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The locus coeruleus (LC) is a small region in the pons and the main source of noradrenaline (NA) to the forebrain. While traditional models suggested that all LC-NA neurons project indiscriminately throughout the brain, accumulating evidence indicates that these cells can be heterogeneous based on their anatomical connectivity and behavioral functionality and exhibit distinct coding modes. How LC-NA neuronal subpopulations are endowed with unique functional properties is unclear. Here, we used a viral-genetic approach for mapping anatomical connectivity at different levels of organization based on inputs and outputs of defined cell classes. Specifically, we studied the whole-brain afferent inputs onto two functionally distinct LC-NA neuronal subpopulations which project to amygdala or medial prefrontal cortex (mPFC). We found that the global input distribution is similar for both LC-NA neuronal subpopulations. However, finer analysis demonstrated important differences in inputs from specific brain regions. Moreover, sex related differences were apparent, but only in inputs to amygdala-projecting LC-NA neurons. These findings reveal a cell type and sex specific afferent input organization which could allow for context dependent and target specific control of NA outflow to forebrain structures involved in emotional control and decision making.

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Introduction: Neuromuscular electrical stimulation (NMES) induces neural plasticity of the central nervous system (CNS) and improves motor function in patients with CNS lesions. However, the extended stimulus duration of NMES reduces its clinical applicability. Transcutaneous spinal direct current stimulation (tsDCS), which increases afferent input, may enhance the effects and reduce the stimulus duration of NMES. This study investigated the excitability of the motor cortex, somatosensory cortex, and spinal motor neurons after the combined stimulation of NMES and tsDCS. Methods: Among the 55 participants in this study, 24 were allocated to experiment 1, 15 to experiment 2, and 16 to experiment 3. They received intervention for 20 min on different days: (1) NMES combined with tsDCS (NMES + tsDCS), (2) NMES combined with sham tsDCS (NMES + sham tsDCS), and (3) sham NMES combined with tsDCS (sham NMES + tsDCS). NMES was delivered to the right common peroneal nerve at 25 Hz with the intensity at 120% of the motor threshold. For tsDCS, the cathodal electrode was positioned on the thoracic 10th-12th vertebral levels, and the anodal electrode was located on the right shoulder. The stimulus intensity was 2.5 mA. In experiment 1, motor evoked potentials (MEPs) and short-latency intracortical inhibition (SICI) were measured by transcranial magnetic stimulation up to 60 min after stimulation. The spinal motor neurons' excitability was assessed by recording the posterior root muscle reflex (PRMR) induced via transcutaneous spinal cord stimulation in experiment 2, and the primary somatosensory cortex excitability was evaluated by recording the somatosensory evoked potentials (SEPs) in experiment 3 up to 15 min after stimulation. Results: Compared to before the stimulation, NMES + tsDCS significantly increased MEP for 60 min or more, and significantly decreased SICI immediately after. Conversely contrast, the PRMR significantly decreased immediately after, and SEPs were unchanged. Discussion: These results suggest that simultaneous afferent inputs from different stimulus positions critically induce primary motor cortex plasticity. The combined stimulation of NMES with tsDCS may facilitate the development of a new neurorehabilitation technique.

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Substantia gelatinosa (SG) neurons, which are located in the spinal dorsal horn (lamina II), have been identified as the "central gate" for the transmission and modulation of nociceptive information. Rebound depolarization (RD), a biophysical property mediated by membrane hyperpolarization that is frequently recorded in the central nervous system, contributes to shaping neuronal intrinsic excitability and, in turn, contributes to neuronal output and network function. However, the electrophysiological and morphological properties of SG neurons exhibiting RD remain unclarified. In this study, whole-cell patch-clamp recordings were performed on SG neurons from parasagittal spinal cord slices. RD was detected in 44.44% (84 out of 189) of the SG neurons recorded. We found that RD-expressing neurons had more depolarized resting membrane potentials, more hyperpolarized action potential (AP) thresholds, higher AP amplitudes, shorter AP durations, and higher spike frequencies in response to depolarizing current injection than neurons without RD. Based on their firing patterns and morphological characteristics, we propose that most of the SG neurons with RD mainly displayed tonic firing (69.05%) and corresponded to islet cell morphology (58.82%). Meanwhile, subthreshold currents, including the hyperpolarization-activated cation current (I h ) and T-type calcium current (I T ), were identified in SG neurons with RD. Blockage of I h delayed the onset of the first spike in RD, while abolishment of I T significantly blunted the amplitude of RD. Regarding synaptic inputs, SG neurons with RD showed lower frequencies in both spontaneous and miniature excitatory synaptic currents. Furthermore, RD-expressing neurons received either Aδ- or C-afferent-mediated monosynaptic and polysynaptic inputs. However, RD-lacking neurons received afferents from monosynaptic and polysynaptic Aδ fibers and predominantly polysynaptic C-fibers. These findings demonstrate that SG neurons with RD have a specific cell-type distribution, and may differentially process somatosensory information compared to those without RD.

