Sensory organization at the spinal segment level is commonly inferred from dermatomal maps that assume a fixed correspondence between cutaneous regions and spinal segments. However, based on the complexities of spinal neuroanatomy and neurophysiology, the distribution of sensory signals within the cord may be broader and less segment-specific than dermatomal maps suggest, leaving the segment-level localization of sensory-evoked activity in humans uncertain. Spinal cord functional magnetic resonance imaging (fMRI) is currently the only technique capable of noninvasively mapping sensory activity with high spatial resolution in the human spinal cord. However, its application remains technically challenging and is limited by the uncertainty in segmental localization. In this study, we leveraged recent advancements in spinal cord fMRI, including spinal nerve rootlet-based spatial normalization, to investigate how sensory information is represented and distributed within the human spinal cord during electrocutaneous stimulation of the third digit of the right hand (i.e., C7 dermatome). Forty healthy adults were scanned with electrocutaneous stimulation at four individualized intensities across multiple runs to quantify (i) the rostrocaudal distribution of sensory-evoked activity, (ii) intensity-dependent changes in detectability and localization, and (iii) the effect of normalization strategy on segmental localization. Across participants, stimulation produced activation localized in the lower cervical cord (e.g., C6-C8), with the most consistent segmental localization near C7. Stronger stimulation increased detectability and produced more consistent segmental localization across participants. Importantly, normalization that incorporated nerve rootlet landmarks sharpened localization and improved sensitivity relative to conventional intervertebral disc-based alignment. This highlights the value of functionally relevant anatomical landmarks for group inference in the spinal cord. Responses were strongest in the initial run and attenuated with repetition, suggesting habituation or adaptation that can bias multi-run paradigms if unmodeled. Together, our results define practical acquisition and analysis conditions (e.g., stimulation strength, anatomical alignment strategy, and run structure) under which segment-level spinal sensory responses can be detected, thereby supporting more reliable studies of human spinal cord future basic and translational studies, including pain mechanisms, sensory function, and spinal injury.

Objective Using an Approach Motivation Research Domain Criteria framework, this prospective study aims to investigate the mechanisms and risk factors for worsening depressive symptoms and risk for insulin resistance in youth with depression and obesity. Method To accomplish these aims, 120 overweight girls and boys (ages 9-17 years) seeking treatment for moderate to severe depressive symptoms, will be assessed at baseline, 6 months, and 24 months with behavioral and cognitive markers of how they regulate their approach to rewarding stimuli, serum markers of insulin sensitivity, and clinical markers of depression. Youth will be scanned with multimodal MRI at baseline and at 6 months. Discussion We aim to determine whether worsening depressive symptoms in youth with depression and risk for insulin resistance is mediated by changes in neural reward circuitry, and to identify clinical, demographic, and familial risk factors for developing worsening depression in these youth. This knowledge will be vitally important to mental health and primary care professionals who have limited empirical evidence on which to base and sequence clinical decisions. It also has potential to inform the pathophysiology of other common disorders associated with dysfunctional Approach Motivation (e.g., social media and substance misuse) and the development of novel empirical targets for treating these complex problems in youth. Diversity & Inclusion Statement We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. We worked to ensure that the study questionnaires were prepared in an inclusive way. Diverse cell lines and/or genomic datasets were not available. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group. While citing references scientifically relevant for this work, we also actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our reference list.

Chronic pain poses a substantial public health burden. Elucidating how the healthy central nervous system (CNS) differentially encodes objective stimulus intensity and subjective experiences of pain perception may offer key insights into the central mechanisms contributing to chronic pain. Functional MRI (fMRI) combined with controlled noxious stimulation provides a powerful means to explore neural representations of nociception and pain perception. Here, we applied noxious heat at three intensities (46 °C, 47 °C, 48 °C, 8 trials each randomized) to the right forearm of 28 healthy women during simultaneous spinal cord-brain fMRI to investigate how distributed corticospinal activity and connectivity encode stimulus intensity and subjective pain. Activity increased with stimulus temperature across regions involved in pain processing-including somatosensory, motor, prefrontal, insular, and subcortical areas-as well as in the ipsilateral dorsal and ventral spinal cord. Spinal-brain functional connectivity was observed between the right dorsal horn and pain-related brain regions such as primary and secondary somatosensory cortex, insula, anterior cingulate cortex, thalamus, and periaqueductal gray, and was positively associated with individual pain ratings. Using representational similarity analysis (RSA), we found that multivoxel activation patterns in the brain and spinal cord, as well as corticospinal connectivity patterns, reliably tracked stimulus temperature, while only subsets of cortical regions (e.g., insula, sensorimotor, and frontal cortices) encoded subjective pain. Notably, spinal cord representations were primarily organized by stimulus temperature rather than perceived pain intensity. These findings demonstrate that simultaneous spinal cord-brain fMRI combined with multivariate modeling can identify sensory and perceptual components of nociceptive processing across the neuroaxis. Such approaches advance mechanistic understanding of pain and may inform the development of CNS-based biomarkers for chronic pain assessment and intervention.

