Non-invasive, Brain-controlled Functional Electrical Stimulation for Locomotion Rehabilitation in Individuals with Paraplegia.

Spinal cord injury (SCI) impairs the flow of sensory and motor signals between the brain and the areas of the body located below the lesion level. Here, we describe a neurorehabilitation setup combining several approaches that were shown to have a positive effect in patients with SCI: gait training by means of non-invasive, surface functional electrical stimulation (sFES) of the lower-limbs, proprioceptive and tactile feedback, balance control through overground walking and cue-based decoding of cortical motor commands using a brain-machine interface (BMI). The central component of this new approach was the development of a novel muscle stimulation paradigm for step generation using 16 sFES channels taking all sub-phases of physiological gait into account. We also developed a new BMI protocol to identify left and right leg motor imagery that was used to trigger an sFES-generated step movement. Our system was tested and validated with two patients with chronic paraplegia. These patients were able to walk safely with 65-70% body weight support, accumulating a total of 4,580 steps with this setup. We observed cardiovascular improvements and less dependency on walking assistance, but also partial neurological recovery in both patients, with substantial rates of motor improvement for one of them.

Subcortical neuronal ensembles: an analysis of motor task association, tremor, oscillations, and synchrony in human patients.

Deep brain stimulation (DBS) has expanded as an effective treatment for motor disorders, providing a valuable opportunity for intraoperative recording of the spiking activity of subcortical neurons. The properties of these neurons and their potential utility in neuroprosthetic applications are not completely understood. During DBS surgeries in 25 human patients with either essential tremor or Parkinson's disease, we acutely recorded the single-unit activity of 274 ventral intermediate/ventral oralis posterior motor thalamus (Vim/Vop) neurons and 123 subthalamic nucleus (STN) neurons. These subcortical neuronal ensembles (up to 23 neurons sampled simultaneously) were recorded while the patients performed a target-tracking motor task using a cursor controlled by a haptic glove. We observed that modulations in firing rate of a substantial number of neurons in both Vim/Vop and STN represented target onset, movement onset/direction, and hand tremor. Neurons in both areas exhibited rhythmic oscillations and pairwise synchrony. Notably, all tremor-associated neurons exhibited synchrony within the ensemble. The data further indicate that oscillatory (likely pathological) neurons and behaviorally tuned neurons are not distinct but rather form overlapping sets. Whereas previous studies have reported a linear relationship between power spectra of neuronal oscillations and hand tremor, we report a nonlinear relationship suggestive of complex encoding schemes. Even in the presence of this pathological activity, linear models were able to extract motor parameters from ensemble discharges. Based on these findings, we propose that chronic multielectrode recordings from Vim/Vop and STN could prove useful for further studying, monitoring, and even treating motor disorders.

A distinctive subpopulation of medial septal slow-firing neurons promote hippocampal activation and theta oscillations.

The medial septum-vertical limb of the diagonal band of Broca (MSvDB) is important for normal hippocampal functions and theta oscillations. Although many previous studies have focused on understanding how MSVDB neurons fire rhythmic bursts to pace hippocampal theta oscillations, a significant portion of MSVDB neurons are slow-firing and thus do not pace theta oscillations. The function of these MSVDB neurons, especially their role in modulating hippocampal activity, remains unknown. We recorded MSVDB neuronal ensembles in behaving rats, and identified a distinct physiologically homogeneous subpopulation of slow-firing neurons (overall firing <4 Hz) that shared three features: 1) much higher firing rate during rapid eye movement sleep than during slow-wave (SW) sleep; 2) temporary activation associated with transient arousals during SW sleep; 3) brief responses (latency 15∼30 ms) to auditory stimuli. Analysis of the fine temporal relationship of their spiking and theta oscillations showed that unlike the theta-pacing neurons, the firing of these "pro-arousal" neurons follows theta oscillations. However, their activity precedes short-term increases in hippocampal oscillation power in the theta and gamma range lasting for a few seconds. Together, these results suggest that these pro-arousal slow-firing MSvDB neurons may function collectively to promote hippocampal activation.

Restoration of locomotive function in Parkinson's disease by spinal cord stimulation: mechanistic approach.

