Journal of Neurophysiology

Oliveira, Daniela Souza De; Carbonaro, Marco; Raiteri, Brent James; Botter, Alberto; Ponfick, Matthias; Del Vecchio, Alessandro

doi: 10.1152/jn.00389.2024pmid: 39704677

For individuals with motor complete spinal cord injury (SCI), previous works have shown that spared motor neurons below the injury level can still be voluntarily controlled. In this study, we investigated the behavior of these neurons after SCI by analyzing neural and spatial properties of individual motor units using high-density surface electromyography (HDsEMG) and ultrasound imaging. The dataset for this study is based on motor unit data from our previous work (Oliveira et al., 2024). Eight participants with chronic motor complete SCI and twelve uninjured controls attempted multiple hand movements, guided by a virtual hand, while we recorded forearm muscle activity. We analyzed the common synaptic input to motor neurons with a factorization method and found two dominant motor unit modes in both the SCI and control groups. Each mode was strongly correlated with the virtual hand's flexion or extension movements. The delay between flexion and extension movements and the motor unit modes was similar between groups, suggesting preserved common input to motor neurons after SCI. We classified motor units into task-modulated or non-modulated (i.e., tonic or irregularly firing) based on their discharge patterns and phase difference with virtual hand kinematics and found a higher proportion of non-modulated motor units in the SCI group. At the motor unit action potential level, we found larger motor unit territories after SCI. Finally, we observed distinct movements of paralyzed muscles with concurrent HDsEMG and ultrasound imaging, indicating the presence of highly functional motor units with distinct spared territories after SCI.

Márquez, Natalia I.; Deichler, Alfonso; Fernández‐Aburto, Pedro; Perales, Ignacio; Letelier, Juan-Carlos; Marín, Gonzalo J.; Mpodozis, Jorge; Pallas, Sarah L.

doi: 10.1152/jn.00128.2024pmid: 39705673

Lab rodent species commonly used to study the visual system and its development (hamsters, rats, and mice) are crepuscular/nocturnal, altricial, and possess simpler visual systems than carnivores and primates. To widen the spectra of studied species, here we introduce an alternative model, the Chilean degu (Octodon degus). This diurnal, precocial Caviomorph rodent has a cone enriched, well-structured retina, and well-developed central visual projections. To assess degus’ visual physiological properties, we characterized the visual responses and receptive field (RF) properties of isolated neurons in the superficial layers of the superior colliculus (sSC). To facilitate comparison with studies in other rodent species, we used four types of stimuli: (1) a moving white square, (2) sinusoidal gratings, (3) an expanding black circle (looming), and (4) a stationary black circle. We found that as in other mammalian species RF size increases from superficial to deeper SC layers. Compared to other lab rodents, degus sSC neurons had smaller RF sizes and displayed a broader range of spatial frequency (SF) tunings, including neurons tuned to high SF (up to 0.24 cycles/degree). Also, unlike other rodents approximately half of sSC neurons exhibited linear responses to contrast. Additionally, sSC units showed transient ON-OFF responses to stationary stimuli but increased their firing rates as a looming object increased in size. Our results suggest that degus have higher visual acuity, higher SF tuning, and lower contrast sensitivity than commonly used nocturnal lab rodents, positioning degus as a well-suited species for studies of diurnal vision that are more relevant to humans.

