Biology subjects

Baker, S. N.

Publications and source records attributed to Baker, S. N..

15 recordsLinked to original sources

bioRxiv2026

Phase-targeted Poisson closed-loop peripheral nerve stimulation modulates sensorimotor oscillations in human MEG

Closed-loop brain stimulation offers a promising approach for modulating neural oscillations, but the mechanisms of phase-dependent neuromodulation remain poorly understood. We developed a real-time MEG-based closed-loop system delivering median nerve stimulation using a phase-modulated Poisson process. Sixteen healthy participants (11 female, 5 male) underwent open-loop characterization followed by closed-loop testing of eight phase-offset conditions (0 degrees-315 degrees), each paired with a statistically matched replay control. Closed-loop stimulation induced robust phase-dependent modulation (14.21 +/- 8.24%) versus replay (7.03 +/- 2.95%; p = 0.0003), with consistent phase specificity across participants (circular mean: 70.2 degrees, referenced to each individual's dominant frequency). At the group level, alpha oscillations (8-12 Hz) showed bidirectional modulation (mean boost: +21.0 +/- 19.9% at 0 degrees-135 degrees; mean suppression: -13.3 +/- 10.8% at 180 degrees-315 degrees), while beta oscillations (13-30 Hz) showed predominantly unidirectional suppression (-9.3 +/- 9.6%). Successful fixed-frequency targeting required alignment with each individual's natural peak. Misalignment led to different phase shifts producing power at different frequencies, a phenomenon we term phase-frequency coupling. Dynamic frequency tracking (8-30 Hz) automatically identified and targeted each individual's natural peak, achieving robust bidirectional modulation without prior knowledge of peak location. These findings demonstrate that real-time phase-locked peripheral nerve stimulation selectively modulates sensorimotor oscillations beyond statistically matched open-loop stimulation. The distinct phase-excitability relationships of alpha and beta oscillations, together with the importance of aligning stimulation with individual natural peaks, establish principled guidelines for personalized closed-loop neuromodulation.

neuroscience↗

bioRxiv2026

Extent of damage to descending output from cortex rather than to specific cortical regions drives the emergence of flexor synergy in non-human primates

Obligate flexor synergies are a defining feature of the hemiparetic phenotype following stroke in humans. Although these intrusive synergies can diminish over time, recovery may plateau, leaving some individuals with movements permanently constrained to synergies. Despite their clinical significance, the neural mechanisms underlying the emergence and persistence of abnormal synergies remain poorly understood. To investigate this mechanistically, three macaque monkeys were trained on a reach and grasp task prior to receiving one of three unilateral lesion types: 1) a focal sensorimotor cortical lesion, 2) a combined sensorimotor cortical and magnocellular red nucleus (RNm) lesion, or 3) a lesion of the internal capsule. Upper limb three-dimensional kinematics and EMG cross correlation were used to measure the intrusion of synergies during in synergy vs out of synergy reaching. A combined RNm and cortical lesion produced weakness but no flexor synergy. A similar-sized cortical lesion generated mild synergies which substantially recovered. By contrast, a large internal capsule lesion produced severe, persistent flexor synergy. Collectively, these findings suggest that the emergence of abnormal synergies is determined by the extent of corticofugal disruption, and their persistence depends on the ability of surviving supraspinal motor pathways to regain selective control over muscle contractions.

neuroscience↗

bioRxiv2025

A non-human primate model of Amyotrophic Lateral Sclerosis

Approximately 97% of patients with amyotrophic lateral sclerosis (ALS) have cytoplasmic mislocalization and aggregation of the ubiquitous nuclear protein, TDP-43. Current rodent models of this disease fail to replicate the progressive motor weakness and characteristic histopathology, possibly because of fundamental neuroanatomical and genetic differences between rodents and humans. In this study, the TDP-43 protein was overexpressed in the motor neuron pool of the brachioradialis muscle unilaterally in two six-year-old female rhesus macaques, using an intersectional genetics approach involving infection with genetically modified adeno-associated virus. Magnetic resonance images demonstrated delayed signal hyperintensities limited to the injected brachioradialis that persisted for 6-7 weeks, consistent with motor neuron degeneration and denervation of the targeted muscle. At post-mortem, the virus-mediated focal protein overexpression event was found to induce widespread deposits of pathological phosphorylated TDP-43 throughout the cervical spinal cord and motor cortex bilaterally, indicating an ALS-like spread of proteinopathy from the transfection site.