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In healthy subjects, motor cortex activity and electromyographic (EMG) signals from contracting contralateral muscle show coherence in the beta (15-30 Hz) range. Corticomuscular coherence (CMC) is considered a sign of functional coupling between muscle and brain. Based on prior studies, CMC is altered in stroke, but functional significance of this finding has remained unclear. Here, we examined CMC in acute stroke patients and correlated the results with clinical outcome measures and corticospinal tract (CST) integrity estimated with diffusion tensor imaging (DTI). During isometric contraction of the extensor carpi radialis muscle, EMG and magnetoencephalographic oscillatory signals were recorded from 29 patients with paresis of the upper extremity due to ischemic stroke and 22 control subjects. CMC amplitudes and peak frequencies at 13-30 Hz were compared between the two groups. In the patients, the peak frequency in both the affected and the unaffected hemisphere was significantly (p < 0.01) lower and the strength of CMC was significantly (p < 0.05) weaker in the affected hemisphere compared to the control subjects. The strength of CMC in the patients correlated with the level of tactile sensitivity and clinical test results of hand function. In contrast, no correlation between measures of CST integrity and CMC was found. The results confirm the earlier findings that CMC is altered in acute stroke and demonstrate that CMC is bidirectional and not solely a measure of integrity of the efferent corticospinal tract.

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Locomotor activity requires fine balance control that strongly depends on the afferent input from the load receptors. Following hindlimb unloading (HU), the kinematic and EMG activity of the hindlimbs is known to change significantly. However, the effects of HU on the integrative control mechanisms of posture and locomotion are not clear. The goal of the present study was to evaluate the center of mass (CoM) dynamic stabilization and associated adaptive changes in the trunk and hindlimb muscle activity during locomotion after 7 days of HU. The EMG signals from the muscles of the low lumbar trunk [m. longissimus dorsi (VERT)] and the hind limb [m. tibialis anterior (TA), m. semitendinosus (ST), m. soleus (SOL)] were recorded together with the hindquarter kinematics during locomotion on a treadmill in six rats before and after HU. The CoM lateral shift in the step cycle significantly increased after HU and coincided with the enhanced activity of the VERT. The mean EMG of the TA and the ST flexor activity increased significantly with reduction of their burst duration. These data demonstrate the disturbances of body balance after HU that can influence the basic parameters of locomotor activity. The load-dependent mechanisms resulted in compensatory adjustments of flexor activity toward a faster gait strategy, such as a trot or gallop, which presumably have supraspinal origin. The neuronal underpinnings of these integrative posture and locomotion mechanisms and their possible reorganization after HU are discussed.