PURPOSE:MR acoustic radiation force imaging (MR-ARFI) is an exceptionally promising technique to non-invasively confirm targeting accuracy and estimate exposure of low-intensity transcranial focused ultrasound applications. Implementing MR-ARFI in the human brain has been hindered by (1) sensitivity to subject motion, and (2) insufficient SNR at low (<1.0 MPa) ultrasound pressures. The purpose of this study was to optimize human MR-ARFI to allow reduced ultrasound exposure while at the same time being robust to bulk and physiological motion. METHODS:We developed a novel timeseries approach to MR-ARFI with a single-shot spiral-out MRI sequence and correction for respiratory and cardiac motion artifacts. An MR-compatible four-element 500 kHz focused ultrasound transducer was coupled to the head and targeted to 60 mm depth in five participants. During spiral scans, two 6 ms focused ultrasound pulses (0.5-0.9 MPa in situ) were delivered in on-off blocks of 25 time frames. RESULTS:Our method generates ARFI maps that with correction are largely immune to bulk and pulsatile brain motion with reduced scan time (80 s per acquisition). Robust ARFI signals were observed at the expected target in four human participants, using low intensity ultrasound that does not produce significant tissue heating, confirmed both by simulation and MR thermometry. CONCLUSION:Single shot spiral MR-ARFI is motion robust in human applications, provides reduction in ultrasound exposure, and reduced scan time, enabling iteration for image-guided targeting. This provide persuasive proof-of-principle that MR-ARFI can be used as a tool to guide ultrasound-based precision neural circuit therapeutics.

Functional magnetic resonance imaging (fMRI) of the spinal cord is relevant for studying sensation, movement, and autonomic function. Preprocessing of spinal cord fMRI data involves segmentation of the spinal cord on gradient-echo echo planar imaging (EPI) images. Current automated segmentation methods do not work well on these data, due to the low spatial resolution, susceptibility artifacts causing distortions and signal drop-out, ghosting, and motion-related artifacts. Consequently, this segmentation task demands a considerable amount of manual effort which takes time and is prone to user bias. In this work, we (i) gathered a multi-center dataset of spinal cord gradient-echo EPI with ground-truth segmentations and shared it on OpenNeuro https://openneuro.org/datasets/ds005143/versions/1.3.1 and (ii) developed a deep learning-based model, EPISeg, for the automatic segmentation of the spinal cord on gradient-echo EPI data. We observe a significant improvement in terms of segmentation quality compared with other available spinal cord segmentation models. Our model is resilient to different acquisition protocols as well as commonly observed artifacts in fMRI data. The training code is available at https://github.com/sct-pipeline/fmri-segmentation/, and the model has been integrated into the Spinal Cord Toolbox as a command-line tool.

