Journal of Neurophysiology

Hermus, James; Doeringer, Joseph; Sternad, Dagmar; Hogan, Neville

doi: 10.1152/jn.00082.2023pmid: 37820017

Humans substantially outperform robotic systems in tasks that require physical interaction, despite seemingly inferior muscle bandwidth and slow neural information transmission. The control strategies that enable this performance remain poorly understood. To bridge this gap, this study examined kinematically-constrained motion as an intermediate step between the widely-studied unconstrained motions and sparsely-studied physical interactions. Subjects turned a horizontal planar crank in two directions (clockwise and counterclockwise) at three constant target speeds. With the hand constrained to move in a circle, non-zero forces against the constraint were measured. This experiment exposed two observations that could not result from mechanics alone, but may be attributed to neural control composed of dynamic primitives. A plausible mathematical model of interactive dynamics (mechanical impedance) was assumed and used to 'subtract' peripheral neuromechanics. This method revealed a summary of the underlying neural control in terms of motion-a zero-force trajectory. The estimated zero-force trajectories were approximately elliptical and their orientation differed significantly with turning direction. That is consistent with control using oscillations to generate an elliptical zero-force trajectory. However, for periods longer than 2-5 seconds, motion can no longer be perceived or executed as periodic. Instead, it decomposes into a sequence of submovements, manifest as increased variability. These quantifiable performance limitations support the hypothesis that humans simplify this constrained-motion task by exploiting at least three primitive dynamic actions: oscillations, submovements, and mechanical impedance.

Li, Qi; Xu, Honglu; Chen, Weicong; Su, Andrew; Fu, Michael J.; Walker, Mark F.

doi: 10.1152/jn.00130.2023pmid: 37964728

Retinal image slip during head rotation during head rotation drives motor learning in the rotational vestibulo-ocular reflex (rVOR) and forms the basis of gaze-stability exercises that treat vestibular dysfunction. Clinical exercises, however, are unengaging, cannot easily be titrated to the level of impairment, and provide neither direct feedback nor tracking of the patient's adherence, performance, and progress. To address this, we have developed a custom application for rVOR training based on an interactive computer game. In this study, we tested the ability of this game to induce rVOR learning in individuals with normal vestibular function, and we compared the efficacy of single-step and incremental learning protocols. Eighteen participants played the game twice on different days. All participants tolerated the game and were able to complete both sessions. The game scenario incorporated a series of brief head rotations, similar to active head impulses, that were paired with a dynamic acuity task and with a visual-vestibular mismatch (VVM) intended to increase rVOR gain (single-step: 300 successful trials at 1.5x viewing; incremental: 100 trials each of 1.13x, 1.33x, and 1.5x viewing). Overall, rVOR gain increased by 15 ± 4.7 % (mean ± 95% C.I., p < 0.001). Gains increased similarly for active and passive head rotations, and, contrary to our hypothesis, there was little effect of learning strategy. This study shows that an interactive computer game provides robust rVOR training and has the potential to deliver effective, engaging, and trackable gaze-stability exercises to patients with a range of vestibular dysfunction.

Giangrande, Alessandra; Cerone, Giacinto Luigi; Botter, Alberto; Piitulainen, Harri

doi: 10.1152/jn.00340.2023pmid: 37964731

Proprioception refers to the ability to perceive the position and movement of body segments in space. The cortical aspects of the proprioceptive afference from the body can be investigated using corticokinematic coherence (CKC). CKC accurately quantifies the degree of coupling between cortical activity and limb kinematics, especially if precise proprioceptive stimulation of evoked movements are used. However, there is no evidence on how volitional muscle activation during the proprioceptive stimulation affects CKC strength. Twenty-five healthy volunteers (28.8 ± 7 yr, 11 females) participated the experiment that included electroencephalographic (EEG), electromyographic (EMG) and kinematic recordings. 2-Hz ankle-joint rotations were elicited through a movement actuator in two conditions: passive condition with relaxed ankle and active condition with constant 5-Nm plantar flexion exerted during the stimulation. In total, 6-min of data were recorded per condition. CKC strength was defined as the maximum coherence value among all the EEG channels at the 2-Hz-movement frequency for each condition separately. Both conditions resulted in significant CKC peaking at the Cz electrode over the foot area of the primary sensorimotor (SM1) cortex. Stronger CKC was found for the active (0.13 ± 0.14) than passive (0.03 ± 0.04) condition (P < 0.01). The results indicated that volitional activation of the muscles intensifies the neuronal proprioceptive processing in the SM1 cortex. This finding could be explained both by peripheral sensitization of the ankle joint proprioceptors and central modulation of the neuronal proprioceptive processing in the spinal and cortical levels.