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The nucleus accumbens (NAc) is the ventral part of the striatum and the interface between cognition, emotion, and action. It is composed of three major subnuclei: i.e., NAc core (NAcC), lateral shell (NAcLS), and medial shell (NAcMS), which exhibit functional heterogeneity. Thus, determining the synaptic inputs of the subregions of the NAc is important for understanding the circuit mechanisms involved in regulating different functions. Here, we simultaneously labeled subregions of the NAc with cholera toxin subunit B conjugated with multicolor Alexa Fluor, then imaged serial sections of the whole brain with a fully automated slide scanning system. Using the interactive WholeBrain framework, we characterized brain-wide inputs to the NAcC subdomains, including the rostral, caudal, dorsal, and ventral subdomains (i.e., rNAcC, cNAcC, dNAcC, and vNAcC, respectively) and the NAc subnuclei. We found diverse brain regions, distributed from the cerebrum to brain stem, projecting to the NAc. Of the 57 brain regions projecting to the NAcC, the anterior olfactory nucleus (AON) exhibited the greatest inputs. The input neurons of rNAcC and cNAcC are two distinct populations but share similar distribution over the same upstream brain regions, whereas the input neurons of dNAcC and vNAcC exhibit slightly different distributions over the same upstream regions. Of the 55 brain regions projecting to the NAcLS, the piriform area contributed most of the inputs. Of the 72 brain regions projecting to the NAcMS, the lateral septal nucleus contributed most of the inputs. The input neurons of NAcC and NAcLS share similar distributions, whereas the NAcMS exhibited brain-wide distinct distribution. Thus, the NAcC subdomains appeared to share the same upstream brain regions, although with distinct input neuron populations and slight differences in the input proportions, whereas the NAcMS subnuclei received distinct inputs from multiple upstream brain regions. These results lay an anatomical foundation for understanding the different functions of NAcC subdomains and NAc subnuclei.

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KEY POINTS: Cutaneous reflexes were tested to examine the neuronal mechanisms contributing to muscle spasms in humans with chronic spinal cord injury (SCI). Specifically, we tested the effect of Achilles and tibialis anterior tendon vibration on the early and late components of the cutaneous reflex and reciprocal Ia inhibition in the soleus and tibialis anterior muscles in humans with chronic SCI. We found that tendon vibration reduced the amplitude of later but not earlier cutaneous reflex in the antagonist but not in the agonist muscle relative to the location of the vibration. In addition, reciprocal Ia inhibition between antagonist ankle muscles increased with tendon vibration and participants with a larger suppression of the later component of the cutaneous reflex had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration attenuates late cutaneous spasm-like reflex activity, likely via reciprocal inhibitory mechanisms, and may represent a method, when properly targeted, for controlling spasms in humans with SCI. ABSTRACT: The neuronal mechanisms contributing to the generation of involuntary muscle contractions (spasms) in humans with spinal cord injury (SCI) remain poorly understood. To address this question, we examined the effect of Achilles and tibialis anterior tendon vibration at 20, 40, 80 and 120 Hz on the amplitude of the long-polysynaptic (LPR, from reflex onset to 500 ms) and long-lasting (LLR, from 500 ms to reflex offset) cutaneous reflex evoked by medial plantar nerve stimulation in the soleus and tibialis anterior, and reciprocal Ia inhibition between these muscles, in 25 individuals with chronic SCI. We found that Achilles tendon vibration at 40 and 80 Hz, but not other frequencies, reduced the amplitude of the LLR in the tibialis anterior, but not the soleus muscle, without affecting the amplitude of the LPR. Vibratory effects were stronger at 80 than 40 Hz. Similar results were found in the soleus muscle when the tibialis anterior tendon was vibrated. Notably, tendon vibration at 80 Hz increased reciprocal Ia inhibition between antagonistic ankle muscles and vibratory-induced increases in reciprocal Ia inhibition were correlated with decreases in the LLR, suggesting that participants with a larger suppression of later cutaneous reflex activity had stronger reciprocal Ia inhibition from the antagonistic muscle. Our study is the first to provide evidence that tendon vibration suppresses late spasm-like activity in antagonist but not agonist muscles, likely via reciprocal inhibitory mechanisms, in humans with chronic SCI. We argue that targeted vibration of antagonistic tendons might help to control spasms after SCI.