Specific motor symptoms of Parkinson's disease (PD) can be treated effectively with direct electrical stimulation of deep nuclei in the brain. However, this is an invasive procedure, and the fraction of eligible patients is rather low according to currently used criteria. Spinal cord stimulation (SCS), a minimally invasive method, has more recently been proposed as a therapeutic approach to alleviate PD akinesia, in light of its proven ability to rescue locomotion in rodent models of PD. The mechanisms accounting for this effect are unknown but, from accumulated experience with the use of SCS in the management of chronic pain, it is known that the pathways most probably activated by SCS are the superficial fibers of the dorsal columns. We suggest that the prokinetic effect of SCS results from direct activation of ascending pathways reaching thalamic nuclei and the cerebral cortex. The afferent stimulation may, in addition, activate brainstem nuclei, contributing to the initiation of locomotion. On the basis of the striking change in the corticostriatal oscillatory mode of neuronal activity induced by SCS, we propose that, through activation of lemniscal and brainstem pathways, the locomotive increase is achieved by disruption of antikinetic low-frequency (<30 Hz) oscillatory synchronization in the corticobasal ganglia circuits.

Spinal cord stimulation restores locomotion in animal models of Parkinson's disease.

Dopamine replacement therapy is useful for treating motor symptoms in the early phase of Parkinson's disease, but it is less effective in the long term. Electrical deep-brain stimulation is a valuable complement to pharmacological treatment but involves a highly invasive surgical procedure. We found that epidural electrical stimulation of the dorsal columns in the spinal cord restores locomotion in both acute pharmacologically induced dopamine-depleted mice and in chronic 6-hydroxydopamine-lesioned rats. The functional recovery was paralleled by a disruption of aberrant low-frequency synchronous corticostriatal oscillations, leading to the emergence of neuronal activity patterns that resemble the state normally preceding spontaneous initiation of locomotion. We propose that dorsal column stimulation might become an efficient and less invasive alternative for treatment of Parkinson's disease in the future.

Brain-machine interfaces: past, present and future.

Since the original demonstration that electrical activity generated by ensembles of cortical neurons can be employed directly to control a robotic manipulator, research on brain-machine interfaces (BMIs) has experienced an impressive growth. Today BMIs designed for both experimental and clinical studies can translate raw neuronal signals into motor commands that reproduce arm reaching and hand grasping movements in artificial actuators. Clearly, these developments hold promise for the restoration of limb mobility in paralyzed subjects. However, as we review here, before this goal can be reached several bottlenecks have to be passed. These include designing a fully implantable biocompatible recording device, further developing real-time computational algorithms, introducing a method for providing the brain with sensory feedback from the actuators, and designing and building artificial prostheses that can be controlled directly by brain-derived signals. By reaching these milestones, future BMIs will be able to drive and control revolutionary prostheses that feel and act like the human arm.

Computing with thalamocortical ensembles during different behavioural states.

A series of recent studies have indicated that ensembles of neurones, distributed within the neural structures that form the primary thalamocortical loop (TCL) of the trigeminal component of the rat somatosensory system, change the way they respond to similar tactile stimuli, according to both the behavioural strategy employed by animals to gather information and the animal's internal brain states. These findings suggest that top-down influences, which are more likely to play a role during active discrimination than during passive whisker stimulation, may alter the pattern of neuronal firing within both the distinct layers of the primary somatosensory cortex (S1) and the ventral posterior medial nucleus (VPM). We propose that through this physiological process, which involves concurrent dynamic modulations at both cellular and circuit levels in the TCL, rats can either optimize the detection of novel or hard to sense stimuli or they can analyse complex patterns of multi-whisker stimulation, during natural exploration of their surrounding environment.

Reduction of single-neuron firing uncertainty by cortical ensembles during motor skill learning.

Motor skill learning is usually characterized by shortening of response time and performance of faster, more stereotypical movements. However, little is known about the changes in neural activity that underlie these behavioral changes. Here we used chronically implanted electrode arrays to record neuronal activity in the rat primary motor cortex (MI) as animals learned to execute movements in two directions. Strong modulation of MI single-neuron activity was observed while movement duration of the animal decreased. Despite many learning-induced changes, the precision with which single neurons fire did not improve with learning. Hence, prediction of movement direction from single neurons was bounded. In contrast, prediction of movement direction using neuronal ensembles improved significantly with learning, suggesting that, with practice, neuronal ensembles learn to overcome the uncertainty introduced by single-neuron stochastic activity.