neuroscience↗

bioRxiv2025

Spinal Motor Neuron Pools May be Partly Driven by Impulsive Common Inputs

Spinal motor neurons serve as the link between the nervous system and muscles. As the final common pathway of the neuromuscular system, they receive inputs from both higher-level controllers and afferent pathways. It is often assumed that spinal motor neurons are primarily driven by continuous common inputs (cCI) within different frequency bands. Within this framework, the motor neuron pool behaves as a linear amplifier of the cCI. However, this framework overlooks the possibility that motor neurons could also be driven by impulsive common inputs (iCI), which can induce synchronization among them and disrupt the linear transmission of other synaptic inputs at the pool level. To test this hypothesis, computational simulations and experimental data from human subjects were used to characterize different aspects related to motor neuron spiking synchronization at the pool level. Our findings suggest that, indeed, iCI can account for relevant features observed in experimental data such as the presence of synchronization events at the pool level. We also observed that such impulsive inputs can affect the linearity in the transmission of cCI by the motor neuron pool. This study represents pioneering indirect evidence of the existence of iCI as inputs to motor neurons. Significant StatementMotor unit pool behavior in terms of spiking synchronization and spectral content typically observed in experimental recordings cannot be reproduced in simulations that only use continuous common inputs (cCI) to motor neurons. This study shows, for the first time, evidence supporting that spinal motor neurons receive a portion of their synaptic input in the form of impulsive common inputs (iCI) that synchronize their activity. The study also shows how such iCI can affect the linear transmission of other cCI by the motor neuron pool.

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bioRxiv2025

Kinematic Dissection of Arm Paresis after Focal New M1, Old M1 and Red Nucleus Lesions in Non-Human Primates

Cortical and subcortical lesions to the motor system, as often occur with stroke, typically lead to transitions through a stereotyped upper limb recovery sequence. After initial weakness and loss of dexterity, spasticity and fixed muscle coactivation patterns (synergies) appear. Early work suggested that different features arise from distinct primary motor cortex (M1) subdivisions. Here we investigated this with modern methods, using ischemic lesions of various cortical areas and electrocoagulation lesions of magnocellular red nucleus (RNm) in rhesus monkeys. Nine animals were trained on a reach and grasp task; hand kinematics were assessed with markerless tracking. The proportion of damaged cortical layer V cells in each cortical area was quantified, and corresponding kinematic effects evaluated. Reaching speed showed greater and more persistent reductions with larger lesions to the posterior part of M1 on the gyrus (Posterior Old M1 in Stricks terminology). Initial increases in trajectory variability were more consistent with greater damage within the central sulcus (New M1); these partially recovered. Lesions involving Anterior Old M1 (Area 4s in Hines terminology) had no additive negative effects. An extensive cortical lesion, which combined New and Old M1 with pre-motor and somatosensory cortex damage did not produce a worse or more persistent deficit than lesions limited to M1, suggesting that loss of arm control arose mainly from damage to descending pathways rather than cortico-cortical interactions. Lesions of RNm led to long-lasting slowing of reach, but no increase in variability. Subsequent cortical lesions to Old M1 led to more severe effects, and worse recovery, than without the preceding RNm lesion. This suggests an important neural compensatory role for the rubrospinal tract following cortical damage in monkey, which is not available in humans where the rubrospinal tract is vestigial. None of the lesions investigated led to overt abnormal synergies. The results are consistent with known differences in descending connections from each area: New M1 has fast cortico-motoneuronal output, known to be important for fine motor control (here assessed by trajectory variability); Old M1 has cortico-reticular connections able to activate the reticulospinal tract, important for generating the high forces needed for fast movements.

