Regeneration of Propriospinal Axons in Rat Transected Spinal Cord Injury through a Growth-Promoting Pathway Constructed by Schwann Cells Overexpressing GDNF.

Unsuccessful axonal regeneration in transected spinal cord injury (SCI) is mainly attributed to shortage of growth factors, inhibitory glial scar, and low intrinsic regenerating capacity of severely injured neurons. Previously, we constructed an axonal growth permissive pathway in a thoracic hemisected injury by transplantation of Schwann cells overexpressing glial-cell-derived neurotrophic factor (SCs-GDNF) into the lesion gap as well as the caudal cord and proved that this novel permissive bridge promoted the regeneration of descending propriospinal tract (dPST) axons across and beyond the lesion. In the current study, we subjected rats to complete thoracic (T11) spinal cord transections and examined whether these combinatorial treatments can support dPST axons' regeneration beyond the transected injury. The results indicated that GDNF significantly improved graft-host interface by promoting integration between SCs and astrocytes, especially the migration of reactive astrocyte into SCs-GDNF territory. The glial response in the caudal graft area has been significantly attenuated. The astrocytes inside the grafted area were morphologically characterized by elongated and slim process and bipolar orientation accompanied by dramatically reduced expression of glial fibrillary acidic protein. Tremendous dPST axons have been found to regenerate across the lesion and back to the caudal spinal cord which were otherwise difficult to see in control groups. The caudal synaptic connections were formed, and regenerated axons were remyelinated. The hindlimb locomotor function has been improved.

Long ascending propriospinal neurons are heterogenous and subject to spinal cord injury induced anatomic plasticity.

Long ascending propriospinal neurons (LAPNs) are a subset of spinal interneurons that provide direct connectivity between distant spinal segments. Here, we focus specifically on an anatomically defined population of "inter-enlargement" LAPNs with cell bodies at L2/3 and terminals at C5/6. Previous studies showed that silencing LAPNs in awake and freely moving animals disrupted interlimb coordination of the hindlimbs, forelimbs, and heterolateral limb pairs. Surprisingly, despite a proportion of LAPNs being anatomically intact post- spinal cord injury (SCI), silencing them improved locomotor function but only influenced coordination of the hindlimb pair. Given the functional significance of LAPNs pre- and post-SCI, we characterized their anatomy and SCI-induced anatomical plasticity. This detailed anatomical characterization revealed three morphologically distinct subsets of LAPNs that differ in soma size, neurite complexity and/or neurite orientation. Following a mild thoracic contusive SCI there was a marked shift in neurite orientation in two of the LAPN subsets to a more dorsoventral orientation, and collateral densities decreased in the cervical enlargement but increased just caudal to the injury epicenter. These post-SCI anatomical changes potentially reflect maladaptive plasticity and an effort to establish new functional inputs from sensory afferents that sprout post-SCI to achieve circuitry homeostasis.

Silencing long-descending inter-enlargement propriospinal neurons improves hindlimb stepping after contusive spinal cord injuries.

Spinal locomotor circuitry is comprised of rhythm generating centers, one for each limb, that are interconnected by local and long-distance propriospinal neurons thought to carry temporal information necessary for interlimb coordination and gait control. We showed previously that conditional silencing of the long ascending propriospinal neurons (LAPNs) that project from the lumbar to the cervical rhythmogenic centers (L1/L2 to C6), disrupts right-left alternation of both the forelimbs and hindlimbs without significantly disrupting other fundamental aspects of interlimb and speed-dependent coordination (Pocratsky et al., 2020). Subsequently, we showed that silencing the LAPNs after a moderate thoracic contusive spinal cord injury (SCI) resulted in better recovered locomotor function (Shepard et al., 2021). In this research advance, we focus on the descending equivalent to the LAPNs, the long descending propriospinal neurons (LDPNs) that have cell bodies at C6 and terminals at L2. We found that conditional silencing of the LDPNs in the intact adult rat resulted in a disrupted alternation of each limb pair (forelimbs and hindlimbs) and after a thoracic contusion SCI significantly improved locomotor function. These observations lead us to speculate that the LAPNs and LDPNs have similar roles in the exchange of temporal information between the cervical and lumbar rhythm generating centers, but that the partial disruption of the pathway after SCI limits the independent function of the lumbar circuitry. Silencing the LAPNs or LDPNs effectively permits or frees-up the lumbar circuitry to function independently.

