Reflexive skin twitches are stereotypical behaviours, triggered in most mammals by mechanosensory stimuli. The neural circuits controlling this behaviour are thought to lie in the spinal cord, with motor neurons positioned in the lower cervical spinal cord innervating the cutaneous maximus muscle responsible for the twitches. The spatial matching of the motor output to the location of the sensory stimulus points to selective innervation of particular cutaneous maximus motor neurons by specific sensory-responsive circuits organised in a spatially-dependent manner. Using mouse genetics and viral tracing, we observed that a subset of dorso-lateral dI3 neurons forms ascending projections to motor neurons mediating skin twitches. Their projections are somatotopically organized to map a two dimensional space onto specific sub-compartments of the cutaneous maximus motor pool. Furthermore, direct optogenetic stimulation of thoraco-lumbar dI3 ascending projections in the cervical spinal cord induces skin twitches. Together, we demonstrate the circuit basis of a spinal sensory-motor representation of the dorsolateral trunk that participates in an ethological behaviour shared by most mammals allowing them to reduce the burdens of irritants such as insects.

Multi-limb coordination is vital for mammalian locomotion. While coordination requires reliable organization of limb movements, it also requires flexibility to adapt to environmental demands. In natural settings, animals must navigate diverse terrains that impose unique challenges. Climbing, for example, introduces constraints due to gravitational load, substrate variability, and the need for behaviors like reaching and grasping. Understanding how animals accommodate these demands provides insight into the flexibility of motor systems supporting locomotion. To address this, we developed a naturalistic climbing assay to investigate multi-limb coordination in freely moving mice. Climbing gait emulated aspects of horizontal locomotion, including a speed-dependent decrease in duty factor. However, coordination between homologous limb pairs was asymmetric, with forelimbs favoring anti-phase movements and hindlimbs showing a tendency toward in-phase movements. Notably, mice adjusted this strategy to overcome vertical gaps. Our results reveal that mice engage unique coordination strategies during climbing and adapt them to navigate vertical challenges.

Successful movement requires continuous adjustments in response to changes in internal and external environments. To do so, neural circuits continuously compare efference copies of motor commands with sensory input to respond to sensory prediction errors. Some responses need to be very fast and, for limbs, likely occur in as yet undefined spinal cord circuits. Here, we describe spinal circuits involving dI3 neurons, showing that they receive multimodal sensory inputs and direct efferent copies from both Renshaw cells and motor neurons. We further show that they form connections to motor pools, including diverging connections to antagonist motor nuclei. Reducing dI3 neuronal activity diminished stumbling responses, as did disrupting Renshaw cell circuits, providing evidence for a comparator role of dI3 neurons for online corrections. Together, our findings reveal a pivotal role for dI3 neurons functioning as comparators of internal predictions and external sensory feedback to mediate rapid corrections of ongoing movements. ### Competing Interest Statement Robert M. Brownstone is a co-founder and director of Sania Therapeutics Inc. Wellcome Trust, https://ror.org/029chgv08, 221610/Z/20/Z, 227433/Z/23/Z, 225674/Z/22/Z Royal Society, NIF\R1\192316 Canadian Institutes of Health Research, https://ror.org/01gavpb45, PJT 180556, PJT 162357 Biotechnology and Biological Sciences Research Council, BB/S005943/1

BACKGROUND:Emerging trials demonstrate that neuromodulation, especially spinal cord stimulation, improves function for those with chronic spinal cord injury. Their design - uncontrolled and unblinded - is justified by the claim that sham conditions are unethical and/or impossible. In the absence of controlled trials, the functional benefits of spinal cord stimulation cannot be distinguished from the effects of placebo. OBJECTIVES:To discuss the validity of the claim that placebo control conditions are infeasible in spinal cord stimulation research, and to propose feasible solutions for including sham conditions that would account for placebo effects. RESULTS:Placebo effects are likely to occur in spinal cord stimulation studies, given the high levels of participant expectations of an effect, natural fluctuations in symptoms associated with spinal cord injury, regression towards the mean, the Hawthorne effect, presence of concurrent interventions, and the absence of blinding in existing studies. Options for placebo control conditions could include adding an "untreated" control group, using "placebo-resistant" outcomes, adding an active comparator group or sham stimulation, or investing in parasthesia-free stimulation. Additionally, wherever feasible, blinding of both participants and assessors should be pursued. CONCLUSIONS:The current evidence base for spinal cord stimulation is undermined by the lack of rigorous sham controls, and the argument that such controls are unethical or unfeasible do not withstand scrutiny. We propose strategies for the inclusion of placebo controls in future trials and encourage investigators to prioritize these approaches to ensure the true benefit of spinal cord stimulation can be determined.