INTRODUCTION:Hand motor control depends on intricate brain-spinal cord interactions that regulate muscle activity. Hand function can be disrupted by injury to the brain, spinal cord, and peripheral nerves leading to weakness and impaired coordination. Functional MRI (fMRI) can map motor-related neural activity and potentially characterize the mechanisms underlying hand weakness and diminished coordination. Although brain motor control has been extensively studied, spinal cord mechanisms remain less explored. Here we use simultaneous brain-spinal cord fMRI to map neural activity related to hand strength and dexterity across the central nervous system using force matching and finger tapping tasks. This study pioneers the use of simultaneous brain-spinal cord fMRI to comprehensively map hand function, offering novel insights into coordinated motor processing across the central nervous system. METHODS:We performed simultaneous brain-spinal cord fMRI in 28 right-handed healthy volunteers (age: 40.0 ± 13.8 years, 14 females, 14 males) using a 3T GE SIGNA Premier scanner equipped with a 21-channel head-neck coil. Participants performed a force-matching task at 10%, 20%, and 30% of maximum voluntary contraction using a hand dynamometer. For the finger tapping task, participants completed button-presses at 1 Hz with a 5-button response pad for three task levels: single-digit response with the second digit only (low), single-digit response with all digits in a sequential order (medium), single-digit response with all digits in a random order (high). Visual cues and feedback were provided during the tasks.Brain and spinal cord images were processed separately using FSL and the Spinal Cord Toolbox, with motion correction, physiological noise filtering, and spatial normalization to standard templates. Subject level activity maps were generated and entered into group level analyses to explore both activations and deactivations. For the brain, we used a mixed effect design with a voxelwise threshold of Z score > 3.10 and cluster threshold of p < 0.05. For the spinal cord, we used a fixed effect design with a voxelwise threshold of Z score > 1.64 and cluster threshold of p < 0.05. Region of interest (ROI) analyses were conducted to examine localized changes in activation across task levels. RESULTS:Both tasks elicited activation in motor and sensory regions of the brain and spinal cord, with graded responses in the left primary motor (M1), left primary sensory (S1) cortex, and right spinal cord gray matter across task levels. Deactivation of the right M1 and S1 was also present for both tasks. Deactivation of the left spinal cord gray matter was present in the high task level of the force matching task. The ROI analysis findings complemented the group level activity maps. DISCUSSION:Our study provides a detailed map of brain-spinal cord interactions in hand function, revealing graded neural activation and inhibition patterns across motor and sensory regions. Interhemispheric inhibition, reflected in right M1 deactivation, likely restricts extraneous motor output during unilateral tasks. For force matching, the deactivation of the left ventral and dorsal horns of the spinal cord, provides the first evidence that the inhibition of motor areas during a unilateral motor task extends to the spinal cord. Whether this inhibition results from direct descending modulation from the brain or interneuronal inhibition in the cord remains to be interrogated. These findings expand our understanding of central motor control mechanisms and could inform rehabilitation strategies for individuals with motor impairments. CONCLUSIONS:Our simultaneous brain-spinal cord fMRI approach provides novel insights into the neural coordination of hand function, enhancing our understanding of motor control and its modulation. This approach may offer a foundation for studying motor dysfunction in conditions such as stroke, spinal cord injury, and neurodegenerative diseases.

Non-invasive neuroimaging serves as a valuable tool for investigating the mechanisms within the central nervous system (CNS) related to somatosensory and motor processing, emotions, memory, cognition, and other functions. Despite the extensive use of brain imaging, spinal cord imaging has received relatively less attention, regardless of its potential to study peripheral communications with the brain and the descending corticospinal systems. To comprehensively understand the neural mechanisms underlying human sensory and motor functions, particularly in pathological conditions, simultaneous examination of neuronal activity in both the brain and spinal cord becomes imperative. Although technically demanding in terms of data acquisition and analysis, a growing but limited number of studies have successfully utilized specialized acquisition protocols for corticospinal imaging. These studies have effectively assessed sensorimotor, autonomic, and interneuronal signaling within the spinal cord, revealing interactions with cortical processes in the brain. In this mini-review, we aim to examine the expanding body of literature that employs cutting-edge corticospinal imaging to investigate the flow of sensorimotor information between the brain and spinal cord. Additionally, we will provide a concise overview of recent advancements in functional magnetic resonance imaging (fMRI) techniques. Furthermore, we will discuss potential future perspectives aimed at enhancing our comprehension of large-scale neuronal networks in the CNS and their disruptions in clinical disorders. This collective knowledge will aid in refining combined corticospinal fMRI methodologies, leading to the development of clinically relevant biomarkers for conditions affecting sensorimotor processing in the CNS.

