This work introduces a multimodal framework that combines single-pulse transcranial magnetic stimulation of the primary motor cortex with SC-fMRI to probe TMS-evoked spinal activity in humans and demonstrates that concurrent TMS–SCfMRI can capture, in vivo, how cortical drive is expressed within human spinal circuitry.
Abstract
The spinal cord serves as a crucial relay for motor commands, yet the role of its local circuitry in sensorimotor integration remains poorly understood. Most non-invasive cortical stimulation studies, rely on electrophysiological readouts or inferred spinal function from corticospinal anatomy, leaving the downstream impact of cortical stimulation on spinal circuitry largely uncharted in vivo. Advances in spinal cord functional MRI (SC-fMRI) now enable spatially resolved imaging of segmental gray and white matter and their interactions with descending cortical inputs. Here, we introduce a multimodal framework that combines single-pulse transcranial magnetic stimulation (TMS) of the primary motor cortex with SC-fMRI to probe TMS-evoked spinal activity in humans. Using graded TMS intensities, we examined blood oxygenation level-dependent (BOLD) responses in the cervical spinal cord and asked how spinal activation depends on effective engagement of the descending motor system. Our findings reveal robust, intensity-dependent spinal BOLD responses aligned with descending pathways, with activation concentrated in expected territories such as the lateral corticospinal tract and ventral horn at segments innervating the stimulated hand muscle. By linking peripheral output to segment- and pathway-resolved spinal signals, these results demonstrate that concurrent TMS–SCfMRI can capture, in vivo, how cortical drive is expressed within human spinal circuitry and provide a new framework to measure spinal contributions to sensorimotor control with spatial specificity beyond traditional peripheral readouts. Graphical Abstract
Reliable noninvasive measurement of human brainstem activity during motor control remains challenging due to small anatomical structures and physiological noise, yet it is essential for understanding descending contributions to rapid feedback control. We used brainstem-optimized whole brain functional magnetic resonance imaging (fMRI) to examine whether task-dependent modulation of stretch-evoked motor responses in humans are associated with changes in activation within reticulospinal regions of the human brainstem. A behavioral validation experiment (N=10), in which participants were instructed to resist or yield to brief wrist perturbations, confirmed task-dependent modulation of long-latency responses (LLRs). In a separate imaging cohort (N=26), participants performed the same tasks during fMRI using an MRI-compatible robotic device and a multi-echo acquisition with physiological noise compensation. Imaging analyses revealed greater blood-oxygen-level-dependent signal during Resist compared to Yield while controlling for background contraction and proprioceptive input, with activation distributed bilaterally across the pons and medulla in regions consistent with major reticulospinal nuclei. Laterality analyses demonstrated a rostrocaudal gradient, with relatively ipsilateral-biased activation in the medulla shifting toward more contralateral patterns in the pons. These findings indicate that instruction-dependent modulation of stretch-evoked motor responses is associated with measurable changes in human brainstem activation, providing evidence that reticulospinal regions contribute to task-dependent feedback control.
Rebecca C. Nikonowicz, Neha A. Reddy, Michelle C. Medina et al.· Imaging Neuroscience· 0 citations
Voluntary human movement emerges from dynamic interactions between the brain, spinal cord, and sensory afferents. Spinal cord function has proven particularly difficult to study non-invasively in humans due to its deep anatomical location and narrow diameter. As a result, sensorimotor interactions are often studied using cortico-muscular coupling, which captures interactions between brain and muscle but cannot reveal how these signals propagate through the spinal cord. Here, we use concurrent brain and spinal cord imaging with optically pumped magnetometers (OPMs) and electromyography (EMG) to test whether endogenous synchronization within the human sensorimotor system can be detected and characterized non-invasively across cortical, spinal, and muscular levels. Participants (n = 9) performed a sustained isometric hand contraction while we recorded cortical and spinal cord magnetic fields using OPMs and hand muscle activity using EMG, and we compared rhythmic activity propagating through the cortico-spinal-muscular loop with the state at rest. We show that the spinal contribution to cortico-muscular coupling manifests as coherent 10-35 Hz activity linking the contralateral sensorimotor cortex, cervical spinal cord, and muscle. This synchronization forms a distributed, bidirectionally interacting network with physiologically plausible temporal delays. The spatial organization of this activity accords with known sensorimotor anatomy, localizing to cervical segments appropriate for upper-limb control. Our results provide the first direct, non-invasive magnetic field evidence in humans of coherent brain and spinal cord oscillations and demonstrate the feasibility of concurrent, spatiotemporally resolved imaging of the central nervous system to open new avenues for studying human sensorimotor physiology.
