Journal of Neurophysiology

Lin, Shihao; Hari, Krishnapriya; Black, Sophie; Khatmi, Aysan; Fouad, Karim; Gorassini, Monica A.; Li, Yaqing; Lucas-Osma, Ana M.; Fenrich, Keith K.; Bennett, David J.

doi: 10.1152/jn.00482.2022pmid: 37609680

When a muscle is stretched, sensory feedback not only causes reflexes, but also leads to a depolarization of sensory afferents throughout the spinal cord (primary afferent depolarization, PAD), readying the whole limb for further disturbances. This sensory-evoked PAD is thought to be mediated by a trisynaptic circuit, where sensory input activates first order excitatory neurons that activate GABAergic neurons that in turn activate GABAA receptors on afferents to cause PAD, though the identity of these first order neurons is unclear. Here we show that these first order neurons include propriospinal V3 neurons, since they receive extensive sensory input and in turn innervate GABAergic neurons that cause PAD, because optogenetic activation or inhibition of V3 neurons in mice mimics or inhibits sensory-evoked PAD, respectively. Furthermore, persistent inward sodium currents intrinsic to V3 neurons prolong their activity, explaining the prolonged duration of PAD. Also, local optogenetic activation of V3 neurons at one segment causes PAD in other segments, due to the long propriospinal tracts of these neurons, helping to explain the radiating nature of PAD. This in turn facilitates monosynaptic reflex transmission to motoneurons across the spinal cord. Additionally, V3 neurons directly innervate proprioceptive afferents (including Ia), causing a glutamate receptor mediated PAD (glutamate PAD). Finally, increasing the spinal cord excitability with either GABAA receptor blockers or chronic spinal cord injury causes an increase in the glutamate PAD. Overall, we show the V3 neuron has a prominent role in modulating sensory transmission, in addition to its previously described role in locomotion.

Conroy, Christopher; Nanjappa, Rakesh; McPeek, Robert M.

doi: 10.1152/jn.00095.2023pmid: 37671440

Inhibitory tagging is an important feature of many models of saccade target selection, in particular those based on the notion of a neural priority map. The superior colliculus (SC) has been suggested as a potential site of such a map, yet it is unknown if inhibitory tagging is represented in the SC during visual search. In this study, we tested the hypothesis that SC neurons represent inhibitory tagging during search, as might be expected if they contribute to a priority map. To do so, we recorded the activity of SC neurons in a multi-saccade visual-search task. On each trial, a single reward-bearing target was embedded in an array of physically identical, potentially reward-bearing targets and physically distinct, non-reward-bearing distractors. The task was to fixate the reward-bearing target. We found that, in the context of this task, the activity of many SC neurons was greater when their response-field stimulus was a target than when it was a distractor and was reduced when it had been previously fixated relative to when it had not. Moreover, we found that the previous-fixation-related reduction of activity was larger for targets than for distractors and decreased with increasing time (or number of saccades) since fixation. Taken together, the results suggest that fixated stimuli are transiently inhibited in the SC during search, consistent with the notion that inhibitory tagging plays an important role in visual search and that SC neurons represent this inhibition as part of a priority map used for saccade target selection.

Viana Di Prisco, Gonzalo; Marlinski, Vladimir; Beloozerova, Irina N.

doi: 10.1152/jn.00114.2023pmid: 37609687

Visual control of steps is critical in everyday life. Several motor centers are implicated in visual control of steps on a complex surface, however, participation of a large cortical motor area, the premotor cortex, in visual guidance of steps during overground locomotion has not been examined. Here we analyzed the activity of neurons in feline premotor cortex areas 6aα and 6aγ as cats walked on the flat surface where visual guidance of steps is not needed and stepped on crosspieces of a horizontally placed ladder or over barriers where visual control of steps is required. The comparison of neuronal firing between vision-dependent and vision-independent stepping revealed components of the activity related to visual guidance of steps. We found that the firing activity of 59% of neurons was modulated with the rhythm of strides on the flat surface, and the activity of 83-86% of the population changed upon transition to locomotion on the ladder or with barriers. The firing rate and the depth of the stride-related activity modulation of 33 - 44% of neurons changed, and the stride phases where neurons preferred to fire changed for 58 - 73% of neurons. These results indicate that a substantial proportion of areas 6aα and 6aγ neurons is involved in visual guidance of steps. Compared to the primary motor cortex, the proportion of cells the firing activity of which changed upon transition from vision-independent to vision-dependent stepping was lower and the preferred phases of the firing activity changed more often between the tasks.