Chronic widespread pain represents the cardinal symptom of fibromyalgia (FM). While dysfunctions in cerebral pain-modulatory systems were found to contribute, their link to the spinal cord (SC) is missing. This preliminary study aimed to characterize corticospinal mechanisms of aberrant nociceptive processing and physical activity-related descending pain modulation in FM, by means of combined brain-SC functional magnetic resonance imaging. We scanned 10 females (6 FM, aged 22-62; 4 healthy volunteers (HV), aged 33-62) at 3T (GE SIGNA Premier) using an echo-planar imaging pulse sequence (repetition time=2.5s/echo time=30ms/GRAPPA=2) with 30 brain and 13 cervical SC (centered at C6) slices. The experimental design included four conditions (8x each, 13s), randomized: stimulation ON/OFF paired with motor task ON/OFF. Thermal stimuli were applied at right volar forearm (C6 dermatome) at individualized temperatures (6/10, ATS thermode (Medoc)). The motor task consisted of repetitive isometric right-hand gripping (60% of maximal voluntary contraction, Dynamometer (BIOPAC)). We observed higher activity in pain-processing regions in FM than HV during noxious stimulation. Upon stimulation during motor task, greater activity was found within SC dorsal horns (level C6) and brain regions implicated in sensory pain aspects (e.g., insula, S1) in FM compared to HV, while HV demonstrated enhanced activity in regions implicated in pain regulation (e.g., prefrontal cortex, periaqueductal gray, motor cortices), paralleled by lower pain ratings. We identified neural correlates of aberrant pain modulation in FM which might advance understanding of spinal-supraspinal interactions in chronic pain and pain biomarker development. Funded by National Institutes of Health and Swiss National Science Foundation.

Emotion is among the supraspinal processes that modulate pain perception. In fibromyalgia (FM) patients, deficits related to the emotional regulation (ER) of pain have been widely demonstrated. Therefore, it is essential to understand and identify the processes that impact ER of pain in FM patients. In this preliminary study, we investigated the ER in FM patients using functional magnetic resonance imaging (fMRI). 11 patients and 7 healthy volunteers (HV) performed an ER task while thermal heat (tailored to each participant’s 6/10 on a VAS scale) was delivered to their right forearm via ATS thermode (Medoc), in which they were asked to upregulate (INCREASE), downregulate (DECREASE), or be aware of the heat pain (8x per condition in pseudo-randomized order). At the behavioral level, both groups were able to perform the task somewhat to a similar extent as the pain ratings increased (FM: 0.68, HV: 1.04) or decreased (FM: -0.85, HV: -0.63) during upregulation and downregulation (compared to aware condition), respectively. fMRI results demonstrated increased activity in the anterior cingulate cortex, periaqueductal gray, anterior insula, and brainstem during the upregulation of pain (INCREASE >AWARE) in FM, demonstrating the involvement of descending pathways, whereas for downregulation (DECREASE > AWARE), we observed increased activity in visual cortex and lingual gyri. This may imply that the descending modulation pathways that are engaged in the upregulation and downregulation of experimental pain differ between patients vs HV. In the future, we will increase our sample size and investigate the whole neuroaxis including the spinal cord. Funded by NIH (R01NS109450).

Magnetic resonance acoustic radiation force imaging (MR-ARFI) is an exceptionally promising technique to non-invasively confirm targeting accuracy and estimate exposure of low-intensity transcranial focused ultrasound stimulation. MR-ARFI uses magnetic field motion encoding gradients to visualize the MR phase changes generated by microscopic displacements at the ultrasound focus. Implementing MR-ARFI in the human central nervous system has been hindered by 1) phase distortion caused by subject motion, and 2) insufficient signal-to-noise ratio at low (<1.0 MPa) ultrasound pressures. The purpose of this study was to optimize human MR-ARFI to allow reduced ultrasound exposure while at the same time being robust to bulk and physiological motion. We demonstrate that a time series of single-shot spiral acquisitions, while triggering ultrasound on and off in blocks, provides ARFI maps that with correction are largely immune to bulk and pulsatile brain motion. Furthermore, the time series approach allows for a reduction in ultrasound exposure per slice while improving motion robustness with reduced scan time. The focused ultrasound beam can be visualized in an 80 second scan with our protocol, enabling iteration for image-guided targeting. We demonstrated robust ARFI signals at the expected target in 4 participants. Our results provide persuasive proof-of-principle that MR-ARFI can be used as a tool to guide ultrasound-based precision neural circuit therapeutics.

This work presents a new variation on electrostatic clutches that uses gecko‐inspired adhesives instead of friction for its braking force. As a result, it requires no power or normal pressure to remain engaged or disengaged. It requires only a brief pulse of voltage to switch states. In some applications, this capability is desirable for safety reasons. As an illustration, the clutch is incorporated into the needle‐driving axis of a magnetic resonance compatible teleoperated robotic system. Adding the clutch has no effect on imaging quality and provides a fail‐safe brake to prevent the needle axis from dropping in the event of a power failure. As a second application, the clutch is integrated into a force‐controlled robotic gripper where it allows the motor to be turned off while maintaining a static grasping force. In both applications, the 20 ms response time of the clutch prototypes is advantageous to prevent any motion immediately after receiving a braking command. This work additionally presents details on the design and manufacturing process of the gecko‐inspired clutch, including a new, non‐uniform profile for the microscopic adhesive features. The fabricated prototypes are thin (305 µm per layer) and flexible. They provide a controllable, adhesive braking force of 60 kPa per layer. Multiple layers can be assembled to increase the braking force.