Lumbar V3 interneurons provide direct excitatory synaptic input onto thoracic sympathetic preganglionic neurons, linking locomotor, and autonomic spinal systems.

Although sympathetic autonomic systems are activated in parallel with locomotion, the neural mechanisms mediating this coordination are incompletely understood. Sympathetic preganglionic neurons (SPNs), primarily located in the intermediate laminae of thoracic and upper lumbar segments (T1-L2), increase activation of tissues and organs that provide homeostatic and metabolic support during movement and exercise. Recent evidence suggests integration between locomotor and autonomic nuclei occurs within the brainstem, initiating both descending locomotor and sympathetic activation commands. However, both locomotor and sympathetic autonomic spinal systems can be activated independent of supraspinal input, in part due to a distributed network involving propriospinal neurons. Whether an intraspinal mechanism exists to coordinate activation of these systems is unknown. We hypothesized that ascending spinal neurons located in the lumbar region provide synaptic input to thoracic SPNs. Here, we demonstrate that synaptic contacts from locomotor-related V3 interneurons (INs) are present in all thoracic laminae. Injection of an anterograde tracer into lumbar segments demonstrated that 8-20% of glutamatergic input onto SPNs originated from lumbar V3 INs and displayed a somatotopographical organization of synaptic input. Whole cell patch clamp recording in SPNs demonstrated prolonged depolarizations or action potentials in response to optical activation of either lumbar V3 INs in spinal cord preparations or in response to optical activation of V3 terminals in thoracic slice preparations. This work demonstrates a direct intraspinal connection between lumbar locomotor and thoracic sympathetic networks and suggests communication between motor and autonomic systems may be a general function of the spinal cord.

Spinal control of locomotion before and after spinal cord injury.

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore-hind coupling together with appropriate control of left-right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.

A fresh look at propriospinal interneurons plasticity and intraspinal circuits remodeling after spinal cord injury.

Spinal cord injury (SCI) disrupts communication between the brain-derived descending commands and the intraspinal circuits, the central pattern generator (CPG), that execute movements. Dynamic changes in the interaction of the brain-spinal cord as well as in structure-function relationships play a vital role in the determination of neurological function restoration. These changes also have important clinical implications for the treatment of patients with SCI. After SCI, at both brain and spinal cord levels, detour circuits formation and neuronal plasticity have been linked to functional improvement under the condition of spontaneous recovery as well as electrical stimulation- and rehabilitative training-assisted recovery. The principles governing neural circuit remodeling and the neuronal subtypes specifically involved during the recovery from SCI are largely unknown. In the present review, we focus on how multi-level neural circuits are reconstructed after SCI. We highlight some new studies using rodent and zebrafish SCI models that describe how the intraspinal detour circuits are reconstructed and the important roles of spinal excitatory interneurons.

Corticospinal circuit neuroplasticity may involve silent synapses: Implications for functional recovery facilitated by neuromodulation after spinal cord injury.