Uehara, Shintaro; Yuasa, Akiko; Ushizawa, Kazuki; Kitamura, Shin; Yamazaki, Kotaro; Otaka, Eri; Otaka, Yohei

doi: 10.1152/jn.00455.2022pmid: 37667840

Arm reaching is often impaired in individuals with stroke. Nonetheless, how aiming directions influence reaching performance and how such differences change with motor recovery over time remain unclear. Here, we elucidated kinematic parameters of reaching toward various directions in people with post-stroke hemiparesis in the sub-acute phase. A total of 13 and 15 participants with mild and moderate-to-severe hemiparesis, respectively, performed horizontal reaching in eight directions with their affected and unaffected sides using an exoskeleton robotic device at admission and discharge. The movement time, path length, and number of velocity peaks were computed for the mild group (participants able to reach toward all eight directions). Additionally, the total amount of displacement (i.e., movement quantity) toward two simplified directions (mediolateral or anteroposterior) was evaluated for the moderate-to-severe group (participants who showed difficulty in completing the reaching task). Motor recovery was evaluated using the Fugl-Meyer Assessment.The mild group exhibited decreases in movement parameters when reaching in the anteroposterior direction, irrespective of the side of the arm or motor recovery achieved. The moderate-to-severe group exhibited less movement toward the anteroposterior direction than toward the mediolateral direction at admission; however, this direction-dependent bias in movement quantity decreased, with the movement expanding toward the anteroposterior direction with motor recovery at discharge. These results suggest that direction-dependent differences in the quality and quantity of reaching performance exist in people after stroke, regardless of the presence or severity of hemiparesis. This highlights the need to consider the task work area when designing rehabilitative training.

Timar, Lili; Job, Xavier; Orban de Xivry, Jean-Jacques; Kilteni, Konstantina

doi: 10.1152/jn.00145.2023pmid: 37609705

Touch generated by our voluntary movements is attenuated both at the perceptual and neural level compared to touch of the same intensity delivered to our body by another person or machine. This somatosensory attenuation phenomenon relies on the integration of somatosensory input and predictions about the somatosensory consequences of our actions. Previous studies have reported increased somatosensory attenuation in elderly people, proposing an overreliance on sensorimotor predictions to compensate for age-related declines in somatosensory perception; however, recent results have challenged this direct relationship. In a preregistered study, we used a force-discrimination task to assess whether aging increases somatosensory attenuation and whether this increase is explained by decreased somatosensory precision in elderly individuals. Although 94% of our sample (n = 108, 21-77 years old) perceived their self-generated touches as weaker than externally generated touches of identical intensity (somatosensory attenuation) regardless of age, we did not find a significant increase in somatosensory attenuation in our elderly participants (65-77 years old), but a trend when considering only the oldest subset (69-77 years old). Moreover, we did not observe a significant age-related decline in somatosensory precision or a significant relationship of age with somatosensory attenuation. Together, our results suggest that aging exerts a limited influence on the perception of self-generated and externally generated touch and indicate a less direct relationship between somatosensory precision and attenuation in the elderly individuals than previously proposed.

Chung, Yu-Chen; Shemmell, Jonathan; Kumala, Caitlin; Soedirdjo, Subaryani D. H.; Dhaher, Yasin Y.

doi: 10.1152/jn.00202.2023pmid: 37646076

Estimating the state of tract-specific inputs to spinal motoneurons is critical to understand movement deficits induced by neurological injury and potential pathways to recovery, but remains challenging in humans. In this study we explored the capability of trans-spinal magnetic stimulation (TSMS) to modulate distal reflex circuits in young adults. TSMS was applied over thoracic spine to condition soleus H-reflexes involving sacral-level motoneurons. Three TSMS intensities below motor threshold were applied at inter-stimulus intervals (ISIs) between 2-20 ms relative to peripheral nerve stimulation (PNS). While low intensity TSMS yielded no changes in H-reflexes across ISIs, the two higher stimulus intensities yielded two phases of H-reflex inhibition: a relatively long-lasting period at 2-9 ms ISIs, and a short phase at 11-12 ms ISIs. H-reflex inhibition at 2 ms ISI was uniquely dependent on TSMS intensity. To identify the candidate neural pathways contributing to H-reflex suppression, we constructed a tract-specific conduction time estimation model. Based upon our model, H-reflex inhibition at 11-12 ms ISIs is likely a manifestation of orthodromic transmission along the lateral reticulospinal tract. In contrast, the inhibition at 2 ms ISI likely reflects orthodromic transmission along sensory fibers with activation reaching brain, before descending along motor tracts. Multiple pathways may contribute to H-reflex modulation between 4-9 ms ISIs, orthodromic transmission along sensorimotor tracts and antidromic transmission of multiple motor tracts. Our findings suggest that non-invasive TSMS can influence motoneuron excitability at distal segments and that the contribution of specific tracts to motoneuron excitability may be distinguishable based upon conduction velocities.

Wang, Allison B.; Housley, Stephen N.; Ludvig, Daniel; Franz, Colin K.; Flores, Ann Marie; Cope, Timothy C.; Perreault, Eric J.

doi: 10.1152/jn.00299.2022pmid: 37671425

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.