Vaughn, Mitchell J.; Yellamelli, Nandini; Burger, R. Michael; Haas, Julie S.

doi: 10.1152/jn.00260.2024pmid: 39706150

The thalamic reticular nucleus (TRN) is a thin shell of gap junction coupled GABAergic inhibitory neurons that regulate afferent sensory relay of the thalamus. The TRN receives dopaminergic innervation from the midbrain, and it is known to express high concentrations of D1 and D4 receptors. Although dopaminergic modulation of presynaptic inputs to TRN has been described, the direct effect of dopamine on TRN neurons and its electrical synapses is largely unknown. Here, we confirmed D1 and D4 expression and show that D2 receptors are also expressed in TRN. To characterize how dopamine affects both neuronal excitability and electrical synapse coupling strength in the TRN, we performed dual whole-cell patch-clamp recordings of TRN neurons and injected them with 500-ms current pulses to measure input resistance, rheobase, spiking frequency, and coupling conductance. Measurements were taken before and after bath application of dopamine or agonists for either D1, D2, or D4 receptors. Our results show that bath application of dopamine did not consistently modulate excitability or electrical synapse strength. However, application of specific dopamine receptor agonists revealed that activation of D1 and D4 receptors increase input resistance, and activation of D2-like receptors lower maximum tonic spike rate. Notably, D2 and D4 receptors depressed electrical synapses. Together, our results suggest that coactivation of D1, D2, and D4 receptors may result in crosstalk due to opposing signaling cascades. Further, we show that selective dopamine receptor engagement has substantial potential to modulate TRN circuitry.

Horrocks, Max; Mohn, Jennifer L.; Jaramillo, Santiago

doi: 10.1152/jn.00411.2024pmid: 39726382

Psychedelics are known to induce profound perceptual distortions, yet the neural mechanisms underlying these effects, particularly within the auditory system, remain poorly understood. In this study, we investigated the effects of the psychedelic compound 2,5-Dimethoxy-4-iodoamphetamine (DOI), a serotonin 2A receptor agonist, on the activity of neurons in the auditory cortex of awake mice. We examined whether DOI administration alters sound-frequency tuning, variability in neural responses, and deviance detection (a neural process reflecting the balance between top-down and bottom-up processing). Our results show that while DOI does not alter the frequency selectivity of auditory cortical neurons in a consistent manner, it increases trial-by-trial variability in responses and consistently diminishes the neural distinction between expected (standard) and unexpected (oddball) stimuli. This reduction in deviance detection was primarily driven by a decrease in the response to oddball sounds, suggesting that DOI dampens the auditory cortex’s sensitivity to unexpected events. These findings provide insights into how psychedelics disrupt sensory processing and shed light on the neural mechanisms underlying the altered perception of auditory stimuli observed in the psychedelic state.

Gonzalez-Burgos, Guillermo; Miyamae, Takeaki; Nishihata, Yosuke; Krimer, Olga L.; Wade, Kirsten; Fish, Kenneth N.; Arion, Dominique; Cai, Zhao-Lin; Xue, Mingshan; Stauffer, William R.; Lewis, David A.

doi: 10.1152/jn.00326.2024pmid: 39740351

The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in primate cognition, integrating multimodal information to generate top-down signals for cognitive control. During cognitive tasks, the DLPFC displays activity patterns of exceptional complexity and duration not observed in other cortical areas or species. These activity patterns are likely associated with the unique physiological and morphological properties of primate DLPFC pyramidal neurons (PNs). However, little is known about how the distinctive in vivo activity of the primate DLPFC regulates the unique properties of its PNs. To test whether manipulating neuronal excitability in area 46 of the rhesus monkey DLPFC in vivo affects synaptic inputs onto PNs, we used adeno-associated viral vector (AAV)-mediated overexpression of Kir2.1 channels, a genetic silencing tool previously shown to decrease neuronal excitability and firing activity in vivo. At 7 to 12 weeks post-AAV microinjections into DLPFC area 46, we assessed the effects of Kir2.1 overexpression using patch clamp recordings from PNs in acute slices. We found that Kir2.1 overexpression significantly reduced PN excitability via the effects of the AAV-encoded Kir2.1 channels. Moreover, recordings of synaptic currents showed that Kir2.1 overexpression significantly reduced excitatory synaptic strength without affecting inhibitory synapses. Thus, we show for the first time that changing neuronal excitability with recombinant DNA tools delivered via AAVs can efficiently modify synaptic properties in the primate neocortex. Moreover, we report that manipulating neuronal excitability in vivo affects synaptic properties in ways that seem to differ between the primate DLPFC network and the rodent cortex.

