to orientation discontinuities. Here, we use pseudorandom multiregion grating stimuli of two frame durations (20 and 40 ms) to probe and compare texture boundary responses in V1 and V2 in anesthetized macaque monkeys. In V1, responses to texture boundaries were observed for only the 40 ms frame duration and were independent of the orientation of the texture boundary. However, in transient V2 neurons, responses to such texture boundaries were robust for both frame durations and were stronger for boundaries parallel to the neuron's preferred orientation. The dependence of these processes on stimulus duration and orientation indicates that responses to texture boundaries in V2 arise independently of contextual modulations in V1. In addition, because the responses in transient V2 neurons are sensitive to the orientation of the texture boundary but those of V1 neurons are not, we suggest that V2 responses are the correlate of texture boundary detection, whereas contextual modulation in V1 serves other purposes, possibly related to orientation "pop-out."

Cannabinoid neuromodulation in the adult early visual cortex.

Sensory processing is an active process involving the interaction of ongoing cortical activity with incoming stimulus information. However, the modulators and circuits involved in this interaction are incompletely understood. One potential candidate is the cannabinoid-signaling system, which is known to modulate the dynamics of cortical networks. Here, we show that in the primate primary and secondary visual cortices, the cannabinoid CP55940 modulates not only population dynamics but also influences the dynamics of the stimulus-response relationship of individual neurons. At the population level, CP55940 decreases EEG power, LFP power, and LFP coherence. At the single-neuron level, intrinsic spike train dynamics appear relatively unchanged, but visual receptive fields are altered: CP55940 induced an overall delay and broadening of the temporal component of V1 and V2 spatiotemporal receptive fields. Our findings provide neurophysiologic evidence for a link between cannabinoid-signaling, network dynamics and the function of a canonical cortical circuit.

Sparse coding and high-order correlations in fine-scale cortical networks.

Connectivity in the cortex is organized at multiple scales, suggesting that scale-dependent correlated activity is particularly important for understanding the behaviour of sensory cortices and their function in stimulus encoding. We analysed the scale-dependent structure of cortical interactions by using maximum entropy models to characterize multiple-tetrode recordings from primary visual cortex of anaesthetized macaque monkeys (Macaca mulatta). We compared the properties of firing patterns among local clusters of neurons (<300 microm apart) with those of neurons separated by larger distances (600-2,500 microm). Here we report that local firing patterns are distinctive: whereas multi-neuronal firing patterns at larger distances can be predicted by pairwise interactions, patterns within local clusters often show evidence of high-order correlations. Surprisingly, these local correlations are flexible and rapidly reorganized by visual input. Although they modestly reduce the amount of information that a cluster conveys, they also modify the format of this information, creating sparser codes by increasing the periods of total quiescence, and concentrating information into briefer periods of common activity. These results imply a hierarchical organization of neuronal correlations: simple pairwise correlations link neurons over scales of tens to hundreds of minicolumns, but on the scale of a few minicolumns, ensembles of neurons form complex subnetworks whose moment-to-moment effective connectivity is dynamically reorganized by the stimulus.

Characterization of trial-to-trial fluctuations in local field potentials recorded in cerebral cortex of awake behaving macaque.

In analyzing neurophysiologic data, individual experimental trials are usually assumed to be statistically independent. However, many studies employing functional imaging and electrophysiology have shown that brain activity during behavioral tasks includes temporally correlated trial-to-trial fluctuations. This could lead to spurious results in statistical significance tests used to compare data from different interleaved behavioral conditions presented throughout an experiment. We characterize trial-to-trial fluctuations in local field potentials recorded from the frontal cortex of a macaque monkey performing an oculomotor delayed response task. Our analysis identifies slow fluctuations (<0.1 Hz) of spectral power in 22/27 recording sessions. These trial-to-trial fluctuations are non-Gaussian, and call into question the statistical utility of standard trial shuffling. We compare our results with evidence for slow fluctuations in human functional imaging studies and other electrophysiologic studies in nonhuman primates.

Modulation of arousal regulation with central thalamic deep brain stimulation.