van der Willigen, Robert F.; Versnel, Huib; van Opstal, A. John

doi: 10.1152/jn.00129.2023pmid: 37965933

Human speech and vocalizations in animals are rich in joint spectrotemporal (S-T) modulations, wherein acoustic changes in both frequency and time are functionally related. In principle, the primate auditory system could process these complex dynamic sounds based on either an inseparable representation of S-T features, or alternatively, a separable representation. The separability hypothesis implies an independent processing of spectral and temporal modulations. We collected comparative data on the S-T hearing sensitivity in humans and macaque monkeys to a wide range of broadband dynamic spectrotemporal ripple stimuli employing a yes-no signal-detection task. Ripples were systematically varied-as a function of density (spectral modulation-frequency), velocity (temporal modulation-frequency), or modulation depth-to cover a listener's full S-T modulation sensitivity; derived from a total of 87 psychometric ripple detection curves. Audiograms were measured to control for normal hearing. Determined were hearing thresholds, reaction time distributions, and S-T modulation transfer functions (MTFs); both at the ripple detection thresholds, and at supra-threshold modulation depths. Our psychophysically derived MTFs are consistent with the hypothesis that both monkeys and humans employ analogous perceptual strategies: S-T acoustic information is primarily processed separable. Singular-value decomposition (SVD), however, revealed a small but consistent, inseparable spectral-temporal interaction. Finally, SVD analysis of the known visual spatiotemporal contrast-sensitivity function (CSF) highlights that human vision is space-time inseparable to a much larger extent than is the case for S-T sensitivity in hearing. Thus, the specificity with which the primate brain encodes natural sounds appears to be less strict than is required to adequately deal with natural images.

Riggs, Lace M.; Pereira, Edna F. R.; Thompson, Scott M.; Gould, Todd D.

doi: 10.1152/jn.00326.2023pmid: 38050689

(2R,6R)-Hydroxynorketamine (HNK) is a ketamine metabolite that shows rapid antidepressant-like effects in preclinical studies and lacks the adverse NMDA receptor (NMDAR)-inhibition-related properties of ketamine. Investigating how (2R,6R)-HNK exerts its antidepressant actions may be informative in the design of novel pharmacotherapies with improved safety and efficacy. We sought to identify the molecular substrates through which (2R,6R)-HNK induces functional changes at excitatory synapses - a prevailing hypothesis for how rapid antidepressant effects are initiated. We recorded excitatory postsynaptic potentials in hippocampal slices from male Wistar Kyoto rats, which have impaired hippocampal plasticity and are resistant to traditional antidepressants. (2R,6R)-HNK (10 µM) led to a rapid potentiation of electrically-evoked excitatory postsynaptic potentials at Schaffer collateral CA1 stratum radiatum synapses. This potentiation was associated with a decrease in paired pulse facilitation, suggesting an increase in the probability of glutamate release. The (2R,6R)-HNK-induced potentiation was blocked by inhibiting either cyclic adenosine monophosphate (cAMP) or its downstream target, cAMP-dependent protein kinase (PKA). Since cAMP is a potent regulator of brain-derived neurotrophic factor (BDNF) release, we assessed whether (2R,6R)-HNK exerts this acute potentiation through a rapid increase in cAMP-dependent BDNF-TrkB signaling. We found that the cAMP-PKA-dependent potentiation was not dependent on TrkB activation by BDNF, which functionally delimits the acute synaptic effects of (2R,6R)-HNK from its sustained BDNF-dependent actions in vivo. These results suggest that, by potentiating glutamate release via cAMP-PKA signaling, (2R,6R)-HNK initiates acute adaptations in fast excitatory synaptic transmission that promote structural plasticity leading to maintained antidepressant action.

Love, Kassia; Cao, Di; Chang, Joanna C.; Dal’Bello, Lucas R.; Ma, Xuan; O’Shea, Daniel J.; Schone, Hunter R.; Shahbazi, Mahdiyar; Smoulder, Adam

doi: 10.1152/jn.00428.2023pmid: 38057264

Buxton, Richard B.; Wong, Eric C.

