Hindlimb Somatosensory Information Influences Trunk Sensory and Motor Cortices to Support Trunk Stabilization.

Sensorimotor integration in the trunk system is poorly understood despite its importance for functional recovery after neurological injury. To address this, a series of mapping studies were performed in the rat. First, the receptive fields (RFs) of cells recorded from thoracic dorsal root ganglia were identified. Second, the RFs of cells recorded from trunk primary sensory cortex (S1) were used to assess the extent and internal organization of trunk S1. Finally, the trunk motor cortex (M1) was mapped using intracortical microstimulation to assess coactivation of trunk muscles with hindlimb and forelimb muscles, and integration with S1. Projections from trunk S1 to trunk M1 were not anatomically organized, with relatively weak sensorimotor integration between trunk S1 and M1 compared to extensive integration between hindlimb S1/M1 and trunk M1. Assessment of response latency and anatomical tracing suggest that trunk M1 is abundantly guided by hindlimb somatosensory information that is derived primarily from the thalamus. Finally, neural recordings from awake animals during unexpected postural perturbations support sensorimotor integration between hindlimb S1 and trunk M1, providing insight into the role of the trunk system in postural control that is useful when studying recovery after injury.

Effect of spinal cord injury on neural encoding of spontaneous postural perturbations in the hindlimb sensorimotor cortex.

Supraspinal signals play a significant role in compensatory responses to postural perturbations. Although the cortex is not necessary for basic postural tasks in intact animals, its role in responding to unexpected postural perturbations after spinal cord injury (SCI) has not been studied. To better understand how SCI impacts cortical encoding of postural perturbations, the activity of single neurons in the hindlimb sensorimotor cortex (HLSMC) was recorded in the rat during unexpected tilts before and after a complete midthoracic spinal transection. In a subset of animals, limb ground reaction forces were also collected. HLSMC activity was strongly modulated in response to different tilt profiles. As the velocity of the tilt increased, more information was conveyed by the HLSMC neurons about the perturbation due to increases in both the number of recruited neurons and the magnitude of their responses. SCI led to attenuated and delayed hindlimb ground reaction forces. However, HLSMC neurons remained responsive to tilts after injury but with increased latencies and decreased tuning to slower tilts. Information conveyed by cortical neurons about the tilts was therefore reduced after SCI, requiring more cells to convey the same amount of information as before the transection. Given that reorganization of the hindlimb sensorimotor cortex in response to therapy after complete midthoracic SCI is necessary for behavioral recovery, this sustained encoding of information after SCI could be a substrate for the reorganization that uses sensory information from above the lesion to control trunk muscles that permit weight-supported stepping and postural control.NEW & NOTEWORTHY The role of cortical circuits in the encoding of posture and balance is of interest for developing therapies for spinal cord injury. This work demonstrated that unexpected postural perturbations are encoded in the hindlimb sensorimotor cortex even in the absence of hindlimb sensory feedback. In fact, the hindlimb sensorimotor cortex continues to encode for postural perturbations after complete spinal transection.

From adagio to allegretto: The changing tempo of theta frequencies in epilepsy and its relation to interneuron function.

Despite decades of research, our understanding of epilepsy, including how seizures are generated and propagate, is incomplete. However, there is growing recognition that epilepsy is more than just the occurrence of seizures, with patients often experiencing comorbid deficits in cognition that are poorly understood. In addition, the available therapies for treatment of epilepsy, from pharmaceutical treatment to surgical resection and seizure prevention devices, often exacerbate deficits in cognitive function. In this review, we discuss the hypothesis that seizure generation and cognitive deficits have a similar pathological source characterized by, but not limited to, deficits in theta oscillations and their influence on interneurons. We present a new framework that describes oscillatory states in epilepsy as alternating between hyper- and hypo-synchrony rather than solely the spontaneous transition to hyper-excitability characterized by the seizures. This framework suggests that as neural oscillations, specifically in the theta range, vary their tempo from a slowed almost adagio tempo during interictal periods to faster, more rhythmic allegretto tempo preictally, they impact the function of interneurons, modulating their ability to control seizures and their role in cognitive processing. This slow wave oscillatory framework may help explain why current therapies that work to reduce hyper-excitability do not completely eliminate seizures and often lead to exacerbated cognitive deficits.