Reach and grasp are critical components of skilled mammalian motor control and their detailed analysis in rodents has been key to deepening our understanding of prehension in the context of health and disease. However, most studies investigating these behaviours focus on isolating forelimb movements with little regard to the whole-body movements that are key for effective behaviour. To address this issue, we designed a novel behavioural approach to investigate reach and grasp during whole-body, vertical locomotion in mice. Using a customizable transparent climbing surface, we show that our behavioural approach can extract key kinematic features of climbing. Mouse climbing gait reflects aspects of quadrupedal locomotion, showing similar phase dependencies on increasing speed, including reduced stance (i.e. grasp) time and duty factor. Analysis of multi-limb coordination indicated that climbing revolves around anti-phasic forepaw movements with less consistency in interlimb coordination in the hindpaws. Fore- and hindpaws also differed in their reach trajectories and velocity profiles. The flexibility of this approach also allows for tailored climbing configurations, which we use to show that mice can adapt to and overcome vertical obstacles. By leveraging naturalistic climbing, our modular behavioural approach enables investigation of complex prehensile behaviours and facilitates new study into the neural circuits underlying whole-body skilled motor control. ### Competing Interest Statement The authors have declared no competing interest.

Studying human motoneuron activity through electromyography (EMG) can yield insights into the operation of fundamental spinal cord microcircuits. Traditional surface and needle electromyography (EMG) methodologies have limited capacity to shed light on the diversity of motor unit (MU) control strategies that may be unique to each individual. Here, we employed high-density surface EMG (HDsEMG) to sample multiple MUs per subject to investigate the dynamics of inhibitory spinal microcircuits in both upper and lower limb control. We characterised the net inhibition as a function of individual MU firing rates, revealing subject-specific relationships. In silico modelling replicated these experimental characteristics and suggested that properties of the inhibitory currents rather than motoneuron size are responsible for net functional inhibition. Our results show that HDsEMG can highlight distinct control strategies across circuits and motor pools, revealing subject-specific properties of inhibitory spinal microcircuits. ### Competing Interest Statement R.M.B. is a co-founder and is on the board of Sania Therapeutics Inc. and consults for Sania Rx Ltd.

Studying human motoneuron activity through electromyography (EMG) can yield insights into the operation of fundamental spinal cord microcircuits. Traditional surface and needle EMG methodologies have limited capacity to shed light on the diversity of motor unit (MU) control strategies that may be unique to each individual. Here, we used high-density surface EMG (HDsEMG) to sample multiple MUs per participant to investigate the features of inhibitory spinal microcircuits in both upper and lower limb control. We characterized the net inhibition as a function of individual MU firing rates, revealing participant-specific relationships. In silico modeling replicated these experimental characteristics and suggested that properties of the inhibitory currents rather than motoneuron size are responsible for net functional inhibition. Our results show that HDsEMG can highlight distinct control strategies across circuits and motor pools, revealing participant-specific properties of inhibitory spinal microcircuits.

Neurophysiological methods are used widely to gain information about motoneuron excitability and axon conduction in neurodegenerative diseases. The F-wave is a common biomarker used to test motoneuron properties in the diagnosis of neurological diseases. Although the origin of the F-wave is a subject of debate, the most widely accepted mechanism posits that the F-wave is generated by the backfiring of motoneurons stimulated antidromically from the periphery. In this study, we developed an ex vivo mouse sciatic nerve-attached spinal cord preparation with sensory axons severed in which stimulation of the whole sciatic nerve or its tibial branch evoked responses with the electrophysiological signatures of F-waves. Manipulations of synaptic transmission by either removal of extracellular calcium or block of post-synaptic glutamate receptors abolished these responses. These results suggest that F-waves are mediated by spinal microcircuits activated by recurrent motor axon collaterals via glutamatergic synapses.