Spinal cord injury (SCI) leads to devastating physical consequences, such as severe sensorimotor dysfunction even lifetime disability, by damaging the corticospinal system. The conventional opinion that SCI is intractable due to the poor regeneration of neurons in the adult central nervous system (CNS) needs to be revisited as the CNS is capable of considerable plasticity, which underlie recovery from neural injury. Substantial spontaneous neuroplasticity has been demonstrated in the corticospinal motor circuitry following SCI. Some of these plastic changes appear to be beneficial while others are detrimental toward locomotor function recovery after SCI. The beneficial corticospinal plasticity in the spared corticospinal circuits can be harnessed therapeutically by multiple contemporary neuromodulatory approaches, especially the electrical stimulation-based modalities, in an activity-dependent manner to improve functional outcomes in post-SCI rehabilitation. Silent synapse generation and unsilencing contribute to profound neuroplasticity that is implicated in a variety of neurological disorders, thus they may be involved in the corticospinal motor circuit neuroplasticity following SCI. Exploring the underlying mechanisms of silent synapse-mediated neuroplasticity in the corticospinal motor circuitry that may be exploited by neuromodulation will inform a novel direction for optimizing therapeutic repair strategies and rehabilitative interventions in SCI patients.

Propriospinal myoclonus: diagnostic value of polymyography and video polysomnography.

Propriospinal myoclonus is a hyperkinetic movement disorder characterized by painless jerks of the axial muscles, mainly in the trunk and hips. A 53-year-old woman was referred to the Sleep Unit with trunk flexion movements in the supine position during the wake-sleep transition and during sleep, with premonitory sensation. We performed 2 video polysomnographic recordings. In the first video polysomnogram, the recording showed jerks of the trunk and abdomen that appeared when the posterior dominant alpha rhythm disappeared; during these jerks the patient stayed at stage 1 or stage 2 of non-rapid eye movement sleep. The second video polysomnogram included several electromyogram electrodes located at the masseter, deltoid, rectus abdominis (T9-T0 level), vastus lateralis, and tibialis anterior muscles. This polysomnogram revealed 123 repetitive arrhythmic jerks with variable duration, usually lasting 500-1,900 ms each (906 ± 0.4 ms). In our patient, propriospinal myoclonus was detected up to stage 2 of non-rapid eye movement sleep and even at rapid eye movement sleep. CITATION: Ramos RW, Viñas LL, Martín ER, Cárdenas CL, Pereda AF, Manzanares LL. Propriospinal myoclonus: diagnostic value of polymyography and video polysomnography. J Clin Sleep Med. 2023;19(5):995-998.

Chx10+V2a interneurons in spinal motor regulation and spinal cord injury.

Chx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.

Expanding the Spectrum of Diabetic Striatopathy: Insights from a Case of Hyperglycemia-Induced Propriospinal Myoclonus.

This video abstract delves into the expanded definition of diabetic striatopathy, linked initially to hyperglycemia-induced choreoballism and striatal hyperintensity on magnetic resonance imaging, but now recognized to encompass a broader range of acute onset, non-choreoballistic movement disorders in diabetes mellitus, including tremors, hemifacial spasm, parkinsonism, different types of myoclonus, dystonia, restless leg syndrome, ataxia, and dyskinesias. We report the case of a 45-year-old female patient with type-2 diabetes mellitus who developed propriospinal myoclonus, characterized by painless, involuntary jerky movements of the bilateral lower limbs in a supine position after admission for suspected rhino-orbital mucormycosis. The abnormal movements resolved entirely following the control of her blood glucose levels, suggesting a direct correlation between hyperglycemia and the clinical picture. This case highlights the importance of considering a wide range of differential diagnoses for abnormal lower limb movements in diabetic patients, emphasizing the need for accurate identification of movement semiology, routine bedside capillary blood glucose checks, and prompt hyperglycemia management to resolve such movement disorders effectively.

[A case of idiopathic propriospinal myoclonus accompanied by giant somatosensory evoked potential].

A 41-year-old man visited our clinic because of headache with fever, suggestive of aseptic meningitis. His headache improved in a few days. His neurological examination showed positive jolt accentuation and myoclonus of the thoracoabdominal muscles extending to extremities upon patellar tapping. His myoclonus had been occurring spontaneously from early adolescence, especially in relaxed states such as drowsiness. The myoclonus was not triggered by tactile, auditory, or visual stimulation. Polymyography revealed that the myoclonus originated around the T4 spinal level and slowly propagated both upward and downward. These findings were indicative of spontaneous and reflex propriospinal myoclonus (PSM). No abnormalities were seen on brain and spinal MRI. Furthermore, the amplitude of the cortical component of the somatosensory evoked potential (SEP) after electrical stimulation of the tibial nerve was enlarged bilaterally. It was speculated that the ascending signals from the myoclonus generator at T4 to S1 may have modulated the excitability and inhibitory function of S1 in this patient. This report may be the first case of idiopathic PSM accompanied by giant SEP.