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Spasticity affects approximately 65% of persons with spinal cord injury (SCI) and negatively impacts function and quality of life. Whole body vibration (WBV) appears to reduce spasticity and improve walking function; however, the optimal dose (frequency/duration) is not known. We compared single-session effects of four different WBV frequency/duration dose conditions on spasticity and walking speed, in preparation for a planned multi-session study. Thirty-five participants with motor-incomplete SCI received four different doses of WBV: high frequency (50 Hz)/short duration (180 s), high frequency/long duration (360 s), low frequency (30 Hz)/short duration, and low frequency/long duration, plus a control intervention consisting of sham electrical stimulation. In all conditions, participants stood on the WBV platform for 45-s bouts with 1 min rest between bouts until the requisite duration was achieved. The frequency/duration dose order was randomized across participants; sessions were separated by at least 1 week. Quadriceps spasticity was measured using the pendulum test at four time points during each session: before, immediately after, 15 min after, and 45 min after WBV. Walking speed was quantified using the 10-m walk test at three time points during each session: baseline, immediately after, and 45 min after WBV. In the full group analysis, no frequency/duration combination was significantly different from the sham-control condition. In participants with more severe spasticity, a greater reduction in stretch reflex excitability was associated with the high frequency/long duration WBV condition. The sham-control condition was associated with effects, indicating that the activity of repeated sitting and standing may have a beneficial influence on spasticity. TRIAL REGISTRATION: NCT02340910 (assigned 01/19/2015).

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Studies of robot-assisted passive stepping paradigms have reported that movement-related afferent inputs strongly inhibit the excitability of the Hoffmann (H) reflex in the soleus (Sol) during walking. However, it is unknown if movement-related afferent inputs have the same effect on the excitability of spinal reflexes in the other lower-limb muscles that are involved in normal walking in healthy subjects. The aim of this study was to examine the effects of movement-related afferent inputs on the spinal reflexes in lower-limb muscles during walking. Spinal reflexes that were elicited by transcutaneous spinal cord stimulation (tSCS) were recorded during passive air standing and air stepping at three stepping velocities (stride frequencies: 14, 25, and 36 strides/min). The amplitude of the spinal reflexes was reduced in most of the recorded muscles during passive air stepping compared with air standing. Furthermore, in the Sol and lateral gastrocnemius, the amplitude of the reflexes during air stepping significantly decreased as stride frequency increased. These results demonstrate that movement-related afferent inputs inhibit spinal reflexes in the Sol and other lower-limb muscles during walking.

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The amplitude of the Hoffmann (H)-reflex in the soleus (Sol) muscle is known to be suppressed during passive stepping compared with during passive standing. The reduction of the H-reflex is not due to load-related afferent inputs, but rather to movement-related afferent inputs from the lower limbs. To elucidate the underlying neural mechanisms of this inhibition, we investigated the effects of the stepping velocity on the Sol H-reflex during robot-assisted passive stepping in 11 healthy subjects. The Sol H-reflexes were recorded during passive standing and stepping at five stepping velocities (stride frequencies: 14, 21, 28, 35, and 42 min(-1)) in the air. The Sol H-reflexes were significantly inhibited during passive stepping as compared with during passive standing, and reduced in size as the stepping velocity increased. These results indicate that the extent of H-reflex suppression increases with increasing movement-related afferent inputs from the lower limbs during passive stepping. The velocity dependence suggests that the Ia afferent inputs from lower-limb muscles around the hip and knee joints are most probably related to this inhibition.

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Involuntary contractions of paralyzed muscles (spasms) commonly disrupt daily activities and rehabilitation after human spinal cord injury (SCI). Our aim was to examine the recruitment, firing rate modulation, and derecruitment of motor units that underlie spasms of thenar muscles after cervical SCI. Intramuscular electromyographic activity (EMG), surface EMG, and force were recorded during thenar muscle spasms that occurred spontaneously or that were triggered by movement of a shoulder or leg. Most spasms were submaximal (mean: 39%, SD: 33 of the force evoked by median nerve stimulation at 50 Hz) with strong relationships between EMG and force (R (2) > 0.69). Unit recruitment occurred over a wide force range (0.2-103% of 50 Hz force). Significant unit rate modulation occurred during spasms (frequency at 25% maximal force: 8.8 Hz, 3.3 SD; at maximal force: 16.1 Hz, 4.1 SD). Mean recruitment frequency (7.1 Hz, 3.2 SD) was significantly higher than derecruitment frequency (5.4 Hz, 2.4 SD). Coactive unit pairs that fired for more than 4 s showed high (R (2) > 0.7, n = 4) or low (R (2):0.3-0.7, n = 12) rate-rate correlations, and derecruitment reversals (21 pairs, 29%). Later recruited units had higher or lower maximal firing rates than lower threshold units. These discrepant data show that coactive motoneurons are drive both by common inputs and by synaptic inputs from different sources during muscle spasms. Further, thenar motoneurons can still fire at high rates in response to various peripheral inputs after SCI, supporting the idea that low maximal voluntary firing rates and forces in thenar muscles result from reduced descending drive.