The increased muscular force output required for some behaviors is achieved via amplification of motoneuron output via cholinergic C-bouton synapses. Work in neonatal mouse motoneurons suggested that modulation of currents mediated by post-synaptically clustered KV2.1 channels is crucial to C-bouton amplification. By focusing on more mature motoneurons, we show that conditional knockout of KV2.1 channels minimally affects either excitability or response to exogenously applied muscarine. Similarly, unlike in neonatal motoneurons or cortical pyramidal neurons, pharmacological blockade of KV2 currents has minimal effect on mature motoneuron firing in vitro. Furthermore, in vivo amplification of electromyography activity and high-force task performance was unchanged following KV2.1 knockout. Finally, we show that KV2.2 is also expressed by spinal motoneurons, colocalizing with KV2.1 opposite C-boutons. We suggest that the primary function of KV2 proteins in motoneurons is non-conducting and that KV2.2 can function in this role in the absence of KV2.1.

Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-TOR1A, we generated a conditional knockout of the torsin family 1 member A (Tor1a) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1a conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.

OBJECTIVE:Little is known about the impact of academic training on Neurosurgery in the United Kingdom (UK). The aim was to understand the early career clinical and research training journeys of potential future clinical academics, with a view to informing future policy and strategy to improve career development for academic neurosurgical trainees and consultants in the UK. METHODS:An online survey from the Society of British Neurological Surgeons (SBNS) academic committee was distributed to both the SBNS and British Neurosurgical Trainee Association (BNTA) mailing lists in early 2022. Neurosurgical trainees for any period between 2007 and 2022 or who had done any dedicated academic or clinical academic placement were encouraged to complete the survey. RESULTS:Sixty responses were received. Six (10%) were females and fifty-four (90%) were males. At the time of response, nine (15.0%) were clinical trainees, four (6.7%) were Academic Clinical Fellows (ACF), six (10.0%) were Academic Clinical Lecturers (ACL), four (6.7%) were post-CCT fellows, eight (13.3%) were NHS consultants, eight (13.3%) were academic consultants, eighteen (30.0%) were out of the programme (OOP) pursuing a PhD potentially returning to training, whilst three (5.0%) had left neurosurgery training entirely and no longer performing clinical neurosurgery. The mentorship was sought in most programmes, which tended to be informal. Self-reported success on a scale of 0 to 10 with 10 being the most successful, was greatest in the MD and the "Other research degree/fellowship group" which does not include a PhD. There was a significant positive association between completing a PhD and having an academic consultant appointment (Pearson Chi-Square = 5.33, p = 0.021). CONCLUSIONS:This study provides a snapshot to better understand the opinions of academic training in neurosurgery within the UK. Establishing clear, modifiable, and achievable goals, as well as providing tools for research success, may contribute to the success of this nationwide academic training.

Elaborate behaviours are produced by tightly controlled flexor-extensor motor neuron activation patterns. Motor neurons are regulated by a network of interneurons within the spinal cord, but the computational processes involved in motor control are not fully understood. The neuroanatomical arrangement of motor and premotor neurons into topographic patterns related to their controlled muscles is thought to facilitate how information is processed by spinal circuits. Rabies retrograde monosynaptic tracing has been used to label premotor interneurons innervating specific motor neuron pools, with previous studies reporting topographic mediolateral positional biases in flexor and extensor premotor interneurons. To more precisely define how premotor interneurons contacting specific motor pools are organized, we used multiple complementary viral-tracing approaches in mice to minimize systematic biases associated with each method. Contrary to expectations, we found that premotor interneurons contacting motor pools controlling flexion and extension of the ankle are highly intermingled rather than segregated into specific domains like motor neurons. Thus, premotor spinal neurons controlling different muscles process motor instructions in the absence of clear spatial patterns among the flexor-extensor circuit components.

Summary Dystonia, a neurological disorder defined by abnormal postures and disorganised movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal circuits constitute the final pathway for motor control, we sought to determine their contribution to the movement disorder. Focusing on the most common inherited dystonia, DYT1- TOR1A , we confined a conditional knockout of Tor1a to the spinal cord and dorsal root ganglia (DRG) and found that these mice recapitulated the phenotype of the human condition, developing early onset generalised torsional dystonia. Physiologically, these mice bore the hallmark features of dystonia: spontaneous contractions at rest, excessive sustained contractions during voluntary movements including co-contractions of motor antagonists, and altered sensory-motor reflexes. Furthermore, spinal locomotor circuits were impaired. Together, these data challenge current understanding of dystonia, and lead to broader insights into spinal cord function and movement disorder pathophysiology.

