Journal of Neurophysiology

Fuller, David D.; Trejo-Lopez, Jorge A.; Yachnis, Anthony T.; Sunshine, Michael D.; Rana, Sabhya; Bindi, Victoria E.; Byrne, Barry J.; Smith, Barbara K.

doi: 10.1152/jn.00190.2021pmid: 34191636

Pompe disease (PD) is a neuromuscular disorder caused by a mutation in the acid alpha-glucosidase (GAA) gene. Late-onset PD patients retain some GAA activity and present symptoms later in life, with fatality mainly associated with respiratory failure. This case study presents diaphragm electrophysiology and a histological analysis of the brainstem, spinal cord, and diaphragm, from a male PD patient diagnosed with late-onset PD at age 35. The patient was wheelchair dependent by age 38, required nocturnal ventilation at age 40, 24-hour non-invasive ventilation by age 43, and passed away from respiratory failure at age 54. Diaphragm electromyography recorded using indwelling "pacing" wires showed asynchronous bursting between the left and right diaphragm during brief periods of independent breathing. The synchrony declined over a 4-year period preceding respiratory failure. Histological assessment indicated motoneuron atrophy in the medulla and rostral spinal cord. Hypoglossal (soma size: 421 ± 159 µm2) and cervical motoneurons (soma size: 487 ± 189 µm2) had an atrophied, elongated appearance. In contrast, lumbar (soma size: 1363 ± 677 µm2) and sacral motoneurons (soma size: 1411 ± 633 µm2) had the ballooned morphology typical of early-onset PD. Diaphragm histology indicated loss of myofibers. These results are consistent with neuromuscular degeneration and the concept that effective PD therapy will need to target the central nervous system, in addition to skeletal and cardiac muscle.

Derosiere, Gerard; Thura, David; Cisek, Paul; Duque, Julie

doi: 10.1152/jn.00038.2021pmid: 34191623

Humans and other animals often need to balance the desire to gather sensory information (to make the best choice) with the urgency to act, facing a speed-accuracy tradeoff (SAT). Given the ubiquity of SAT across species, extensive research has been devoted to understanding the computational mechanisms allowing its regulation at different timescales, including from one context to another, and from one decision to another. However, animals must frequently change their SAT on even shorter timescales - i.e., over the course of an ongoing decision - and little is known about the mechanisms that allow such rapid adaptations. The present study aimed at addressing this issue. Human subjects performed a decision task with changing evidence. In this task, subjects received rewards for correct answers but incurred penalties for mistakes. An increase or a decrease in penalty occurring halfway through the trial promoted rapid SAT shifts, favoring speeded decisions either in the early or in the late stage of the trial. Importantly, these shifts were associated with stage-specific adjustments in the accuracy criterion exploited for committing to a choice. Those subjects who decreased the most their accuracy criterion at a given decision stage exhibited the highest gain in speed, but also the highest cost in terms of performance accuracy at that time. Altogether, the current findings offer a unique extension of previous work, by suggesting that dynamic changes in accuracy criterion allow the regulation of the SAT within the timescale of a single decision.

Henrich, Mauricio Carlos; Frahm, Ken Steffen; Andersen, Ole Kæseler

doi: 10.1152/jn.00155.2021pmid: 34191609

Spatial information of nociceptive stimuli applied in the skin of healthy humans is integrated in the spinal cord to determine the appropriate withdrawal reflex response. Double-simultaneous stimulus applied in different skin sites are integrated, eliciting a larger reflex response. The temporal characteristics of the stimuli also modulate the reflex e.g. by temporal summation. The primary aim of this study was to investigate how the combined tempo-spatial aspects of two stimuli are integrated in the nociceptive system. This was investigated by delivering single and double simultaneous stimulation, and sequential stimulation with different inter-stimulus intervals (ISIs ranging 30-500 ms.) to the sole of the foot of fifteen healthy subjects. The primary outcome measure was the size of the nociceptive withdrawal reflex (NWR) recorded from the Tibialis Anterior (TA) and Biceps Femoris (BF) muscles. Pain intensity was measured using an NRS scale. Results showed spatial summation in both TA and BF when delivering simultaneous stimulation. Simultaneous stimulation provoked larger reflexes than sequential stimulation in TA, but not in BF. Larger ISIs elicited significantly larger reflexes in TA, while the opposite pattern occurred in BF. This differential modulation between proximal and distal muscles suggests the presence of spinal circuits eliciting a functional reflex response based on the specific tempo-spatial characteristics of a noxious stimulus. No modulation was observed in pain intensity ratings across ISIs. Absence of modulation in the pain intensity ratings argues for an integrative mechanism located within the spinal cord governed by a need for efficient withdrawal from a potentially harmful stimulus.

