Journal of Neurophysiology

Greenwell, Davin; Vanderkolff, Samia; Feigh, Jacob

doi: 10.1152/jn.00496.2022pmid: 36883755

De novo motor learning is a form of motor learning characterized by the development of an entirely new and distinct motor controller to accommodate a novel motor demand. Inversely, adaptation is a form of motor learning characterized by rapid, unconscious modifications in a previously established motor controller to accommodate small deviations in task demands. As most of the motor learning involves the adaptation of previously established motor controllers, de novo learning can be challenging to isolate and observe. The recent publication from Haith et al. (Haith AM, Yang CS, Pakpoor J, Kita K. J Neurophysiol 128: 982–993, 2022.) details a novel method to investigate de novo learning using a complex bimanual cursor control task. This research is especially important in the context of future brain-machine interface devices that will present users with an entirely novel motor learning demand, requiring de novo learning.

Calalo, Jan A.; Roth, Adam M.; Lokesh, Rakshith; Sullivan, Seth R.; Wong, Jeremy D.; Semrau, Jennifer A.; Cashaback, Joshua G. A.

doi: 10.1152/jn.00472.2022pmid: 36883741

The naturally occurring variability in our movements often poses a significant challenge when attempting to produce precise and accurate actions, which is readily evident when playing a game of darts. Two differing, yet potentially complementary, control strategies that the sensorimotor system may use to regulate movement variability are impedance control and feedback control. Greater muscular co-contraction leads to greater impedance that acts to stabilize the hand, while visuomotor feedback responses can be used to rapidly correct for unexpected deviations when reaching towards a target. Here we examined the independent roles and potential interplay of impedance control and visuomotor feedback control when regulating movement variability. Participants were instructed to perform a precise reaching task by moving a cursor through a narrow visual channel. We manipulated cursor feedback by visually amplifying movement variability and or delaying the visual feedback of the cursor. We found that participants decreased movement variability by increasing muscular co-contraction, aligned with an impedance control strategy. Participants displayed visuomotor feedback responses during the task but, unexpectedly, there was no modulation between conditions. However we did find a relationship between muscular co-contraction and visuomotor feedback responses, suggesting that participants modulated impedance control relative to feedback control. Taken together, our results highlight that the sensorimotor system modulates muscular co-contraction, relative to visuomotor feedback responses, to regulate movement variability and produce accurate actions.

Rudolph, Judith L.; Selen, Luc P. J.; Medendorp, W. Pieter

doi: 10.1152/jn.00294.2022pmid: 36883742

Generalization in motor learning refers to the transfer of a learned compensation to other relevant contexts. The generalization function is typically assumed to be of Gaussian shape, centered on the planned motion, although more recent studies associate generalization with the actual motion. Because motor learning is thought to involve multiple adaptive processes with different time constants, we hypothesized that these processes have different time-dependent contributions to the generalization. Guided by a model-based approach, the objective of the present study was to experimentally examine these contributions. We first reformulated a validated two-state adaptation model as a combination of weighted motor primitives, each specified as a Gaussian-shaped tuning function. Adaptation in this model is achieved by updating individual weights of the primitives of the fast and slow adaptive process separately. Depending on whether updating occurred in a plan-referenced or a motion-referenced manner, the model predicted distinct contributions to the overall generalization by the slow and fast process. We tested 23 participants in a reach adaptation task, using a spontaneous recovery paradigm consisting of five successive blocks of a long adaptation phase to a viscous force field, a short adaptation phase with the opposite force, and an error-clamp phase. Generalization was assessed in eleven movement directions relative to the trained target direction. Results of our participant population fell within a continuum of evidence for plan-referenced to evidence for motion-referenced updating. This mixture may reflect the differential weighting of explicit and implicit compensation strategies among participants.

Mantilla, Carlos B.; Ermilov, Leonid G.; Greising, Sarah M.; Gransee, Heather M.; Zhan, Wen-Zhi; Sieck, Gary C.