Contemori, Samuele; Carroll, Timothy J.

doi: 10.1152/jn.00401.2024pmid: 39835802

Purposeful movement often requires selection of a particular action from a range of alternatives, but how does the brain represent potential actions so that they can be compared for selection, and how are motor commands generated if movement is initiated before the final goal is identified? According to one hypothesis, the brain averages partially prepared motor plans to generate movement when there is goal uncertainty. This is consistent with the idea that motor decision making unfolds through competition between internal representations of alternative actions. An alternative hypothesis holds that only one movement, which is optimised for task performance, is prepared for execution at any time. Under this conception, decisions about the best motor goal given current information are completed upstream from neural circuits that perform motor planning. To distinguish between these hypotheses, we modified (1) experiment in which participants had to start reaching toward targets associated with opposite curl force-fields prior to knowing the correct target to reach. Crucially, we forced the participants to initiate movement immediately after target presentation (i.e. mean reaction times ~250ms) so that they had limited opportunity to deliberate between the available alternatives. We found that the reaching dynamics reflected only those learnt for the selected reach direction, rather than a combination of those for the alternative targets presented, irrespective of the time available to initiate movement. The data are consistent with the conclusion that reaching dynamics were specified downstream of action selection under the target uncertainty conditions of this study.

Therkildsen, Eva Rudjord; Nielsen, Jens Bo; Lorentzen, Jakob

doi: 10.1152/jn.00585.2024pmid: 39718533

Voltage-sensitive calcium channels contribute to depolarization of both motor- and interneurons in animal studies, but less is known of their contribution to human motor control and whether blocking them has potential in future antispasmodic treatment in humans. Therefore, this study investigated the acute effect of Nimodipine on the transmission of human spinal reflex pathways involved in spasticity.In a double-blinded, cross-over study, we measured soleus muscle stretch- and H-reflexes, and tibialis anterior cutaneous reflexes in nineteen healthy subjects before and after Nimodipine (tab-let 60mg) or Baclofen (tablet 25mg). Baclofen was used as a control to compare Nimodipine's effects with known antispastic treatment.Changes in the size of the Hmax/Mmax-ratio, stretch- and cutaneous reflexes following intervention of Nimodipine and Baclofen, respectively, were analysed using a one-way RM-ANOVA.Nimodipine significantly reduced the Hmax/Mmax-ratio (F(2.5,42)=15; p<0.0001) and the normal-ised soleus stretch reflex (F(2.6,47)=4.8; p=0.0073) after administration. A similar tendency was seen following Baclofen (Hmax/Mmax-ratio: F(2.1,39)=4.0; p=0.024; normalised stretch reflex: F(2.8, 50)=2.4; p=0.083). The Mmax-response was unaffected by either intervention. Interestingly, during voluntary soleus activation, the stretch reflex remained unchanged with either treatment. For the cutaneous reflexes, there was a trend toward reduced early inhibition (F(1.6,9.3)=4.5; p=0.050) and subsequent facilitation (F(1.3,8.0)=4.3; p=0.065) after Nimodipine. No severe adverse effects were reported after Nimodipine.These findings suggest that Nimodipine acutely reduced electrophysiological measures related to spasticity in healthy individuals. The effect seemed located at the spinal level, and voluntary contraction counterbalanced the reduction of the stretch reflex, highlighting its relevance for future studies on antispastic therapies.