Meaghan E. Spedden, Maike Schmidt, George C. O’Neill et al.· Current Biology· 1 citation
Summary Epidural spinal cord stimulation has been shown to be a promising neurotechnology to improve upper limb function in people affected by stroke. It is well established that spinal cord stimulation (SCS) targeting the dorsal root entry zone increases excitatory drive to α-motoneurons via the monosynaptic reflex pathway. However, the effects of SCS on inhibitory neural pathways remain unexplored. We hypothesized that SCS improves the neuromotor control of arm movement by strengthening both excitatory and inhibitory circuit function. We show in three individuals with post-stroke motor symptoms that SCS enhances postsynaptic Ia reciprocal inhibition. These changes correlate with enhanced muscle coordination and arm kinematics, resulting in smoother and faster trajectories. Our study provides further insights into the neural targets of spinal cord stimulation and the use of this technology to treat post-stroke motor deficits. This study was registered at ClinicalTrials.gov (NCT04512690).
L. Borda, N. Verma, E. Sorensen et al.· Cell Reports Medicine· 0 citations
Control of upper limb force is crucial for motor skill acquisition. Rodent models have been instrumental in elucidating the behavioral and neural mechanisms underlying skilled movements. Integrating these models with advanced neuroimaging approaches, such as awake functional magnetic resonance imaging (fMRI) in behaving mice, enables whole-brain mapping of motor activity. However, experimental paradigms supporting awake fMRI during upper limb motor behavior in mice remain limited. Here, we developed an MRI-compatible head–fixation system that enables male and female mice to perform a unilateral forepaw force control task for water reward during ultrahigh-field (11.1 T) fMRI. Mice successfully acquired the task, as evidenced by increased rewarded presses, convergence of force output toward the rewarded threshold, and reduced force variability. Significant activation clusters related to forepaw force were identified across multiple cortical regions, including the primary and secondary motor cortex, anterior cingulate cortex, and primary somatosensory cortex. Activation extended to subcortical structures, including the cerebellum, striatum, hypothalamus, and thalamus (ventrolateral and ventroposterior nuclei). Analysis of limb kinematics from synchronized video recordings revealed strong spatial correspondence between forepaw-related and force-dependent activation maps. Region-of-interest analyses further identified engagement of medullary structures, specifically the lateral rostral medulla and caudal medulla (CauM), in forepaw force control. Notably, the cerebellum and CauM exhibited later peak responses relative to cortical regions. Together, these results establish a robust framework for awake fMRI during forelimb motor tasks and provide a comprehensive map of cortical, subcortical, and brainstem circuits underlying forelimb force control in mice.
V. Jindal, Jason Veizaj, Zoë Schuler et al.· eNeuro· 0 citations
This work demonstrates for the first time in humans that clinical-grade lumbosacral epidural paddle arrays capture sufficient fine-scale spatiotemporal structure to decode these overlapping inputs from highly overlapping, volume-conducted epidural fields.
Alexander G. Steele, M. Candela, Gracie Hufft et al.· Research Square· 0 citations
Activity in WDR neurons is established as a core component of the N1 potential, supporting the use of spinal SEPs as a translational biomarker of analgesic target engagement within the dorsal horn of anaesthetised Wistar rats.
Kenneth A J Steel, Tony Blockeel, E. Ajay et al.· bioRxiv· 0 citations
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