How Do I Find Clues About Where Myoclonus Is Originating?

Myoclonus is defined as a brief and jerky shock-like involuntary movement caused by abrupt muscle contraction or sudden cessation of ongoing muscular activity. Myoclonus can be generated by abnormal activity in different parts of the nervous system, both peripheral and central, including cortical and subcortical structures. According to the presumed neural generator, myoclonus is classified as cortical, subcortical (including myoclonus-dystonia and brainstem/reticular myoclonus), spinal (including segmental spinal and propriospinal myoclonus), and peripheral. The identification of myoclonus subtypes, and therefore its potential source, is clinically important because it can guide diagnosis and treatment. In this video lecture (Video), we reviewed how to determine myoclonus origin. We first reviewed the clinical features typical of each myoclonus subtype. We, then, explored the electrophysiological techniques that can aid in the differential diagnosis of myoclonus, based on its origin. In conclusion, we provided a clinical and electrophysiological overview on how to find clues about neural generators of myoclonus.

Surgical Treatment of Propriospinal Myoclonus: A Case Report.

Propriospinal myoclonus (PSM) is a rare segmental movement disorder characterized by repetitive irregular myoclonic jerks of the trunk and/or axial limbs at the resting state. It is imperative to make a correct diagnosis as other movement disorders can be mistaken for or mask PSM. Therefore, a battery of neuroimaging and neurophysiological testing must be undertaken. In our case report, we discuss a patient who was diagnosed with PSM concurrently with cervical degenerative stenosis and then had a successful outcome via surgical decompression and arthrodesis of the cervical spine. We documented the patient's postoperative course and achievement of complete remission, sustained at a 41-month follow-up. We then grouped our case together with five other PSM cases in the literature to offer readers a broader context of the role of surgical spinal intervention in ameliorating PSM.

The role of V3 neurons in speed-dependent interlimb coordination during locomotion in mice.

Speed-dependent interlimb coordination allows animals to maintain stable locomotion under different circumstances. The V3 neurons are known to be involved in interlimb coordination. We previously modeled the locomotor spinal circuitry controlling interlimb coordination (Danner et al., 2017). This model included the local V3 neurons that mediate mutual excitation between left and right rhythm generators (RGs). Here, our focus was on V3 neurons involved in ascending long propriospinal interactions (aLPNs). Using retrograde tracing, we revealed a subpopulation of lumbar V3 aLPNs with contralateral cervical projections. V3OFF mice, in which all V3 neurons were silenced, had a significantly reduced maximal locomotor speed, were unable to move using stable trot, gallop, or bound, and predominantly used a lateral-sequence walk. To reproduce this data and understand the functional roles of V3 aLPNs, we extended our previous model by incorporating diagonal V3 aLPNs mediating inputs from each lumbar RG to the contralateral cervical RG. The extended model reproduces our experimental results and suggests that locally projecting V3 neurons, mediating left-right interactions within lumbar and cervical cords, promote left-right synchronization necessary for gallop and bound, whereas the V3 aLPNs promote synchronization between diagonal fore and hind RGs necessary for trot. The model proposes the organization of spinal circuits available for future experimental testing.

Characterization of interlimb interaction via transcutaneous spinal stimulation of cervical and lumbar spinal enlargements.