Long-lasting novelty-induced neuronal reverberation during slow-wave sleep in multiple forebrain areas.

The discovery of experience-dependent brain reactivation during both slow-wave (SW) and rapid eye-movement (REM) sleep led to the notion that the consolidation of recently acquired memory traces requires neural replay during sleep. To date, however, several observations continue to undermine this hypothesis. To address some of these objections, we investigated the effects of a transient novel experience on the long-term evolution of ongoing neuronal activity in the rat forebrain. We observed that spatiotemporal patterns of neuronal ensemble activity originally produced by the tactile exploration of novel objects recurred for up to 48 h in the cerebral cortex, hippocampus, putamen, and thalamus. This novelty-induced recurrence was characterized by low but significant correlations values. Nearly identical results were found for neuronal activity sampled when animals were moving between objects without touching them. In contrast, negligible recurrence was observed for neuronal patterns obtained when animals explored a familiar environment. While the reverberation of past patterns of neuronal activity was strongest during SW sleep, waking was correlated with a decrease of neuronal reverberation. REM sleep showed more variable results across animals. In contrast with data from hippocampal place cells, we found no evidence of time compression or expansion of neuronal reverberation in any of the sampled forebrain areas. Our results indicate that persistent experience-dependent neuronal reverberation is a general property of multiple forebrain structures. It does not consist of an exact replay of previous activity, but instead it defines a mild and consistent bias towards salient neural ensemble firing patterns. These results are compatible with a slow and progressive process of memory consolidation, reflecting novelty-related neuronal ensemble relationships that seem to be context- rather than stimulus-specific. Based on our current and previous results, we propose that the two major phases of sleep play distinct and complementary roles in memory consolidation: pretranscriptional recall during SW sleep and transcriptional storage during REM sleep.

Gustatory processing is dynamic and distributed.

The process of gustatory coding consists of neural responses that provide information about the quantity and quality of food, its generalized sensation, its hedonic value, and whether it should be swallowed. Many of the models presently used to analyze gustatory signals are static in that they use the average neural firing rate as a measure of activity and are unimodal in the sense they are thought to only involve chemosensory information. We have recently elaborated upon a dynamic model of gustatory coding that involves interactions between neurons in single as well as in spatially separate, gustatory and somatosensory regions. We propose that the specifics of gustatory responses grow not only out of information ascending from taste receptor cells, but also from the cycling of information around a massively interconnected system.

Thalamocortical [correction of Thalamcortical] optimization of tactile processing according to behavioral state.

We propose a conceptual model that describes the operation of the main thalamocortical loop of the rat somatosensory system. According to this model, the asynchronous convergence of ascending and descending projections dynamically alters the physiological properties of thalamic neurons in the ventral posterior medial (VPM) nucleus as rats shift between three behavioral states. Two of these states are characterized by distinct modes of rhythmic whisker movements. We posit that these simultaneous shifts in exploratory behavioral strategy and in the physiological properties of VPM neurons allow rats to either (i) optimize the detection of stimuli that are novel or difficult to sense or (ii) process complex patterns of multi-whisker stimulation.

Depression at thalamocortical synapses: the key for cortical neuronal adaptation?

Neuronal adaptation to repetitive sensory stimuli is ubiquitous in the mammalian cortex. Despite its prevalence, the cellular mechanisms underlying this basic physiological property remain a matter of dispute. In this issue of Neuron, Chung et al. provide conclusive evidence that depression of thalamocortical synapses may play a significant role in the expression of neuronal adaptation in the rat somatosensory cortex.

Dynamic shifting in thalamocortical processing during different behavioural states.

Recent experiments in our laboratory have indicated that as rats shift the behavioural strategy employed to explore their surrounding environment, there is a parallel change in the physiological properties of the neuronal ensembles that define the main thalamocortical loop of the trigeminal somatosensory system. Based on experimental evidence from several laboratories, we propose that this concurrent shift in behavioural strategy and thalamocortical physiological properties provides rats with an efficient way to optimize either the detection or analysis of complex tactile stimuli.