Adaptation of Thalamic Neurons Provides Information about the Spatiotemporal Context of Stimulus History.

Adaptation of neural responses due to the history of sensory input has been observed across all sensory modalities. However, the computational role of adaptation is not fully understood, especially when one considers neural coding problems in which adaptation increases the ambiguity of the neural responses to simple stimuli. To address this, we quantified the impact of adaptation on the information conveyed by thalamic neurons about paired whisker stimuli in male rat. At the single neuron level, although paired-pulse adaptation reduces the information about the present stimulus, the information per spike increases. Moreover, the adapted response can convey significant amounts of information about whether, when and where a previous stimulus occurred. At the population level, ambiguity of the adapted responses about the present stimulus can be compensated for by large numbers of neurons. Therefore, paired-pulse adaptation does not reduce the discriminability of simple stimuli. It provides information about the spatiotemporal context of stimulus history.SIGNIFICANCE STATEMENT The present work provides a computational framework that demonstrates how adaptation allows neurons to encode spatiotemporal dynamics of stimulus history.

Increased neuronal synchrony prepares mesial temporal networks for seizures of neocortical origin.

OBJECTIVE: To gain understanding of the neuronal mechanisms underlying regional seizure spread, the impact of regional synchrony between seizure focus and downstream networks on neuronal activity during the transition to seizure in those downstream networks was assessed. METHODS: Seven patients undergoing diagnostic intracranial electroencephalographic studies for surgical resection of epileptogenic regions were implanted with subdural clinical electrodes into the cortex (site of seizure initiation) and mesial temporal lobe (MTL) structures (downstream) as well as microwires into MTL. Neural activity was recorded (24/7) in parallel with the clinical intracranial electroencephalogram recordings for the duration of the patient's diagnostic stay. Changes in (1) regional synchrony (ie, coherence) between the presumptive neocortical seizure focus and MTL, (2) local synchrony between MTL neurons and their local field potential, and (3) neuronal firing rates within MTL in the time leading up to seizure were examined to study the mechanisms underlying seizure spread. RESULTS: In seizures of neocortical origin, an increase in regional synchrony preceded the spread of seizures into MTL (predominantly hippocampal). Within frequencies similar to those of regional synchrony, MTL networks showed an increase in unit-field coherence and a decrease in neuronal firing rate, specifically for inhibitory interneuron populations but not pyramidal cell populations. SIGNIFICANCE: These results suggest a mechanism of spreading seizures whereby the seizure focus first synchronizes local field potentials in downstream networks to the seizure activity. This change in local field coherence modifies the activity of interneuron populations in these downstream networks, which leads to the attenuation of interneuronal firing rate, effectively shutting down local interneuron populations prior to the spread of seizure. Therefore, regional synchrony may influence the failure of downstream interneurons to prevent the spread of the seizures during generalization.

Dissociating movement from movement timing in the rat primary motor cortex.

Neural encoding of the passage of time to produce temporally precise movements remains an open question. Neurons in several brain regions across different experimental contexts encode estimates of temporal intervals by scaling their activity in proportion to the interval duration. In motor cortex the degree to which this scaled activity relies upon afferent feedback and is guided by motor output remains unclear. Using a neural reward paradigm to dissociate neural activity from motor output before and after complete spinal transection, we show that temporally scaled activity occurs in the rat hindlimb motor cortex in the absence of motor output and after transection. Context-dependent changes in the encoding are plastic, reversible, and re-established following injury. Therefore, in the absence of motor output and despite a loss of afferent feedback, thought necessary for timed movements, the rat motor cortex displays scaled activity during a broad range of temporally demanding tasks similar to that identified in other brain regions.

Trial-to-trial variability in the responses of neurons carries information about stimulus location in the rat whisker thalamus.