Kelley, Craig; Antic, Srdjan D.; Carnevale, Nicholas T.; Kubie, John L.; Lytton, William W.

doi: 10.1152/jn.00160.2023pmid: 37609720

Rhythmic activity is ubiquitous in neural systems, with theta-resonant pyramidal neurons integratingrhythmic inputs in many cortical structures. Impedance analysis has been widely used to examinefrequency-dependent responses of neuronal membranes to rhythmic inputs, but it assumes that the neuronalmembrane is a linear system, requiring the use of small signals to stay in a near-linear regime. However,postsynaptic potentials are often large and trigger nonlinear mechanisms (voltage-gated ion channels). Thegoals of this work were to 1. develop an analysis method to evaluate membrane responsesin this nonlinear domain and 2. explore phase relationships between rhythmic stimuli and subthreshold and spiking membrane potential (Vmemb) responses in models of theta-resonant pyramidal neurons. Responses in these output regimes were asymmetrical, with different phase shifts during hyperpolarizing and depolarizing half-cycles.Suprathreshold theta-rhythmic stimuli produced nonstationary Vmemb responses .Sinusoidal inputs produced phase retreat: action potentials occurred progressively later in cycles of theinput stimulus, resulting from adaptation. Sinusoidal current with increasing amplitude overcycles produced phase advance: action potentials occurred progressively earlier. Phase retreat,phase advance, and subthreshold phase shifts were modulated by multiple ion channel conductances. Our results suggest differential responses of cortical neurons depending on the frequency of oscillatory input, which will play a role inneuronal responses to shifts in network state. We hypothesize that intrinsic cellular properties complementnetwork properties and contribute to in vivo phase-shift phenomena such as phase precession, seen in placeand grid cells, and phase roll, also observed in hippocampal CA1 neurons.

Bruce, Christina D.; Magnuson, Justine R.; McNeil, Chris J.

doi: 10.1152/jn.00132.2023pmid: 37671448

According to current guidelines, when measuring voluntary activation (VA) using transcranial magnetic stimulation (TMS), stimulator output (SO) should not exceed the intensity that, during a maximal voluntary contraction (MVC), elicits a motor evoked potential (MEP) from the antagonist muscle >15-20% of its maximal M-wave amplitude. However, VA is based on agonist evoked-torque responses (i.e., superimposed twitch; SIT and estimated resting twitch; ERT), which means limiting SO based on electromyographic (EMG) responses will often lead to a submaximal SIT and ERT, possibly underestimating VA. Therefore, the purpose of this study was to compare elbow flexor VA calculated using the original method (i.e., intensity based on MEP size; SOMEP) and a method based solely on eliciting the largest SIT at 50% MVC torque (SOSIT), regardless of triceps brachii MEP size. Fifteen healthy, young participants performed 10 sets of brief contractions at 100, 75, and 50% MVC torque, with TMS delivered at SOMEP (73.0±13.5%) or SOSIT (92.0±10.8%) for five sets each. Although the mean ERT torque was greater using SOSIT (15.2±4.8Nm) compared to SOMEP (13.0±3.7Nm; P=0.031), the SIT amplitude at 100% MVC torque was not different (SOMEP: 0.69±0.49Nm vs. SOSIT: 0.74±0.52Nm; P=0.604). Despite the ERT disparity, VA scores were not different between SOMEP (94.6±3.5%) and SOSIT (95.0±3.3%; P=0.572). Even though SOSIT did not lead to a higher VA score than the SOMEP method, it has the benefit of yielding the same result without the need to record antagonist EMG or perform MVCs when determining SO, which can induce fatigue prior to measuring VA.

Kasiri, Maral; Biffi, Emilia; Ambrosini, Emilia; Pedrocchi, Alessandra; Sanger, Terence D.

doi: 10.1152/jn.00214.2023pmid: 37584081

The tradeoff between speed and accuracy is a well-known constraint for human movement, but previous work has shown that this tradeoff can be modified by practice, and the quantitative relationship between speed and accuracy may be an indicator of skill in some tasks. We have previously shown that children with dystonia are able to adapt their movement strategy in a ballistic throwing game to compensate for increased variability of movement. Here we test whether children with dystonia can adapt and improve skill learnt on a trajectory task. We use a novel task in which children move a spoon with a marble between two targets. Difficulty is modified by changing the depth of the spoon. Our results show that both healthy children and children with acquired dystonia move more slowly with the more difficult spoons, and both groups improve the relationship between speed and spoon difficulty following one week of practice. By tracking the marble position in the spoon, we show that children with dystonia use a larger fraction of the available variability, whereas healthy children adopt a much safer strategy and remain farther from the margins, as well as learning to adopt and have more control over the marble's utilized area by practice. Together, our results show that both healthy children and children with dystonia choose trajectories that compensate for risk and inherent variability, and that the increased variability in dystonia can be modified with continued practice.