neuroscience↗

bioRxiv2025

A spinal origin for the obligate flexor synergy in the non-human primate: Implications for control of reaching

Stroke survivors frequently develop the flexor synergy, an obligate co-contraction of shoulder abductors and elbow flexors; the neural substrate has proven elusive. Here we trained healthy monkeys to generate isometric elbow and shoulder torques to move an on-screen cursor, and recorded neuron firing from motor cortical areas and the reticular formation. In all regions we found cells correlated with activity around a single joint. Neurons coding co-contractions showed a bias towards combinations orthogonal to the post-stroke flexor synergy, e.g. shoulder abduction with elbow extension. Threshold microstimulation in the spinal cord but not in either motor cortex or the reticular formation generated coactivation aligned to the flexor synergy. We suggest the evolution of prehension required descending systems either to control or bypass locomotion-dedicated spinal circuits. Loss of descending input after stroke constrains the upper limb to spinal synergies best suited to primitive locomotor functions.

neuroscience↗

bioRxiv2025

High-density, Identified Cell Recordings from Motor Cortex of Awake Behaving Macaques using 1024-channel SiNAPS-NHP Probes

Objective/BackgroundAcquiring bioelectric signals from many single neurons in primate brain remains challenging. Chronic implants offer a reasonable channel count ([~]100) but sample only a small, fixed region of the cortex. Acutely inserted electrodes can sample from a wider region by making new penetrations each day. The aim of this study was to develop an active dense CMOS probe and experimental procedures to demonstrate acute large-scale single unit recordings from behaving monkeys. MethodsA single-shank CMOS probe was specifically designed for intracortical macaque recordings. The device is based on SiNAPS technology, with additional multiplexing circuits to minimize output lines. Synchronous sampling at 20 kHz/channel from >2k electrode-pixels is achieved with multiple probe systems. Experiments were performed in behaving macaques, achieving multiple day insertions in the motor cortex. Methods were developed to extract spontaneous spiking times of antidromically-identified neurons. ResultsThe probe (10.7 mm in length, 158 m in width, 50 m in thickness) provides a regular array of 1024 electrodes (14 x 14 m2) arranged in 4 columns with an interelectrode pitch of 30 m. Dural penetration is eased by a small pilot hole; the optimized insertion procedure allows recordings from many different sites. Some cells were identified by antidromic activation as pyramidal tract neurons, which project to the spinal cord. ConclusionThis probe configuration can reach the anterior bank of the central sulcus, which contains many corticospinal cells that connect directly to motoneurons. SignificanceThis study is an important advance in the toolkit of primate neurophysiology.

neuroscience↗

bioRxiv2025

Breathing-Driven Modulation of Reticulospinal Tract Activity

The reticulospinal tract (RST) plays a pivotal role in motor control, especially during recovery after neurological injuries such as stroke and spinal cord injury (SCI). Understanding how RST activity is modulated offers valuable insights into improving motor function recovery. Recent studies have demonstrated that breathing rhythms influence brain activity. This study explores how respiratory rhythms modulate RST excitability during motor tasks, using the StartReact paradigm to examine reaction times (RTs) across visual (VRT), visual-auditory (VART), and visual-auditory startling (VSRT) conditions. We measured RTs in three muscles (first dorsal interosseous, flexor digitorum superficialis, and biceps) in healthy adult participants (n=13, both sexes) performing multi-joint movements. RTs were longest in the VRT condition and significantly decreased when auditory stimuli were added (VART), with further reductions observed in the VSRT condition. Additionally, respiratory phase transitions, particularly from inspiration to expiration (IE), significantly influenced RTs, with the shortest RTs observed during these transitions in the VSRT condition. These findings suggest that RST excitability is dynamically modulated by respiratory rhythms. This modulation of the RST by respiratory phase transitions could inform future neurorehabilitation strategies, such as respiratory-phase-aligned stimulation, to enhance motor recovery following corticospinal lesions. Ultimately, this approach may optimize the timing of interventions, improving outcomes in conditions such as stroke and SCI. Significance StatementBrainstem pathways play a crucial role in motor recovery after stroke, and understanding how these pathways change during recovery is key to optimizing their participation in rehabilitation. This study demonstrates how respiratory rhythms influence these brainstem pathways. Using the StartReact paradigm, we show that muscle response times are faster when transitioning from inspiration to expiration. These findings suggest that the bodys natural breathing rhythms can enhance motor output by activating these pathways. This could inform innovative rehabilitation strategies, such as aligning interventions with specific respiratory phases, to improve motor recovery in stroke and spinal cord injury. Our research highlights the potential for personalized therapies that harness the bodys intrinsic rhythms to optimize recovery.