From the perspective of neural coding, the considerable trial-to-trial variability in the responses of neurons to sensory stimuli is puzzling. Trial-to-trial response variability is typically interpreted in terms of "noise" (i.e., it represents either intrinsic noise of the system or information unrelated to the stimuli). However, trial-to-trial response variability can be considerably different across stimuli, suggesting that it could also provide an important contribution to the information conveyed by the neural responses about the stimuli. To test this hypothesis, we addressed the problem of discriminating stimulus location from the spike-count responses of neurons recorded in the ventro-postero-medial (VPM) nucleus of the thalamus in anesthetized rats. Using a recently developed information theory approach, we verified that differences between stimuli in the trial-to-trial spike-count variability of the responses provided an important contribution to the overall information carried by the neurons. In addition, we found that the relatively reliable (sub-Poisson) firing regime of our VPM neurons was not only more informative, but also more redundant between neurons compared with a more variable (Poisson) firing regime with the same total number of spikes. The typical increase in trial-to-trial response variability from the periphery to the cortex could therefore serve as a strategy to reduce redundancy between neurons and promote efficient sparse coding distributed in large populations of neurons. Overall, our data suggest that the trial-to-trial response variability plays a critical role in establishing the trade-off between total information and redundancy between neurons in population codes.

Transitioning from global to local computational strategies during brain-machine interface learning.

When learning to use a brain-machine interface (BMI), the brain modulates neuronal activity patterns, exploring and exploiting the state space defined by their neural manifold. Neurons directly involved in BMI control (i.e., direct neurons) can display marked changes in their firing patterns during BMI learning. However, the extent of firing pattern changes in neurons not directly involved in BMI control (i.e., indirect neurons) remains unclear. To clarify this issue, we localized direct and indirect neurons to separate hemispheres in a task designed to bilaterally engage these hemispheres while animals learned to control the position of a platform with their neural signals. Animals that learned to control the platform and improve their performance in the task shifted from a global strategy, where both direct and indirect neurons modified their firing patterns, to a local strategy, where only direct neurons modified their firing rate, as animals became expert in the task. Animals that did not learn the BMI task did not shift from utilizing a global to a local strategy. These results provide important insights into what differentiates successful and unsuccessful BMI learning and the computational mechanisms adopted by the neurons.

Exercise therapy guides cortical reorganization after midthoracic spinal contusion to enhance control of lower thoracic muscles, supporting functional recovery.

Postural control is critical for locomotion, allowing for gait changes, obstacle avoidance and navigation of rough terrain. A major problem after spinal cord injury (SCI) is regaining the control of balance to prevent falls and further injury. While the circuits for locomotor pattern generation reside in the spinal cord, postural control consists of multiple, complex networks that interact at the spinal, brainstem and cortical levels. After complete SCI, cortical reorganization establishes novel control of trunk musculature that is required for weight-supported stepping. In this study, we examined the impact of exercise therapy on cortical reorganization in the more clinically relevant models of both moderate and severe midthoracic contusion injury in the rat. Results demonstrate that both spontaneous recovery and therapy induced recovery of weight-supported stepping utilize cortical reorganization. Moreover, exercise therapy further improves outcome by enhancing cortical control of lower thoracic muscles enabling improvements in interlimb coordination associated with improved balance that increases weight-supported stepping. The outcome of this study suggest that cortical control of posture is key to functional improvement in locomotion. This information can be used to improve the timing and type of therapy after SCI by considering changes along the entire neural axis.

Neural ensemble dynamics in trunk and hindlimb sensorimotor cortex encode for the control of postural stability.

The cortex has a disputed role in monitoring postural equilibrium and intervening in cases of major postural disturbances. Here, we investigate the patterns of neural activity in the cortex that underlie neural dynamics during unexpected perturbations. In both the primary sensory (S1) and motor (M1) cortices of the rat, unique neuronal classes differentially covary their responses to distinguish different characteristics of applied postural perturbations; however, there is substantial information gain in M1, demonstrating a role for higher-order computations in motor control. A dynamical systems model of M1 activity and forces generated by the limbs reveals that these neuronal classes contribute to a low-dimensional manifold comprised of separate subspaces enabled by congruent and incongruent neural firing patterns that define different computations depending on the postural responses. These results inform how the cortex engages in postural control, directing work aiming to understand postural instability after neurological disease.