Yu, Shijing; Mückschel, Moritz; Beste, Christian

doi: 10.1152/jn.00228.2021pmid: 34191635

Cognitive flexibility is an essential prerequisite for goal-directed behavior and daily observations already show that it deteriorates when one is engaged in a task for (too) long time. Yet, the neural mechanisms underlying such fatigability effect in cognitive flexibility are poorly understood. We examined how theta, alpha and beta frequency event-related synchronization and desynchronization processes during a cued memory-based task switching are modulated by time-on-task effects. We put special emphasis on the examination of functional neuroanatomical regions being associated with these modulations using EEG-beamforming. We show clear declines in task switching performance (increased switch costs) with time on task. For processes occurring before rule switching or repetition processes, we show that anticipatory attentional sampling and selection mechanisms associated with fronto-parietal structures are modulated by time on task effects, but also sensory areas (occipital cortex) show fatigability-dependent modulations. After target stimulus presentation, the allocation of processing resources for response selection as reflected by theta-related activity in parietal cortices is compromised with time-on-task. Similarly, seem to a concomitant increase in alpha and beta band related attentional processing or gating mechanisms in frontal and occipital regions. Yet, considering the behavioral data showing an apparent decline in performance, this probably compensatory increase is still insufficient to allow reasonable performance. The same is likely the case for processes occurring before rule switching or repetition processes. Comparative analyses show that modulations of alpha band activity are as strongly modulated by fatigability as theta band activity. Implications of these findings for theoretical concepts on fatigability are discussed.

Jaske, Bianca; Lepreux, Gaëtan; Dürr, Volker

doi: 10.1152/jn.00169.2021pmid: 34161139

In insects the tactile sense is important for near-range orientation and is involved in various behaviors. Nocturnal insects such as the stick insect Carausius morosus continuously explore their surroundings by actively moving their antennae when walking. Upon antennal contact with objects, stick insects show a targeted front-leg movement. As this reaction occurs within 40 ms, descending transfer of information from the brain to the thorax needs to be fast. So far, a number of descending interneurons have been described that may be involved in this reach-to-grasp behavior. One of these is the contralateral ON-type velocity-sensitive neuron (cONv). cONv was found to encode antennal joint-angle velocity during passive movement. Here, we characterize the transient response properties of cONv, including its dependence on joint angle range and direction. Since antennal hair field afferent terminals were shown to arborize close to cONv dendrites, we test whether antennal hair fields contribute to the joint-angle velocity encoding of cONv. To do so, we conducted bilateral extracellular recordings of both cONv interneurons per animal before and after hair field ablations. Our results show that cONv responses are highly transient, with velocity-dependent differences in delay and response magnitude. As yet, the steady state activity level was maintained until the stop of antennal movement, irrespective of movement velocity. Hair field ablation caused a moderate but significant reduction of movement-induced cONv firing rate by up to 40 %. We conclude that antennal proprioceptive hair fields contribute to the velocity-tuning of cONv, though further antennal mechanoreceptors must be involved, too.

Campagnoli, Carlo; Domini, Fulvio; Taylor, Jordan A.

doi: 10.1152/jn.00153.2021pmid: 34161173

Motor learning in visuomotor adaptation tasks results from both explicit and implicit processes, each responding differently to an error signal. While the motor output side of these processes is extensively studied, their visual input side is relatively unknown. We investigated if and how depth perception affects the computation of error information by explicit and implicit motor learning. Two groups of participants threw virtual darts at a virtual dartboard while receiving perturbed endpoint feedback. The Delayed group was allowed to re-aim and their feedback was delayed to emphasize explicit learning, while the Clamped group received clamped cursor feedback which they were told to ignore, and continued to aim straight at the target to emphasize implicit adaptation. Both groups played this game in a highly detailed virtual environment (Depth condition) and in an empty environment (No-Depth condition). The Delayed group showed an increase in error sensitivity under Depth relative to No-Depth conditions. In contrast, the Clamped group adapted to the same degree under both conditions. The movement kinematics of the Delayed participants also changed under the Depth condition, consistent with the target appearing more distant, unlike the Clamped group. A comparison of the Delayed behavioral data with a perceptual task from the same individuals showed that the effect of the Depth condition on the re-aiming direction was consistent with an increase in the scaling of the error distance and size. These findings suggest that explicit and implicit learning processes may rely on different sources of perceptual information.