neuroscience↗

bioRxiv2025

Boosting Motor Cortex Plasticity through Respiratory Phase-Triggered Paired Associative Stimulation

Paired Associative Stimulation (PAS) has shown promise in promoting motor cortex plasticity by using transcranial magnetic stimulation (TMS) paired with peripheral nerve stimulation. However, the effectiveness of PAS is often limited by its short-lived potentiation effects. Recent research indicates that respiratory rhythms can influence cortical excitability, suggesting a potential method to enhance PAS efficacy. This study investigated the impact of synchronizing PAS with respiratory phase transitions - specifically, the transition from inspiration to expiration (I-E) and expiration to inspiration (E-I) - on motor cortical plasticity. We conducted experiments with 18 healthy volunteers (13 females, 5 males) aged 21-45 years, assessing motor-evoked potentials (MEPs) elicited by TMS applied to the left motor cortex. Participants underwent PAS sessions where paired stimuli were delivered either at I-E or E-I transitions, or at random intervals. MEPs were recorded at baseline, immediately post-PAS, and at 10, 20, and 30 minutes post-stimulation. Results showed that PAS triggered at the I-E transition significantly increased MEP amplitudes, with significant differences in MEP amplitudes at 20 minutes post-PAS between the I-E and the other conditions. This highlights the benefit of timing PAS with the I-E transition for enhanced motor cortical plasticity. These findings underscore the potential of integrating respiratory rhythms into neuromodulation techniques to improve therapeutic outcomes. Synchronizing PAS with natural respiratory phases may enhance motor recovery strategies and offers a refined approach for therapeutic interventions. This approach could be particularly relevant for stroke rehabilitation, where enhancing motor cortical plasticity is crucial for recovery. Significance StatementThis study demonstrates that syncing brain stimulation with breathing patterns can enhance motor learning. By coordinating Paired Associative Stimulation (PAS)--a technique that stimulates sensory and motor inputs--with specific phases of the breathing cycle, we observed stronger responses in the motor cortex. This approach not only improves our understanding of brain adaptability but also offers a new way to fine-tune therapeutic techniques. For stroke patients, where regaining motor function is critical, integrating natural body rhythms into treatment could lead to more effective and personalized rehabilitation strategies.

neuroscience↗

bioRxiv2022

Reticulospinal drive increases maximal motoneuron output in humans

Maximal rate of force development in adult humans is determined by the maximal motoneuron output, however the origin of the underlying synaptic inputs remains unclear. Here, we tested a hypothesis that the maximal motoneuron output will increase in response to a startling cue, a stimulus that purportedly activates the pontomedullary reticular formation neurons that make mono- and disynaptic connections to motoneurons via fast-conducting axons. Twenty-two men were required to produce isometric knee extensor forces "as fast and as hard" as possible from rest to 75% of maximal voluntary force, in response to visual (VC), visual-auditory (VAC), or visual-startling cue (VSC). Motoneuron activity was estimated via decomposition of high-density surface electromyogram recordings over the vastus lateralis and medialis muscles. Reaction time was significantly shorter in response to VSC compared to VAC and VC (i.e., the StartReact effect). The VSC further elicited faster neuromechanical responses including a greater number of discharges per motor unit per second and greater maximal rate of force development, with no differences between VAC and VC. We provide evidence, for the first time, that the synaptic input to motoneurons increases in response to a startling cue, suggesting a contribution of subcortical pathways to maximal motoneuron output in humans, likely originating from the pontomedullary reticular formation.