doi: 10.1152/jn.00120.2023pmid: 38056422

Neural population modeling, including the role of neural attractors, is a promising tool for understanding many aspects of brain function. We propose a modeling framework to connect the abstract variables used in modeling to recent cellular level estimates of the bioenergetic costs of different aspects of neural activity, measured in ATP consumed per second per neuron. Based on recent work, an empirical reference for brain ATP use for the awake resting brain was estimated as ~2x109 ATP/s-neuron across several mammalian species. The energetics framework was applied to the Wilson-Cowan (WC) model of two interacting populations of neurons, one excitatory (E) and one inhibitory (I). Attractors were considered exhibiting steady-state behavior and limit cycle behavior, both of which end when the excitatory stimulus ends, and sustained activity that persists after the stimulus ends. The energy cost of limit cycles, with oscillations much faster than the average neuronal firing rate of the population, track more closely with the firing rate than the limit cycle frequency. Self-sustained firing driven by recurrent excitation, though, involves higher firing rates and a higher energy cost. As an example of a simple network in which each node is a WC model, a combination of three nodes can serve as a flexible circuit element that turns on with an oscillating output when input passes a threshold and then persists after the input ends (an 'on-switch'), with moderate overall ATP use. The proposed framework can serve as a guide for anchoring neural population models to plausible bioenergetics requirements.

Bresee, Chris S.; Cooke, Dylan F.; Goldring, Adam B.; Baldwin, Mary K. L.; Pineda, Carlos R.; Krubitzer, Leah A.

doi: 10.1152/jn.00086.2023pmid: 38092416

Primates are characterized by specializations for manual manipulation, including expansion of posterior parietal cortex (PPC) and, in Catarrhines, evolution of a dexterous hand and opposable thumb. Previous studies examined functional interactions between motor cortex and PPC in New World monkeys and galagos, by inactivating M1 and evoking movements from PPC. These studies found that portions of PPC depend on M1 to generate movements. We now add a species that more closely resembles humans in hand morphology and PPC: macaques. Inactivating portions of M1 resulted in all evoked movements being reduced (28%) or completely abolished (72%) at the PPC sites tested (in areas 5L, PF and PFG). Anterior parietal area 2 was similarly affected (26% reduced, 74% abolished) and area 1 was the least affected (12% no effect, 54% reduced, 34% abolished). Unlike previous studies in New World monkeys and galagos, interactions between both non-analogous (heterotopic) and analogous (homotopic) M1 and parietal movement domains were commonly found in most areas. These experiments demonstrate that there may be two parallel networks involved in motor control: a posterior parietal network dependent on M1, and a network that includes area 1 that is relatively independent of M1. Further, it appears that the relative size and number of cortical fields in parietal cortex in different species correlates with homotopic and heterotopic effect prevalence. These functional differences in macaques could contribute to more numerous and varied muscle synergies across major muscle groups, supporting the expansion of the primate manual behavioral repertoire observed in Old World monkeys.

Kreitzer, Matthew A.; Vredeveld, Mason; Tinner, Kaleb; Powell, Alyssa M.; Schantz, Adam W.; Leininger, Rachel; Merillat, Rajapone; Gongwer, Michael W.; Tchernookova, Boriana K.; Malchow, Robert Paul

doi: 10.1152/jn.00321.2023pmid: 38116604

Previous work has shown that activation of tiger salamander retinal radial glial cells by extracellular ATP induces a pronounced extracellular acidification, which has been proposed to be a potent modulator of neurotransmitter release. This study demonstrates that low micromolar concentrations of extracellular ATP similarly induce significant H+ effluxes from Müller cells isolated from the axolotl retina. Müller cells were enzymatically isolated from axolotl retina and H+ fluxes measured from individual cells using self-referencing H+-selective microelectrodes. The increased H+ efflux from axolotl Müller cells induced by extracellular ATP required activation of metabotropic purinergic receptors and was dependent upon calcium released from internal stores. We further found that ATP-evoked increases in H+ efflux from Müller cells of both tiger salamander and axolotl were sensitive to pharmacological agents known to interrupt calmodulin and protein kinase C (PKC) activity: chlorpromazine (CLP), trifluoperazine (TFP), and W-7 (all calmodulin inhibitors) and chelerythrine, a PKC inhibitor, all attenuated ATP-elicited increases in H+ efflux. ATP-initiated H+ fluxes of axolotl Müller cells were also significantly reduced by amiloride, suggesting a significant contribution by sodium-hydrogen exchangers (NHE). In addition, α-cyano-4-hydroxycinnamate (4-cin), a monocarboxylate transport (MCT) inhibitor, also reduced the ATP-induced increase in H+ efflux in both axolotl and tiger salamander Müller cells, and when combined with amiloride, abolished ATP-evoked increase in H+ efflux. These data suggest that axolotl Müller cells are likely to be an excellent model system in which to understand the cell-signaling pathways regulating H+ release from glia and the role this may play in modulating neuronal signaling.