doi: 10.1152/jn.00015.2023pmid: 36883761

Previous studies show that synaptic quantal release decreases during repetitive stimulation, i.e., synaptic depression. The neurotrophin brain-derived neurotrophic factor (BDNF) enhances neuromuscular transmission via activation of tropomyosin-related kinase receptor B (TrkB). We hypothesized that BDNF mitigates synaptic depression at the neuromuscular junction and that the effect is more pronounced at type IIx and/or IIb fibers compared to type I or IIa fibers given the more rapid reduction in docked synaptic vesicles with repetitive stimulation. Rat phrenic nerve-diaphragm muscle preparations were used to determine the effect of BDNF on synaptic quantal release during repetitive stimulation at 50 Hz. An ~40% decline in quantal release was observed during each 330 ms duration train of nerve stimulation (intratrain synaptic depression) and this intratrain decline was observed across repetitive trains (20 trains at 1/s repeated every 5 min for 30 min - 6 sets). BDNF treatment significantly enhanced quantal release at all fiber types (p<0.001). BDNF treatment did not change release probability within a stimulation set but enhanced synaptic vesicle replenishment between sets. In agreement, synaptic vesicle cycling (measured using FM4-64 fluorescence uptake) was increased following BDNF (or neurotrophin-4; NT-4) treatment (~40%; p<0.05). Conversely, inhibiting BDNF/TrkB signaling with the tyrosine kinase inhibitor K252a and TrkB-IgG (which quenches endogenous BDNF or NT-4) decreased FM4-64 uptake (~34% across fiber types; p<0.05). Effects of BDNF were generally similar across all fiber types. We conclude that BDNF/TrkB signaling acutely enhances presynaptic quantal release, and thereby may serve to mitigate synaptic depression and maintain neuromuscular transmission during repetitive activation.

Miller, Luke E.; Jarto, Felix; Medendorp, W. Pieter

doi: 10.1152/jn.00442.2022pmid: 36812143

The spatial limits of sensory acquisition (its sensory horizon) is a fundamental property of any sensorimotor system. In the present study, we sought to determine whether there is a sensory horizon for the human haptic modality. At first blush, it seems obvious that the haptic system is bounded by the space where the body can interact with the environment (e.g., the arm span). However, the human somatosensory system is exquisitely tuned to sensing with tools-blind-cane navigation being a classic example of this. The horizon of haptic perception therefore extends beyond body space, but to what extent is unknown. We first used neuromechanical modelling to determine the theoretical horizon, which we pinpointed as six meters. We then used a psychophysical localization paradigm to behaviorally confirm that humans can haptically localize objects using a six-meter rod. This finding underscores the incredibly flexibility of the brain's sensorimotor representations, as they can be adapted to sense with an object many times longer than the user's own body.

Marciante, Alexandria B.; Mitchell, Gordon S.

doi: 10.1152/jn.00035.2023pmid: 36883762

Inflammation undermines neuroplasticity, including serotonin-dependent phrenic long-term facilitation (pLTF) following moderate acute intermittent hypoxia (mAIH: 3, 5-min episodes, arterial PO2: 40-50 mmHg; 5-min intervals). Mild inflammation elicited by a low dose of the TLR-4 receptor agonist, lipopolysaccharide (LPS; 100 mg/kg, i.p.), abolishes mAIH-induced pLTF by unknown mechanisms. In the CNS, neuroinflammation primes glia, triggering ATP release and extracellular adenosine accumulation. Since spinal adenosine 2A (A2A) receptor activation impairs mAIH-induced pLTF, we hypothesized that spinal adenosine accumulation and A2A receptor activation are necessary in the mechanism whereby LPS impairs pLTF. We report that 24 hours post LPS injection in adult male Sprague Dawley rats: 1) adenosine levels increase in ventral spinal segments containing the phrenic motor nucleus (C3-C5; p=0.010; n=7/group); and 2) cervical spinal A2A receptor inhibition (MSX-3, 10 µM, 12 µL intrathecal) rescues mAIH-induced pLTF. In LPS vehicle treated rats (saline, i.p.), MSX-3 enhanced pLTF versus controls (LPS: 110 ± 16% baseline; controls: 53 ± 6%; p=0.002; n=6/group). In LPS-treated rats, pLTF was abolished as expected (4 ± 6% baseline; n=6), but intrathecal MSX-3 restored pLTF to levels equivalent to MSX-3 treated control rats (120 ± 14% baseline; p<0.001; n=6; vs LPS controls with MSX-3: p=0.539). Thus, inflammation abolishes mAIH-induced pLTF by a mechanism that requires increased spinal adenosine levels and A2A receptor activation. Since repetitive mAIH is emerging as a treatment to improve breathing and non-respiratory movements in people with spinal cord injury or ALS, A2A inhibition may offset undermining effects of neuroinflammation associated with these neuromuscular disorders.