Responses of trigeminal ganglion neurons during natural whisking behaviors in the awake rat.

Rats use their whiskers to locate and discriminate tactile features of their environment. Mechanoreceptors surrounding each whisker encode and transmit sensory information from the environment to the brain via afferents whose cell bodies lie in the trigeminal ganglion (Vg). These afferents are classified as rapidly (RA) or slowly (SA) adapting by their response to stimulation. The activity of these cells in the awake behaving rat is yet unknown. Therefore, we developed a method to chronically record Vg neurons during natural whisking behaviors and found that all cells exhibited (1) no neuronal activity when the whiskers were not in motion, (2) increased activity when the rat whisked, with activity correlated to whisk frequency, and (3) robust increases in activity when the whiskers contacted an object. Moreover, we observed distinct differences in the firing rates between RA and SA cells, suggesting that they encode distinct aspects of stimuli in the awake rat.

Spinal cord injury immediately changes the state of the brain.

Spinal cord injury can produce extensive long-term reorganization of the cerebral cortex. Little is known, however, about the sequence of cortical events starting immediately after the lesion. Here we show that a complete thoracic transection of the spinal cord produces immediate functional reorganization in the primary somatosensory cortex of anesthetized rats. Besides the obvious loss of cortical responses to hindpaw stimuli (below the level of the lesion), cortical responses evoked by forepaw stimuli (above the level of the lesion) markedly increase. Importantly, these increased responses correlate with a slower and overall more silent cortical spontaneous activity, representing a switch to a network state of slow-wave activity similar to that observed during slow-wave sleep. The same immediate cortical changes are observed after reversible pharmacological block of spinal cord conduction, but not after sham. We conclude that the deafferentation due to spinal cord injury can immediately (within minutes) change the state of large cortical networks, and that this state change plays a critical role in the early cortical reorganization after spinal cord injury.

Modelling at-level allodynia after mid-thoracic contusion in the rat.

BACKGROUND: The rat mid-thoracic contusion model has been used to study at-level tactile allodynia, a common type of pain that develops after spinal cord injury (SCI). An important advantage of this model is that not all animals develop hypersensitivity. Therefore, it can be used to examine mechanisms that are strictly related to the development of pain-like behaviour separately from mechanisms related to the injury itself. However, how to separate animals that develop hypersensitivity from those that do not is unclear. METHODS: The aims of the current study were to identify where hypersensitivity and spasticity develop and use this information to identify metrics to separate animals that develop hypersensitivity from those that do not to study differences in their behaviour. To accomplish these aims, a grid was used to localize hypersensitivity on the dorsal trunk relative to thoracic dermatomes and supraspinal responses to tactile stimulation were tallied. These supraspinal responses were used to develop a hypersensitivity score to separate animals that develop hypersensitivity, or pain-like response to nonpainful stimuli. RESULTS: Similar to humans, the development of hypersensitivity could occur with the development of spasticity or hyperreflexia. Moreover, the time course and prevalence of hypersensitivity phenotypes (at-, above-, or below level) produced by this model were similar to that observed in humans with SCI. CONCLUSION: However, the amount of spared spinal matter in the cord did not explain the development of hypersensitivity, as previously reported. This approach can be used to study the mechanisms underlying the development of hypersensitivity separately from mechanisms related to injury alone.

Head-mounted microendoscopic calcium imaging in dorsal premotor cortex of behaving rhesus macaque.

Microendoscopic calcium imaging with one-photon miniature microscopes enables unprecedented readout of neural circuit dynamics during active behavior in rodents. In this study, we describe successful application of this technology in the rhesus macaque, demonstrating plug-and-play, head-mounted recordings of cellular-resolution calcium dynamics from large populations of neurons simultaneously in bilateral dorsal premotor cortices during performance of a naturalistic motor reach task. Imaging is stable over several months, allowing us to longitudinally track individual neurons and monitor their relationship to motor behavior over time. We observe neuronal calcium dynamics selective for reach direction, which we could use to decode the animal's trial-by-trial motor behavior. This work establishes head-mounted microendoscopic calcium imaging in macaques as a powerful approach for studying the neural circuit mechanisms underlying complex and clinically relevant behaviors, and it promises to greatly advance our understanding of human brain function, as well as its dysfunction in neurological disease.