ImportancePain is a silent global epidemic impacting approximately a third of the population. Pharmacological and surgical interventions are primary modes of treatment. Cognitive/behavioural management approaches and interventional pain management strategies are approaches that have been used to assist with the management of chronic pain. Accurate data collection and reporting treatment outcomes are vital to addressing the challenges faced. In light of this, we conducted a systematic evaluation of the current digital application landscape within chronic pain medicine.ObjectiveThe primary objective was to consider the prevalence of digital application usage for chronic pain management. These digital applications included mobile apps, web apps, and chatbots.Data sourcesWe conducted searches on PubMed and ScienceDirect for studies that were published between 1st January 1990 and 1st January 2021.Study selectionOur review included studies that involved the use of digital applications for chronic pain conditions. There were no restrictions on the country in which the study was conducted. Only studies that were peer-reviewed and published in English were included. Four reviewers had assessed the eligibility of each study against the inclusion/exclusion criteria. Out of the 84 studies that were initially identified, 38 were included in the systematic review.Data extraction and synthesisThe AMSTAR guidelines were used to assess data quality. This assessment was carried out by 3 reviewers. The data were pooled using a random-effects model.Main outcome(s) and measure(s)Before data collection began, the primary outcome was to report on the standard mean difference of digital application usage for chronic pain conditions. We also recorded the type of digital application studied (e.g., mobile application, web application) and, where the data was available, the standard mean difference of pain intensity, pain inferences, depression, anxiety, and fatigue.Results38 studies were included in the systematic review and 22 studies were included in the meta-analysis. The digital interventions were categorised to web and mobile applications and chatbots, with pooled standard mean difference of 0.22 (95% CI: −0.16, 0.60), 0.30 (95% CI: 0.00, 0.60) and −0.02 (95% CI: −0.47, 0.42) respectively. Pooled standard mean differences for symptomatologies of pain intensity, depression, and anxiety symptoms were 0.25 (95% CI: 0.03, 0.46), 0.30 (95% CI: 0.17, 0.43) and 0.37 (95% CI: 0.05, 0.69), respectively. A sub-group analysis was conducted on pain intensity due to the heterogeneity of the results (I2 = 82.86%; p = 0.02). After stratifying by country, we found that digital applications were more likely to be effective in some countries (e.g., United States, China) than others (e.g., Ireland, Norway).Conclusions and relevanceThe use of digital applications in improving pain-related symptoms shows promise, but further clinical studies would be needed to develop more robust applications.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/, identifier: CRD42021228343.

Neural motor systems have evolved complex circuits that afford animals a range of behaviours essential for survival. C-bouton synapses arising from cholinergic V0 C interneurons amplify motoneuron activity via muscarine type 2 receptors, thus increasing muscle contraction force. Recent work in neonatal mouse motoneurons suggests that delayed rectifier currents carried by post-synaptically clustered K V 2.1 channels are crucial to C-bouton amplification. Here we use a motoneuron conditional K V 2.1 knockout to show that while K V 2.1 modulates maximal firing in neonatal mice, its removal minimally affects either mature motoneuron firing or the enhanced firing rates in response to exogenously applied muscarine. In keeping with this, pharmacological blockade of K V 2 currents has minimal electrophysiological effects on mature motoneurons. Furthermore, amplification of electromyography activity during high force tasks was unchanged following K V 2.1 deletion. We next show that K V 2.2 is also expressed by spinal motoneurons and colocalises with K V 2.1 opposite C-boutons. We suggest that the primary function of K V 2 proteins – K V 2.1 and K V 2.2 – is non-conducting in motoneurons, and that K V 2.2 can function in the absence of K V 2.1, perhaps to ensure the integrity of the synapse.

Motoneurons are the 'final common path' between the central nervous system (that intends, selects, commands, and organises movement) and muscles (that produce the behaviour). Motoneurons are not passive relays, but rather integrate synaptic activity to appropriately tune output (spike trains) and therefore the production of muscle force. In this chapter, we focus on studies of mammalian motoneurons, describing their heterogeneity whilst providing a brief historical account of motoneuron recording techniques. Next, we describe adult motoneurons in terms of their passive, transition, and active (repetitive firing) properties. We then discuss modulation of these properties by somatic (C-boutons) and dendritic (persistent inward currents) mechanisms. Finally, we briefly describe select studies of human motor unit physiology and relate them to findings from animal preparations discussed earlier in the chapter. This interphyletic approach to the study of motoneuron physiology is crucial to progress understanding of how these diverse neurons translate intention into behaviour.