Franzen, Avery D.; Paulsen, Riley T.; Kabeiseman, Emily J.; Burrell, Brian D.

doi: 10.1152/jn.00494.2022pmid: 36883763

Noxious stimuli or injury can trigger long-lasting sensitization to non-nociceptive stimuli (referred to as allodynia in mammals). Long-term potentiation (LTP) of nociceptive synapses has been shown to contribute to nociceptive sensitization (hyperalgesia) and there is even evidence of heterosynaptic spread of LTP contributing to this type of sensitization. However, it is not clear whether activation of nociceptors elicits heterosynaptic LTP (hetLTP) in non-nociceptive synapses. Previous studies in the medicinal leech (Hirudo verbana) have demonstrated that high frequency stimulation (HFS) of nociceptors produce both homosynaptic LTP as well as hetLTP in non-nociceptive afferent synapses. This hetLTP involves endocannabinoid-mediated disinhibition of non-nociceptive synapses at the presynaptic level, but it is not clear if there are additional processes contributing to this synaptic potentiation. In this study, we found evidence for the involvement of postsynaptic level change and observed that postsynaptic NMDA receptors (NMDAR) were found to be required for this potentiation. Next Hirudo orthologues for known LTP signaling proteins, CamKII and PKCζ, were identified based on sequences from humans, mice, and the marine mollusk Aplysia. In electrophysiological experiments, inhibitors of CamKII (AIP) and PKCζ (ZIP) were found to interfere with hetLTP. Interestingly, CamKII was found to be necessary for both induction and maintenance of hetLTP, while PKCζ was only necessary for maintenance. These findings show activation of nociceptors can elicit a potentiation of non-nociceptive synapses through a process that involves both endocannabinoid-mediated disinhibition and NMDAR-initiated signaling pathways.

Courter, Robert J.; Alvarez, Enrique; Enoka, Roger M.; Ahmed, Alaa A.

doi: 10.1152/jn.00373.2022pmid: 36883754

Movement slowness is a common and disruptive symptom of multiple sclerosis (MS). A potential cause is that individuals with MS slow down to conserve energy as a behavioral adjustment to heightened metabolic costs of movement. To investigate this prospect, we measured the metabolic costs of both walking and seated arm reaching at five speeds in persons with mild MS (pwMS; n = 13; 46.0 ± 7.7yrs) and sex- and age-matched controls (HCs; n = 13; 45.8 ± 7.8yrs). Notably, the cohort of pwMS was highly mobile and no individuals required a cane or aid when walking. We found that the net metabolic power of walking was approximately 20% higher for pwMS across all speeds (p = 0.0185). In contrast, we found no differences in the gross power of reaching between pwMS and HCs (p = 0.492). Collectively, our results suggest that abnormal slowness of movement in MS - particularly reaching - is not the consequence of heightened effort costs and that other sensorimotor mechanisms are playing a considerable role in slowing.

Razmara, Parastoo; Zaveri, Dhruvish; Thannhauser, Megan; Ali, Declan William

doi: 10.1152/jn.00438.2022pmid: 36883767

Given the increasing trend of cannabis use for recreational and therapeutic purposes, a comprehensive examination of cannabis effects is warranted. The principal psychoactive constituent of cannabis, delta-9-tetrahydrocannabinol (THC), is a potent disrupter of neurodevelopment. Nevertheless, the impact of acute exposure to THC on developing motor systems is not well-investigated. In this study, using a neurophysiological whole-cell patch clamp approach we demonstrated that a 30 min exposure to THC can alter spontaneous synaptic activities at neuromuscular junctions of 5-day post-fertilized zebrafish. An increased frequency of synaptic activity and altered decay kinetic properties were documented in the THC-treated larvae. Locomotive behaviours, including swimming activity rate and C-start escape response to sound were also affected by THC. While the THC-treated larvae displayed hyperactivity of their basal swimming levels, their escape response rate to sound stimuli was reduced. These findings suggest that the acute exposure to THC can disrupt neuromuscular transmission and locomotor-driven responses in developing zebrafish.

Larry, Noga; Joshua, Mati

doi: 10.1152/jn.00366.2022pmid: 36883764

Correlated activity between neurons can cause variability in behavior across trials, as trial-by-trial co-fluctuations can propagate downstream through the motor system. The extent to which correlated activity affects behavior depends on the properties of the translation of the population activity into movement. A major hurdle in studying the effects of noise correlations on behavior is that in many cases this translation is unknown. Previous research has overcome this by using models that make strong assumptions about the coding of motor variables. We developed a novel method that estimates the contribution of correlations to behavior with minimal assumptions. Our method partitions noise correlations into correlations that are expressed in a specific behavior, termed behavior-related correlations, and correlations that are not. We applied this method to study the relationship between noise correlations in the frontal eye field (FEF) and pursuit eye movements. We defined a distance metric between the pursuit behavior on different trials. Based on this metric we used a shuffling approach to estimate pursuit-related correlations. Although the correlations were partially linked to variability in the eye movements, even the most constrained shuffle strongly attenuated the correlations. Thus, only a small fraction of FEF correlations is expressed in behavior. We employed simulations to validate our approach, show that it captures behavior-related correlations, and demonstrate its generalizability in different models. We show that the attenuation of correlated activity through the motor pathway could stem from the interplay between the structure of the correlations and the decoder of FEF activity.