Anderson, Andrew J.; Mannion, Damien J.; Quiroga, Maria del Mar; Tescari, Edoardo

doi: 10.1152/jn.00396.2024pmid: 39718514

Analysing reaction time distributions can provide insights into decision-making processes in the brain. The Linear Approach to Threshold with Ergodic Rate (LATER) model is arguably the simplest model for predicting reaction time distributions and can summarise distributions with as few as two free parameters. However, the coordinates for visualising and fitting distributions using LATER (“reciprobit” space) are irregular, making the application of this simple model inaccessible to those without a programming background. Here we describe an open-source R package - LATERmodel - that allows for easy visualisation of reaction time distributions, along with fitting of these using the LATER model. Using canonical data from the literature, we show our tool replicates key features from previous LATER analysis tools, whilst also providing more robust fitting procedures and a more flexible method for fitting sub-populations of very rapid, early responses. Whilst all features of LATERmodel can be used directly in the statistical programming language R, key features are also available through a RShiny graphical user interface to allow researchers without programming background to apply the LATER model to their reaction time data.

Finn, Harrison T.; Parono, Marel; Bye, Elizabeth A.; Taylor, Janet L.; Gandevia, Simon C.; Héroux, Martin E.; Butler, Jane E.

doi: 10.1152/jn.00266.2024pmid: 39718492

Introduction: Lumbar transcutaneous spinal cord stimulation (TSS) evokes synchronized muscle responses, termed spinally evoked motor response (sEMR). Whether the structures TSS activates to evoke sEMRs differ when TSS intensity and waveform are varied is unknown.Methods: In 15 participants (9F:6M), sEMRs were evoked by TSS over L1-L3 (at sEMR threshold and suprathreshold intensities) using conventional (one 400-µs biphasic pulse) or high-frequency burst (ten 40-µs biphasic pulses at 10 kHz) stimulus waveforms in vastus medialis (VM), tibialis anterior (TA) and medial gastrocnemius (MG) muscles. TSS was paired with transcranial magnetic stimulation (TMS) over the contralateral motor cortex at relative interstimulus intervals (ISI) (-10 ms to 11 ms), centred on the ISI when TSS and TMS inputs simultaneously activated VM motoneurones. Doublet TSS were delivered at 80 ms ISI.Results: For VM, the area of the combined response evoked by paired TMS and TSS was not facilitated at any ISI. For TA and MG, combined responses were facilitated by ~40-100% when TMS activated the motoneurones before or at a similar time as TSS, particularly with suprathreshold TSS. Additionally, for TA, there was greater suppression of the second sEMR evoked by TSS doublets using suprathreshold conventional TSS compared to high-frequency burst TSS (p<0.001).Conclusion: The results suggest that for VM, TSS activated predominantly motor axons, but for TA and MG, facilitation of the sEMR by TMS suggests that TSS activated sensory axons. Stimulation waveforms had similar outcomes in most conditions.

Yan, Xinyue; Zhang, Xiwei; Huang, Chuan; Jiang, Yujuan; Wan, Chunxiao

doi: 10.1152/jn.00588.2024pmid: 39835801

Vagus nerve stimulation (VNS) has been commonly employed for the functional rehabilitation of stroke patients. This study aimed to investigate the therapeutic effects of transcranial direct current stimulation on the vagus nerve (TDCSVN) in improving dysphagia in stroke patients. Patients experiencing dysphagia following a stroke were diagnosed with dysphagia using a water swallow test. Swallowing function was evaluated using the standard swallowing scale score and the functional dysphagia scale. Serum levels of interleukin (IL)-1β and IL-8 were measured using enzyme-linked immunosorbent assays. TDCSVN treatment resulted in a significantly greater reduction in both the standard swallowing scale and functional dysphagia scale scores when compared to conventional treatment. Furthermore, TDCSVN treatment led to a notable increase in hemoglobin and albumin levels, suggesting a more substantial improvement in dysphagia compared to conventional methods. Additionally, TDCSVN treatment was more effective in decreasing serum levels of IL-1β and IL-8 in dysphagic patients following a stroke. TDCSVN treatment demonstrated a significant inhibitory effect on inflammatory cytokines, resulting in a more pronounced improvement in dysphagia among stroke patients.