To investigate the effects of central thalamic deep brain stimulation (CT/DBS) on behavior and frontal cortical function, we conducted experiments in an awake, behaving macaque monkey performing tasks that required sustained attention and working memory. Results of this preliminary study revealed that CT/DBS can lead to an improvement, a decrement, a mixed or have no effect on behavior.

Subpopulations of neurons in visual area v2 perform differentiation and integration operations in space and time.

The interconnected areas of the visual system work together to find object boundaries in visual scenes. Primary visual cortex (V1) mainly extracts oriented luminance boundaries, while secondary visual cortex (V2) also detects boundaries defined by differences in texture. How the outputs of V1 neurons are combined to allow for the extraction of these more complex boundaries in V2 is as of yet unclear. To address this question, we probed the processing of orientation signals in single neurons in V1 and V2, focusing on response dynamics of neurons to patches of oriented gratings and to combinations of gratings in neighboring patches and sequential time frames. We found two kinds of response dynamics in V2, both of which were different from those of V1 neurons. While V1 neurons in general preferred one orientation, one subpopulation of V2 neurons ("transient") showed a temporally dynamic preference, resulting in a preference for changes in orientation. The second subpopulation of V2 neurons ("sustained") responded similarly to V1 neurons, but with a delay. The dynamics of nonlinear responses to combinations of gratings reinforced these distinctions: the dynamics enhanced the preference of V1 neurons for continuous orientations and the preference of V2 transient neurons for discontinuous ones. We propose that transient neurons in V2 perform a differentiation operation on the V1 input, both spatially and temporally, while the sustained neurons perform an integration operation. We show that a simple feedforward network with delayed inhibition can account for the temporal but not for the spatial differentiation operation.

Laminar and orientation-dependent characteristics of spatial nonlinearities: implications for the computational architecture of visual cortex.

A full understanding of the computations performed in primary visual cortex is an important yet elusive goal. Receptive field models consisting of cascades of linear filters and static nonlinearities may be adequate to account for responses to simple stimuli such as gratings and random checkerboards, but their predictions of responses to complex stimuli such as natural scenes are only approximately correct. It is unclear whether these discrepancies are limited to quantitative inaccuracies that reflect well-recognized mechanisms such as response normalization, gain controls, and cross-orientation suppression or, alternatively, imply additional qualitative features of the underlying computations. To address this question, we examined responses of V1 and V2 neurons in the monkey and area 17 neurons in the cat to two-dimensional Hermite functions (TDHs). TDHs are intermediate in complexity between traditional analytic stimuli and natural scenes and have mathematical properties that facilitate their use to test candidate models. By exploiting these properties, along with the laminar organization of V1, we identify qualitative aspects of neural computations beyond those anticipated from the above-cited model framework. Specifically, we find that V1 neurons receive signals from orientation-selective mechanisms that are highly nonlinear: they are sensitive to phase correlations, not just spatial frequency content. That is, the behavior of V1 neurons departs from that of linear-nonlinear cascades with standard modulatory mechanisms in a qualitative manner: even relatively simple stimuli evoke responses that imply complex spatial nonlinearities. The presence of these findings in the input layers suggests that these nonlinearities act in a feedback fashion.

A Bayesian statistical analysis of behavioral facilitation associated with deep brain stimulation.

Deep brain stimulation (DBS) is an established therapy for Parkinson's Disease and is being investigated as a treatment for chronic depression, obsessive compulsive disorder and for facilitating functional recovery of patients in minimally conscious states following brain injury. For all of these applications, quantitative assessments of the behavioral effects of DBS are crucial to determine whether the therapy is effective and, if so, how stimulation parameters can be optimized. Behavioral analyses for DBS are challenging because subject performance is typically assessed from only a small set of discrete measurements made on a discrete rating scale, the time course of DBS effects is unknown, and between-subject differences are often large. We demonstrate how Bayesian state-space methods can be used to characterize the relationship between DBS and behavior comparing our approach with logistic regression in two experiments: the effects of DBS on attention of a macaque monkey performing a reaction-time task, and the effects of DBS on motor behavior of a human patient in a minimally conscious state. The state-space analysis can assess the magnitude of DBS behavioral facilitation (positive or negative) at specific time points and has important implications for developing principled strategies to optimize DBS paradigms.

Attentional modulation of adaptation in V4.