Short-training Algorithm for Online Brain-machine Interfaces Using One-photon Microendoscopic Calcium Imaging.

Calcium imaging has great potential to be applied to online brain-machine interfaces (BMIs). As opposed to two-photon imaging settings, a one-photon microendoscopic imaging device can be chronically implanted and is subject to little motion artifacts. Traditionally, one-photon microendoscopic calcium imaging data are processed using the constrained nonnegative matrix factorization (CNMFe) algorithm, but this batched processing algorithm cannot be applied in real-time. An online analysis of calcium imaging data algorithm (or OnACIDe) has been proposed, but OnACIDe updates the neural components by repeatedly performing neuron identification frame-by-frame, which may decelerate the update speed if applying to online BMIs. For BMI applications, the ability to track a stable population of neurons in real-time has a higher priority over accurately identifying all the neurons in the field of view. By leveraging the fact that 1) microendoscopic recordings are rather stable with little motion artifacts and 2) the number of neurons identified in a short training period is sufficient for potential online BMI tasks such as cursor movements, we proposed the short-training CNMFe algorithm (stCNMFe) that skips motion correction and neuron identification processes to enable a more efficient BMI training program in a one-photon microendoscopic setting.

Exercise induces cortical plasticity after neonatal spinal cord injury in the rat.

Exercise-induced cortical plasticity is associated with improved functional outcome after brain or nerve injury. Exercise also improves functional outcomes after spinal cord injury, but its effects on cortical plasticity are not known. The goal of this investigation was to study the effect of moderate exercise (treadmill locomotion, 3 min/d, 5 d/week) on the somatotopic organization of forelimb and hindlimb somatosensory cortex (SI) after neonatal thoracic transection. We used adult rats spinalized as neonates because some of these animals develop weight-supported stepping, and, therefore, the relationship between cortical plasticity and stepping could also be examined. Acute, single-neuron mapping was used to determine the percentage of cortical cells responding to cutaneous forelimb stimulation in normal, spinalized, and exercised spinalized rats. Multiple single-neuron recording from arrays of chronically implanted microwires examined the magnitude of response of these cells in normal and exercised spinalized rats. Our results show that exercise not only increased the percentage of responding cells in the hindlimb SI but also increased the magnitude of the response of these cells. This increase in response magnitude was correlated with behavioral outcome measures. In the forelimb SI, neonatal transection reduced the percentage of responding cells to forelimb stimulation, but exercise reversed this loss. This restoration in the percentage of responding cells after exercise was accompanied by an increase in their response magnitude. Therefore, the increase in responsiveness of hindlimb SI to forelimb stimulation after neonatal transection and exercise may be due, in part, to the effect of exercise on the forelimb SI.

Continuous infusion of an agonist of the tumor necrosis factor receptor 2 in the spinal cord improves recovery after traumatic contusive injury.

AIM: The activation of the TNFR2 receptor is beneficial in several pathologies of the central nervous system, and this study examines whether it can ameliorate the recovery process following spinal cord injury. METHODS: EHD2-sc-mTNFR2 , an agonist specific for TNFR2, was used to treat neurons exposed to high levels of glutamate in vitro. In vivo, it was infused directly to the spinal cord via osmotic pumps immediately after a contusion to the cord at the T9 level. Locomotion behavior was assessed for 6 weeks, and the tissue was analyzed (lesion size, RNA and protein expression, cell death) after injury. Somatosensory evoked potentials were also measured in response to hindlimb stimulation. RESULTS: The activation of TNFR2 protected neurons from glutamate-mediated excitotoxicity through the activation of phosphoinositide-3 kinase gamma in vitro and improved the locomotion of animals following spinal cord injury. The extent of the injury was not affected by infusing EHD2-sc-mTNFR2 , but higher levels of neurofilament H and 2', 3'-cyclic-nucleotide 3'-phosphodiesterase were observed 6 weeks after the injury. Finally, the activation of TNFR2 after injury increased the neural response recorded in the cortex following hindlimb stimulation. CONCLUSION: The activation of TNFR2 in the spinal cord following contusive injury leads to enhanced locomotion and better cortical responses to hindlimb stimulation.

