Pharmacological blocking of spinal GABA receptors in monkeys reduces sensory transmission to the spinal cord, thalamus, and cortex.

A century of research established that GABA inhibits proprioceptive inputs presynaptically to sculpt spinal neural inputs into skilled motor output. Recent results in mice challenged this theory by showing that GABA can also facilitate action potential conduction in proprioceptive afferents. Here, we tackle this controversy in monkeys, the most human-relevant animal model, and show that GABA receptors (GABARs) indeed facilitate sensory inputs to spinal motoneurons and interneurons and that this mechanism also influences sensory transmission to supraspinal centers.

Potentiation of cortico-spinal output via targeted electrical stimulation of the motor thalamus.

Cerebral white matter lesions prevent cortico-spinal descending inputs from effectively activating spinal motoneurons, leading to loss of motor control. However, in most cases, the damage to cortico-spinal axons is incomplete offering a potential target for therapies aimed at improving volitional muscle activation. Here we hypothesize that, by engaging direct excitatory connections to cortico-spinal motoneurons, stimulation of the motor thalamus could facilitate activation of surviving cortico-spinal fibers thereby immediately potentiating motor output.

The effects of neuron morphology and spatial distribution on the selectivity of dorsal root ganglion stimulation.

For prosthesis users, sensory feedback that appears to come from the missing limb can improve function, confidence, and phantom limb pain. Numerous pre-clinical studies have considered stimulation via penetrating microelectrodes at the dorsal root ganglion (DRG) as a potential approach for somatosensory neuroprostheses. However, to develop clinically translatable neuroprosthetic devices, a less invasive approach, such as stimulation via epineural macroelectrodes, would be preferable.

Dysfunction of proprioceptive sensory synapses is a pathogenic event and therapeutic target in mice and humans with spinal muscular atrophy.

Spinal muscular atrophy (SMA) is a neurodegenerative disease characterized by a varying degree of severity that correlates with the reduction of SMN protein levels. Motor neuron degeneration and skeletal muscle atrophy are hallmarks of SMA, but it is unknown whether other mechanisms contribute to the spectrum of clinical phenotypes. Here, through a combination of physiological and morphological studies in mouse models and SMA patients, we identify dysfunction and loss of proprioceptive sensory synapses as key signatures of SMA pathology.

Biophysics of Frequency-Dependent Variation in Paresthesia and Pain Relief during Spinal Cord Stimulation.

The neurophysiological effects of spinal cord stimulation (SCS) for chronic pain are poorly understood, resulting in inefficient failure-prone programming protocols and inadequate pain relief. Nonetheless, novel stimulation patterns are regularly introduced and adopted clinically. Traditionally, paresthetic sensation is considered necessary for pain relief, although novel paradigms provide analgesia without paresthesia.