physiology↗

bioRxiv2022

Transcranial alternating current stimulation does not modulate corticospinal activity in humans

Transcranial alternating current stimulation (TACS) is commonly used to synchronise the output of a cortical area to other parts of the nervous system, but evidence for this based on brain recordings in humans is challenging. The brain transmits beta oscillations (~21Hz) to tonically contracted limb muscles linearly and through the fastest corticospinal pathways. Therefore, muscle activity may be used as a proxy measure for the level of beta entrainment in the corticospinal tract due to TACS over motor cortex. Here, we assessed if TACS is able to modulate the neural inputs to muscles, which would provide an indirect evidence for TACS-driven neural entrainment. In the first part of this study, we ran a series of simulations of motor neuron (MN) pools receiving inputs from corticospinal neurons with different levels of beta entrainment. Results indicated that MNs should be highly sensitive to changes in corticospinal beta activity. Then, we ran experiments on healthy human subjects (N=10) in which TACS (at 1mA) was delivered over the motor cortex at 21Hz (beta stimulation), or at 7Hz or 40Hz (control conditions) while the abductor digiti minimi (ADM) or the tibialis anterior muscle (TA) were tonically contracted. Muscle activity was measured using high-density electromyography, which allowed us to decompose the spiking activity of pools of motor units innervating the studied muscles. By analysing motor unit pool activity, we observed that none of the tested TACS conditions could consistently alter the spectral characteristics of the common neural inputs received by the muscles. These results suggest that 1mA-TACS over motor cortex given at frequencies in the beta band does not affect corticospinal beta entrainment. Highlights- TACS is commonly used to entrain the communication between brain regions - It is challenging to find direct evidence supporting TACS-driven neural entrainment - Simulations show that motor neurons are sensitive to corticospinal beta entrainment - Motor unit activity from human muscles does not support TACS-driven entrainment

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bioRxiv2021

Interfacing Spinal Motor Units in Non-Human Primates Identifies a Principal Neural Component for Force Control Constrained by the Size Principle

Motor units convert the last neural code of movement into muscle forces. The classic view of motor unit control is that the central nervous system sends common synaptic inputs to motoneuron pools and that motoneurons respond in an orderly fashion dictated by the size principle. This view however is in contrast with the large number of dimensions observed in motor cortex which may allow individual and flexible control of motor units. Evidence for flexible control of motor units may be obtained by tracking motor units longitudinally during the performance of tasks with some level of behavioural variability. Here we identified and tracked populations of motor units in the brachioradialis muscle of two macaque monkeys during ten sessions spanning over one month during high force isometric contractions with a broad range of rate of force development (1.8 - 38.6 N{middle dot}m{middle dot}s-1). During the same sessions we recorded intramuscular EMG signals from 16 arm muscles of both limbs and elicited the full recruitment through neural stimulation of the median and deep radial nerves. We found a very stable recruitment order and discharge characteristics of the motor units over sessions and contraction trials. The small deviations from orderly recruitment were observed between motor units with close recruitment thresholds, and only during high rate of force development. Moreover, we also found that one component explained more than ~50% of the motor unit discharge rate variance, and that the remaining components could be described as a time-shifted version of the first, as it could be predicted from the interplay between the size principle of recruitment and one common input. In conclusion, our results show that motoneurons recruitment is determined by the interplay of the size principle and common input and that this recruitment scheme is not violated over time nor by the speed of the contractions.

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bioRxiv2020

Only the fastest corticospinal fibers contribute to beta corticomuscular coherence