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This paper investigates the influence of the leg afferent input, induced by a leg assistive robot, on the decoding performance of a BMI system. Specifically, it focuses on a decoder based on the event-related (de)synchronization (ERD/ERS) of the sensorimotor area. The EEG experiment, performed with healthy subjects, is structured as a 3 × 2 factorial design, consisting of two factors: "finger tapping task" and "leg condition." The former is divided into three levels (BMI classes), being left hand finger tapping, right hand finger tapping and no movement (Idle); while the latter is composed by two levels: leg perturbed (Pert) and leg not perturbed (NoPert). Specifically, the subjects' leg was periodically perturbed by an assistive robot in 5 out of 10 sessions of the experiment and not moved in the remaining sessions. The aim of this study is to verify that the decoding performance of the finger tapping task is comparable between the two conditions NoPert and Pert. Accordingly, a classifier is trained to output the class of the finger tapping, given as input the features associated with the ERD/ERS. Individually for each subject, the decoding performance is statistically compared between the NoPert and Pert conditions. Results show that the decoding performance is notably above chance, for all the subjects, under both conditions. Moreover, the statistical comparison do not highlight a significant difference between NoPert and Pert in any subject, which is confirmed by feature visualization.

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OBJECTIVE: The present study investigated the effects of continuous theta-burst stimulation (cTBS) over primary somatosensory (SI) and motor (M1) cortices on motor-evoked potentials (MEPs) and short-latency afferent inhibition (SAI). METHODS: MEPs and SAI were recorded from the first dorsal interosseous (FDI) muscle of the right hand following 30Hz cTBS over left-hemisphere SI and M1 delivered to the same participants in separate sessions. Measurements were taken before and up to 60min following cTBS. RESULTS: CTBS over M1 suppressed MEPs and did not alter SAI. In contrast cTBS over SI facilitated MEPs and decreased median and digital nerve evoked SAI. CONCLUSIONS: These findings indicate that SAI amplitude is influenced by cTBS over SI but not M1, suggesting an important role for SI in the modulation of this circuit. These data provide further evidence that cTBS over SI versus M1 has opposite effects on corticospinal excitability. SIGNIFICANCE: To date, plasticity-inducing TMS protocols delivered over M1 have failed to modulate SAI, and the present research continues to support these findings. However, in young adults, cTBS over SI acts to reduce SAI and simultaneously increase corticospinal excitability. Future studies may investigate the potential to modulate SAI via targeting neural activity within SI.

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Anatomic studies have demonstrated that the mesolimbic dopamine system receives a substantial afferent input from a variety of regions ranging from the prefrontal cortex through to the brain stem. However, how these afferents regulate dopamine neuron activity is still largely unknown. The mesopontine tegmentum provides a significant input to ventral tegmental area (VTA) dopamine neurons, and it has been demonstrated that discrete subdivisions within this region differentially alter dopamine neuron activity. Thus the laterodorsal tegmental nucleus provides a tonic input essential for maintaining burst firing of dopamine neurons, whereas the pedunculopontine tegmental (PPTg) nucleus regulates a transition from single-spike firing to burst firing. In contrast, the recently identified rostromedial tegmental nucleus provides an inhibitory input to the VTA and decreases spontaneous dopamine neuron activity. Here, we demonstrate that an area adjacent to the PPTg regulates both population activity as well as burst firing of VTA dopamine neurons. Specifically, N-methyl-d-aspartic acid (NMDA) activation of the lateral mesopontine tegmentum produces an increase in the number of spontaneously active dopamine neurons and an increase in the average percentage of burst firing of dopamine neurons. This increase in neuronal activity was correlated with extracellular dopamine efflux in the nucleus accumbens, as measured by in vivo microdialysis. Taken together, we provide further evidence that the mesopontine tegmentum regulates discrete dopamine neuron activity states that are relevant for the understanding of dopamine system function in both normal and disease states.

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