Plante, Amber E.; Whitt, Joshua P.; Meredith, Andrea L.

doi: 10.1152/jn.00089.2021pmid: 34191630

Mammalian circadian (24-hour) rhythms are timed by the pattern of spontaneous action potential firing in the suprachiasmatic nucleus (SCN). This oscillation in firing is produced through circadian regulation of several membrane currents, including large-conductance Ca2+- and voltage-activated K+ (BK) and L-type Ca2+ channel (LTCC) currents. During the day, steady-state BK currents depend mostly on LTCCs for activation, while at night, they depend predominantly on RyRs. However, the contribution of these Ca2+ channels to BK channel activation during action potential firing has not been thoroughly investigated. In this study, we used a pharmacological approach to determine that both LTCCs and RyRs contribute to the baseline membrane potential of SCN action potential waveforms, as well as action potential-evoked BK current, during the day and night, respectively. Since the baseline membrane potential is a major determinant of circadian firing rate, we focused on the LTCCs contributing to low voltage activation of BK channels during the subthreshold phase. For these experiments, two LTCC subtypes found in SCN (CaV1.2 and CaV1.3) were co-expressed with BK channels in heterologous cells, where their differential contributions could be separately measured. CaV1.3 channels produced currents that were shifted to more hyperpolarized potentials compared to CaV1.2, resulting in increased subthreshold Ca2+ and BK currents during an action potential command. These results show that while multiple Ca2+ sources in SCN can contribute to the activation of BK current during an action potential, specific BK-CaV1.3 partnerships may optimize the subthreshold BK current activation that is critical for firing rate regulation.

Simha, Surabhi N.; Wong, Jeremy D.; Selinger, Jessica C.; Abram, Sabrina J.; Donelan, J. Maxwell

doi: 10.1152/jn.00311.2020pmid: 34161744

When in a new situation, the nervous system may benefit from adapting its control policy. In determining whether or not to initiate this adaptation, the nervous system may rely on some features of the new situation. Here we tested whether one such feature is salient cost savings. We changed cost saliency by manipulating the gradient of participants' energetic cost landscape during walking. We hypothesized that steeper gradients would cause participants to spontaneously adapt their step frequency to lower costs. To manipulate the gradient, a mechatronic system applied controlled fore-aft forces to the waist of participants as a function of their step frequency as they walked on a treadmill. These forces increased the energetic cost of walking at high step frequencies and reduced it at low step frequencies. We successfully created three cost landscapes of increasing gradients, where the natural variability in participants' step frequency provided cost changes of 3.6% (shallow), 7.2% (intermediate) and 10.2% (steep). Participants did not spontaneously initiate adaptation in response to any of the gradients. Using metronome-guided walking-a previously established protocol for eliciting initiation of adaptation-participants next experienced a step frequency with a lower cost. Participants then adapted by -1.41±0.81 (p=0.007) normalized units away from their originally preferred step frequency obtaining cost savings of 4.80±3.12% That participants would adapt under some conditions, but not in response to steeper cost gradients, suggests that the nervous system does not solely rely on the gradient of energetic cost to initiate adaptation in novel situations.

Rungta, Satya; Basu, Debaleena; Sendhilnathan, Naveen; Murthy, Aditya

doi: 10.1152/jn.00141.2021pmid: 34232741

A hallmark of intelligent behavior is that we can separate intention from action. To understand the mechanism that gates the flow of information between motor planning and execution, we compared the activity of frontal eye field neurons with motor unit activity from neck muscles in the presence of an intervening delay period in which spatial information regarding the target was available to plan a response. Whereas spatially-specific delay period activity was present in the activity of frontal eye field neurons, it was absent in motor unit activity. Nonetheless, motor unit activity was correlated with the time it took to initiate saccades. Interestingly, we observed a heterogeneity of responses amongst motor units, such that only units with smaller amplitudes showed a clear modulation during the delay period. These small amplitude motor units also had higher spontaneous activity compared to the units which showed modulation only during the movement epoch. Taken together, our results suggest the activity of smaller motor units convey temporal information and explains how the delay period primes muscle activity leading to faster reaction times.

Hayman, Mordechai; Arzy, Shahar

doi: 10.1152/jn.00695.2020pmid: 34133237

"Mental travel" is a cognitive concept embodying the human capacity to intentionally disengage from the here and now, and mentally experience the world from different perspectives. We explored how individuals mentally "travel" to the point-of-view (POV) of other people in varying levels of personal closeness and from these perspectives process these people's social network. Under fMRI, participants were asked to "project" themselves to the POVs of four different people: a close other, a non-close other, a famous-person, and their own-self, and rate the level of affiliation (closeness) to different individuals in the respective social network. Participants were always faster making judgments from their own POV compared to other POVs (self-projection effect) and for people who were personally closer to their adopted POV (social-distance effect). Brain activity at the medial prefrontal and anterior cingulate cortex in the self-POV was higher, compared to all other conditions. Activity at the right temporoparietal junction and medial parietal cortex was found to distinguish between the personally related (self, close and non-close others) and unrelated (famous-person) people. No difference was found between mental travel to the POVs of close and non-close others. Regardless of POV, the precuneus, anterior cingulate cortex, prefrontal cortex, and temporoparietal junction distinguished between close and distant individuals within the different social networks. Representational similarity analysis implicated the left retrosplenial cortex as crucial for social distance processing across all POVs. These distinctions suggest several constraints regarding our ability to adopt others' POV, and process not only ours but also other people's social networks.