The use of transcutaneous electrical spinal stimulation (TSS) to modulate sensorimotor networks after neurological insult has garnered much attention from both researchers and clinicians in recent years. Although many different stimulation paradigms have been reported, the interlimb effects of these neuromodulation techniques have been little studied. The effects of multisite TSS on interlimb sensorimotor function are of particular interest in the context of neurorehabilitation, as these networks have been shown to be important for functional recovery after neurological insult. The present study utilized a condition-test paradigm to investigate the effects of interenlargement TSS on spinal motor excitability in both cervical and lumbosacral motor pools. Additionally, comparison was made between the conditioning effects of lumbosacral and cervical TSS and peripheral stimulation of the fibular nerve and ulnar nerve, respectively. In 16/16 supine, relaxed participants, facilitation of spinally evoked motor responses (sEMRs) in arm muscles was seen in response to lumbosacral TSS or fibular nerve stimulation, whereas facilitation of sEMRs in leg muscles was seen in response to cervical TSS or ulnar nerve stimulation. The decreased latency between TSS- and peripheral nerve-evoked conditioning implicates interlimb networks in the observed facilitation of motor output. The results demonstrate the ability of multisite TSS to engage interlimb networks, resulting in the bidirectional influence of cervical and lumbosacral motor output. The engagement of interlimb networks via TSS of the cervical and lumbosacral enlargements represents a feasible method for engaging spinal sensorimotor networks in clinical populations with compromised motor function.NEW & NOTEWORTHY Bidirectional interlimb modulation of spinal motor excitability can be evoked by transcutaneous spinal stimulation over the cervical and lumbosacral enlargements. Multisite transcutaneous spinal stimulation engages spinal sensorimotor networks thought to be important in the recovery of function after spinal cord injury.

Síndrome de la mano inútil con astereognosia secundaria a un astrocitoma cervical / Useless hand syndrome with astereognosis secondary to a cervical astrocytoma

Resumen El presente caso es un ejemplo del síndrome de la mano inútil de Oppenheim secundario a un astrocitoma cervical alto. La pérdida sensorial propioceptiva y discriminativa suspendida con conservación de la termoalgesia y el tacto crudo en ambas extremidades superiores es secundaria al daño a la entrada de la raíz dorsal y al núcleo cuneiforme. La torpeza y las dificultades para una prensión precisa con la mano se deben al daño del núcleo proprioespinal en las astas dorsales a nivel C3-C4. Este núcleo integra influencias excitadoras descendentes del tracto corticoespinal e interneuronas inhibitorias controladas por los sistemas descendentes y las aferencias de las extremidades anteriores. Probablemente la pérdida de las aferentes cervicales propioceptivas inhibitorias sea la culpable de las dificultades para agarrar con las manos.

The present case is an example of the useless hand syndrome of Oppenheim secondary to a high cervical astrocytoma. The suspended proprioceptive and discriminative sensory loss with conservation of thermoalgesia and crude touch in both upper extremities is secondary to damage to dorsal root entry and cuneate nucleus. The clumsiness and difficulties in precise grasping with the hand are due to damage of the propriospinal nucleus in the dorsal horns at C3-C4 level. This nucleus integrates descending excitatory influences from corticospinal tract and inhibitory interneurons controlled by descending systems and the forelimb afferents. Probably the loss of the inhibitory proprioceptive cervical afferents is the culprit of the difficulties in grasping by the hands.

Double viral vector intersectional approaches for pathway-selective manipulation of motor functions and compensatory mechanisms.

Selective manipulation of particular subcomponent of neural circuits is crucial for understanding the functional architecture of neural systems and for development of the future therapeutic strategies against neurological disorders. In this article, I review how the intersectional approaches with double viral vector technique was introduced for the pathway-selective manipulation of spinal circuits. In this technique, a retrograde gene transfer vector is injected into the terminal area of the targeted neurons and an anterograde vector is injected at the location of their somata. Either by using the Tet-transactivator or Cre-loxP system, the experimenter can chemogenetically or optogenetically manipulate the transmission of the target pathway originated from the double-infected neurons. This technique was first developed for manipulation of spinal cord interneurons in the macaque monkeys by selective expression of tetanus neurotoxin and successfully affected the dexterous hand movements. Currently, this technique is widely used on a variety of neural pathways both in rodents and primates in combination with a variety of retrograde vectors and a variety of optogenetic and chemogenetic tools. The advantage of this technique is that it is not necessary to generate transgenic animals. Knowledge of the cell-type specific promotors is not needed. Manipulation is achieved primarily by injection of two viral vectors based on the anatomical knowledge and it is applicable in a variety of animal species including primates. The pros, cons and future direction of this technique are discussed.