Adaptation and visual attention are two processes that alter neural responses to luminance contrast. Rapid contrast adaptation changes response size and dynamics at all stages of visual processing, while visual attention has been shown to modulate both contrast gain and response gain in macaque extrastriate visual cortex. Because attention aims to enhance behaviorally relevant sensory responses while adaptation acts to attenuate neural activity, the question we asked is, how does attention alter adaptation? We present here single-unit recordings from V4 of two rhesus macaques performing a cued target detection task. The study was designed to characterize the effects of attention on the size and dynamics of a sequence of responses produced by a series of flashed oriented gratings parametric in luminance contrast. We found that the effect of attention on the response dynamics of V4 neurons is inconsistent with a mechanism that only alters the effective stimulus contrast, or only rescales the gain of the response. Instead, the action of attention modifies contrast gain early in the task, and modifies both response gain and contrast gain later in the task. We also show that responses to attended stimuli are more closely locked to the stimulus cycle than unattended responses, and that attended responses show less of the phase lag produced by adaptation than unattended responses. The phase advance generated by attention of the adapted responses suggests that the attentional gain control operates in some ways like a contrast gain control utilizing a neural measure of contrast to influence dynamics.

Responses of V1 neurons to two-dimensional hermite functions.

Neurons in primary visual cortex are widely considered to be oriented filters or energy detectors that perform one-dimensional feature analysis. The main deviations from this picture are generally thought to include gain controls and modulatory influences. Here we investigate receptive field (RF) properties of single neurons with localized two-dimensional stimuli, the two-dimensional Hermite functions (TDHs). TDHs can be grouped into distinct complete orthonormal bases that are matched in contrast energy, spatial extent, and spatial frequency content but differ in two-dimensional form, and thus can be used to probe spatially specific nonlinearities. Here we use two such bases: Cartesian TDHs, which resemble vignetted gratings and checkerboards, and polar TDHs, which resemble vignetted annuli and dartboards. Of 63 isolated units, 51 responded to TDH stimuli. In 37/51 units, we found significant differences in overall response size (21/51) or apparent RF shape (28/51) that depended on which basis set was used. Because of the properties of the TDH stimuli, these findings are inconsistent with simple feedforward nonlinearities and with many variants of energy models. Rather, they imply the presence of nonlinearities that are not local in either space or spatial frequency. Units showing these differences were present to a similar degree in cat and monkey, in simple and complex cells, and in supragranular, infragranular, and granular layers. We thus find a widely distributed neurophysiological substrate for two-dimensional spatial analysis at the earliest stages of cortical processing. Moreover, the population pattern of tuning to TDH functions suggests that V1 neurons sample not only orientations, but a larger space of two-dimensional form, in an even-handed manner.

Analysis of perisaccadic field potentials in the occipitotemporal pathway during active vision.

Eye movement potentials (EMPs) associated with saccades appear in both subcortical and cortical structures of the primate visual system. In this study, EMPs are recorded across sites in the occipitotemporal (OT) pathway of monkeys performing a pattern-recognition task. We characterize pair recordings of saccade-triggered local field potentials (LFPs) in early extrastriate and inferotemporal regions of the ventral visual pathway using time-frequency spectrograms. Parameters of the spectrograms, including the centroids of identified regions of interest in the time-frequency plane, are extracted and analyzed. Comparisons among the distributions of the extracted parameters reveal that the occipital lobe EMPs are largely postsaccadic events centered at 100 ms after saccade onset that are typically not influenced in timing by the direction of the saccade or the appearance of a stimulus transient appearing either before or after the saccade. The occipital lobe EMPs also demonstrate a significant shift in frequency content during their transient time course that is influenced, in a few cases, by saccade direction. Temporal lobe EMPs, on the other hand, may be centered in either the presaccadic or postsaccadic intervals; the time of their appearance is significantly influenced by the direction of the saccade. Temporal lobe EMPs demonstrate less frequency modulation than those recorded in the occipital lobe. The prevalence of EMPs in the OT pathway suggests that many cortical regions important for pattern recognition can be modulated by saccades. The timing and frequency characteristics of these signals suggest that the nature of this perisaccadic modulation varies across the cortex.