Biomimetic brain machine interfaces for the control of movement.

Quite recently, it has become possible to use signals recorded simultaneously from large numbers of cortical neurons for real-time control. Such brain machine interfaces (BMIs) have allowed animal subjects and human patients to control the position of a computer cursor or robotic limb under the guidance of visual feedback. Although impressive, such approaches essentially ignore the dynamics of the musculoskeletal system, and they lack potentially critical somatosensory feedback. In this mini-symposium, we will initiate a discussion of systems that more nearly mimic the control of natural limb movement. The work that we will describe is based on fundamental observations of sensorimotor physiology that have inspired novel BMI approaches. We will focus on what we consider to be three of the most important new directions for BMI development related to the control of movement. (1) We will present alternative methods for building decoders, including structured, nonlinear models, the explicit incorporation of limb state information, and novel approaches to the development of decoders for paralyzed subjects unable to generate an output signal. (2) We will describe the real-time prediction of dynamical signals, including joint torque, force, and EMG, and the real-time control of physical plants with dynamics like that of the real limb. (3) We will discuss critical factors that must be considered to incorporate somatosensory feedback to the BMI user, including its potential benefits, the differing representations of sensation and perception across cortical areas, and the changes in the cortical representation of tactile events after spinal injury.

A rodent brain-machine interface paradigm to study the impact of paraplegia on BMI performance.

BACKGROUND: Most brain machine interfaces (BMI) focus on upper body function in non-injured animals, not addressing the lower limb functional needs of those with paraplegia. A need exists for a novel BMI task that engages the lower body and takes advantage of well-established rodent spinal cord injury (SCI) models to study methods to improve BMI performance. NEW METHOD: A tilt BMI task was designed that randomly applies different types of tilts to a platform, decodes the tilt type applied and rights the platform if the decoder correctly classifies the tilt type. The task was tested on female rats and is relatively natural such that it does not require the animal to learn a new skill. It is self-rewarding such that there is no need for additional rewards, eliminating food or water restriction, which can be especially hard on spinalized rats. Finally, task difficulty can be adjusted by making the tilt parameters. RESULTS: This novel BMI task bilaterally engages the cortex without visual feedback regarding limb position in space and animals learn to improve their performance both pre and post-SCI.Comparison with Existing Methods: Most BMI tasks primarily engage one hemisphere, are upper-body, rely heavily on visual feedback, do not perform investigations in animal models of SCI, and require nonnaturalistic extrinsic motivation such as water rewarding for performance improvement. Our task addresses these gaps. CONCLUSIONS: The BMI paradigm presented here will enable researchers to investigate the interaction of plasticity after SCI and plasticity during BMI training on performance.

Serotonin receptor and dendritic plasticity in the spinal cord mediated by chronic serotonergic pharmacotherapy combined with exercise following complete SCI in the adult rat.

Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy. 5-HT, 5-HT2AR, 5-HT1AR, and dendritic densities were quantified both early (1 week) and late (9 weeks) after SCI, and also following therapeutic interventions (5-HT pharmacotherapy, bike therapy, or a combination). Interestingly, chronic 5-HT pharmacotherapy largely normalized spinal 5-HTR upregulation following injury. Improvement in locomotor behavior was not correlated to 5-HTR density. These results support the hypothesis that chronic 5-HT pharmacotherapy can mediate recovery following SCI, despite acting on largely normal spinal 5-HTR levels. We next assessed spinal dendritic plasticity and its potential role in locomotor recovery. Single therapies did not normalize the loss of dendritic density after SCI. Groups displaying significantly atrophied dendritic processes were rarely able to achieve weight supported open-field locomotion. Only a combination of 5-HT pharmacotherapy and bike therapy enabled significant open-field weigh-supported stepping, mediated in part by restoring spinal dendritic density. These results support the use of combined therapies to synergistically impact multiple markers of spinal plasticity and improve motor recovery.