A common way to study human corticospinal transmission is with transcranial magnetic stimulation. However, this is biased to activity in the fastest conducting axons. It is unclear whether conclusions obtained in this context are representative of volitional activity in mild-to-moderate contractions. A possible alternative to overcome this limitation is to study the corticospinal transmission of endogenously generated brain activity. Here we study the transmission speeds of cortical beta rhythms travelling to the muscles during steady contractions. To do this, we introduce new methods to improve delay estimates in the corticomuscular transmission of beta rhythms, and which we validate both in simulations and experimentally. Applying these approaches to experimental data from humans, we show that corticomuscular beta transmission delays are only 1-2ms longer than expected from the fastest corticospinal pathway. Simulations using realistic distributions of the conduction velocities for descending axons projecting to lower motoneurons suggest two scenarios that can explain these results: either a very small fraction of only the fastest corticospinal axons selectively transmit beta activity, or else the entire pool does. The implications that these two scenarios have for our understanding of corticomuscular interactions are discussed in the final part of this manuscript. SIGNIFICANCEWe present and validate an improved methodology to measure the delay in the transmission of cortical beta activity to tonically active muscles. The estimated corticomuscular beta transmission delays which this yields are remarkably similar to those expected from transmission in the fastest corticospinal axons. A simulation of beta transmission along a pool of corticospinal axons using a realistic distribution of fiber diameters suggests two possible mechanisms by which fast corticomuscular transmission is achieved: either a very small fraction of descending axons transmits beta activity to the muscles or, alternatively, the entire population does and natural cancellation of slow channels occurs due to the distribution of axon diameters in the corticospinal tract.

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bioRxiv2019

Slowly-conducting pyramidal tract neurons in macaque and rat

Anatomical studies report a large proportion of fine myelinated fibres in the primate pyramidal tract (PT), while very few pyramidal tract neurons (PTNs) with slow conduction velocities (CV) (< [~]10 m/s) are reported electrophysiologically. This discrepancy might reflect recording bias towards fast PTNs or prevention of antidromic invasion by recurrent inhibition of slow PTNs from faster axons. We investigated these factors in recordings made with a polyprobe (32 closely-spaced contacts) from motor cortex of anaesthetised rats (n=2) and macaques (n=3), concentrating our search on PTNs with long antidromic latencies. We identified 21 rat PTNs with antidromic latencies > 2.6 ms and estimated CV 3-8 m/s, and 67 macaque PTNs (> 3.9ms, CV 6-12 m/s). Spikes of most slow PTNs were small and present on only some recording contacts, while spikes from simultaneously recorded fast-conducting PTNs were large and appeared on all contacts. Antidromic thresholds were similar for fast and slow PTNS, while spike duration was considerably longer in slow PTNs. Most slow PTNs showed no signs of failure to respond antidromically. A number of tests, including intracortical microinjection of bicuculline (GABAA antagonist), failed to provide any evidence that recurrent inhibition prevented antidromic invasion of slow PTNs. Our results suggest that recording bias is the main reason why previous studies were dominated by fast PTNs.

physiology↗

bioRxiv2019

Modulation of Rapid Visual Responses during Reaching by Multimodal Stimuli

The reticulospinal tract plays an important role in primate upper limb function, but methods for assessing its activity are limited. One promising approach is to measure rapid visual responses (RVRs) in arm muscle activity during a visually-cued reaching task; these may arise from a tecto-reticulospinal pathway. We investigated whether changes in reticulospinal excitability can be assessed non-invasively using RVRs, by pairing the visual stimuli of the reaching task with electrical stimulation of the median nerve, galvanic vestibular stimulation or loud sounds, all of which are known to activate the reticular formation.\n\nSurface electromyogram recordings were made from the right deltoid of healthy human subjects as they performed fast reaching movements towards visual targets. Stimuli were delivered up to 200ms before target appearance and RVR was quantified as the EMG amplitude in a window 75-125ms after visual target onset. Median nerve, vestibular and auditory stimuli all consistently facilitated the RVRs, as well as reducing the latency of responses. We propose that this reflects modulation of tecto-reticulospinal excitability, suggesting that the amplitude of RVRs can be used to assess changes in brainstem excitability non-invasively in humans.\n\nNew & NoteworthyShort latency responses in arm muscles evoked during a visually-driven reaching task have previously been proposed to be tecto-reticulospinal in origin. We demonstrate that these responses can be facilitated by pairing the appearance of a visual target with stimuli that activate the reticular formation - median nerve, vestibular and auditory stimuli. We propose that this reflects non-invasive measurement and modulation of reticulospinal excitability.

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