Exploring propriospinal neuron-mediated neural circuit plasticity using recombinant viruses after spinal cord injury.

Propriospinal neurons (PSNs) play a crucial role in motor control and sensory processing and contribute to plastic reorganization of spinal circuits responsible for recovery from spinal cord injury (SCI). Due to their scattered distribution and various intersegmental projection patterns, it is challenging to dissect the function of PSNs within the neuronal network. New genetically encoded tools, particularly cell-type-specific transgene expression methods using recombinant viral vectors combined with other genetic, pharmacologic, and optogenetic approaches, have enormous potential for visualizing PSNs in the neuronal circuits and monitoring and manipulating their activity. Furthermore, recombinant viral tools have been utilized to promote the intrinsic regenerative capacities of PSNs, towards manipulating the 'hostile' microenvironment for improving functional regeneration of PSNs. Here we summarize the latest development in this fast-moving field and provide a perspective for using this technology to dissect PSN physiological role in contributing to recovery of function after SCI.

Silencing long ascending propriospinal neurons after spinal cord injury improves hindlimb stepping in the adult rat.

Long ascending propriospinal neurons (LAPNs) are a subpopulation of spinal cord interneurons that directly connect the lumbar and cervical enlargements. Previously we showed, in uninjured animals, that conditionally silencing LAPNs disrupted left-right coordination of the hindlimbs and forelimbs in a context-dependent manner, demonstrating that LAPNs secure alternation of the fore- and hindlimb pairs during overground stepping. Given the ventrolateral location of LAPN axons in the spinal cord white matter, many likely remain intact following incomplete, contusive, thoracic spinal cord injury (SCI), suggesting a potential role in the recovery of stepping. Thus, we hypothesized that silencing LAPNs after SCI would disrupt recovered locomotion. Instead, we found that silencing spared LAPNs post-SCI improved locomotor function, including paw placement order and timing, and a decrease in the number of dorsal steps. Silencing also restored left-right hindlimb coordination and normalized spatiotemporal features of gait such as stance and swing time. However, hindlimb-forelimb coordination was not restored. These data indicate that the temporal information carried between the spinal enlargements by the spared LAPNs post-SCI is detrimental to recovered hindlimb locomotor function. These findings are an illustration of a post-SCI neuroanatomical-functional paradox and have implications for the development of neuronal- and axonal-protective therapeutic strategies and the clinical study/implementation of neuromodulation strategies.

Widening spinal injury research to consider all supraspinal cell types: Why we must and how we can.

The supraspinal connectome consists of dozens of neuronal populations that project axons from the brain to the spinal cord to influence a wide range of motor, autonomic, and sensory functions. The complexity and wide distribution of supraspinal neurons present significant technical challenges, leading most spinal cord injury research to focus on a handful of major pathways such as the corticospinal, rubrospinal, and raphespinal. Much less is known about many additional populations that carry information to modulate or compensate for these main pathways, or which carry pre-autonomic and other information of high value to individuals with spinal injury. A confluence of technical developments, however, now enables a whole-connectome study of spinal cord injury. Improved viral labeling, tissue clearing, and automated registration to 3D atlases can quantify supraspinal neurons throughout the murine brain, offering a practical means to track responses to injury and treatment on an unprecedented scale. Here we discuss the need for expanded connectome-wide analyses in spinal injury research, illustrate the potential by discussing a new web-based resource for brain-wide study of supraspinal neurons, and highlight future prospects for connectome analyses.