We present a novel fMRI acquisition that mitigates susceptibility-induced off-resonance and simultaneously captures brainstem, spinal cord, and brain. Brainstem and spinal cord are imaged in high spatial resolution whereas brain resolution is standard. This fMRI acquisition is applied in a noxious pressure-pain experiment from which we observe activation in brain, spinal cord, and brainstem pons & medulla.

We previously reported the rapid OCD symptom reduction of ketamine, a glutamate N-methyl-d-aspartate (NMDA) receptor antagonist, vs saline infusions in a proof-of-concept crossover trial (n=15) in unmedicated adults with OCD. Building on this initial finding, we evaluated the efficacy of ketamine in a larger group of unmedicated OCD patients with improved control conditions (active placebo control condition).

number of pain episodes.Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for ontological analysis of the four significant modules and key biological processes identified were inflammatory response and cellular response to lipopolysaccharide.Cytoscape was used to construct a protein-protein interaction network and the 10 top hub genes identified in hierarchical order were: TNF, CCR5, CCR1, CCL2, CXCL2, ITGAM, CCL7, CXCL3, TLR2 and MMP9.These genes, as part of the inflammatory response, support the immune system contributes to increased pain episode frequency.Identified hub genes may be leveraged as therapeutic targets for reducing SCD pain episodes.1R61NS114954-01.T a g g e d E n d

Introduction:tDCS is a non-invasive neuromodulation technique that has been widely studied both as a therapy for neuropsychiatric diseases and for cognitive enhancement. However, recent meta-analyses have reported significant inconsistencies amongst tDCS studies. Enhancing empirical understanding of current flow in the brain may help elucidate some of these inconsistencies.Methods:We investigated tDCS-induced current distribution by injecting a low frequency current waveform in a phantom and in vivo. MR phase images were collected during the stimulation and a time-series analysis was used to reconstruct the magnetic field. A current distribution map was derived from the field map using Ampere's law.Results:The current distribution map in the phantom showed a clear path of current flow between the two electrodes, with more than 75% of the injected current accounted for. However, in brain, the results did evidence a current path between the two target electrodes but only some portion ( 25%) of injected current reached the cortex demonstrating that a significant fraction of the current is bypassing the brain and traveling from one electrode to the other external to the brain, probably due to conductivity differences in brain tissue types. Substantial inter-subject and intra-subject (across consecutive scans) variability in current distribution maps were also observed in human but not in phantom scans.Discussions:An in-vivo current mapping technique proposed in this study demonstrated that much of the injected current in tDCS was not accounted for in human brain and deviated to the edge of the brain. These findings would have ramifications in the use of tDCS as a neuromodulator and may help explain some of the inconsistencies reported in other studies.

Neuromodulation of deep brain structures via transcranial ultrasound stimulation (TUS) is a promising, but still elusive approach to non-invasive treatment of brain disorders. The purpose of this study was to confirm that MR-guided TUS of the lateral geniculate nucleus (LGN) can modulate visual evoked potentials (VEPs) in the intact large animal; and to study the impact on cortical brain oscillations. The LGN on one side was identified with T2-weighted MRI in sheep (all male, n = 9). MR acoustic radiation force imaging (MR-ARFI) was used to confirm localization of the targeted area in the brain. Electroencephalographic (EEG) signals were recorded, and the visual evoked potential (VEP) peak-to-peak amplitude (N70 and P100) was calculated for each trial. Time–frequency spectral analysis was performed to elucidate the effect of TUS on cortical brain dynamics. The VEP peak-to-peak amplitude was reversibly suppressed relative to baseline during TUS. Dynamic spectral analysis demonstrated a change in cortical oscillations when TUS is paired with visual sensory input. Sonication-associated microscopic displacements, as measured by MR-ARFI, correlated with the TUS-mediated suppression of visual evoked activity. TUS non-invasively delivered to LGN can neuromodulate visual activity and oscillatory dynamics in large mammalian brains.