Biology subjects

Fetz, E. E.

Publications and source records attributed to Fetz, E. E..

12 recordsLinked to original sources

bioRxiv2026

Volitional control of a recurrent brain computer interface via covert reinforcement of endogenous reward networks

Recurrent brain-computer interfaces (rBCIs) deliver targeted stimulation to one brain region based on neural activity recorded and processed in real-time at another. In a volitionally controlled rBCI, the user must also learn to intentionally produce the triggering neural activity, a process typically facilitated by an external reward. However, reliance on an external reward introduces a delay between the triggering event and reinforcement that can slow association between the two and, ultimately, control of the rBCI (particularly for neural activity not directly related to an observable behavior such as a goal-directed movement). The constraint to an external reward also limits studies of neural dynamics during natural, free behavior. In contrast, delivering activity-dependent stimulation directly to the brain's own reward centers - i.e., covert reinforcement - would bypass the need for external feedback, enabling precise temporal coupling between triggering events and reward and allowing for unrestrained rBCI use. Here, we show that rats can gain volitional control of an rBCI using activity-dependent electrical stimulation of the medial forebrain bundle as a sole reinforcer. Animals successfully learned to modulate motor unit discharge rates as well as specific electrocorticographic frequency bands (beta and gamma) to self-trigger stimulation. Furthermore, rats demonstrated flexible control by independently modulating distinct spectral features from the same cortical site. These findings suggest that covert reinforcement of endogenous reward networks can drive operant conditioning of specific neural signals during unrestrained behavior, opening new avenues for adaptive BCIs and closed-loop psychiatric therapies.

neuroscience↗

bioRxiv2026

Spinal cord population activity lacks rotational dynamics during an alternating isometric task in macaque

Recent studies report rotational population dynamics in spinal cord neuronal activity during rhythmic movements, suggesting computational principles shared with motor cortex. Here we show that primate cervical spinal cord activity does not exhibit rotational dynamics during an alternating single-joint isometric wrist task, instead it displays low-dimensional alternating population patterns. Positive controls confirm presence of rotational structure in motor cortex activity during the same task, indicating distinct computational strategies across the motor axis. Cortical neurons with post-spike effects on motoneurons had activity with dynamics resembling cortical rather than spinal populations.

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bioRxiv2026

Spatial Distribution of Cortical Output Zones Affecting Combinations of Forelimb Muscles in the Monkey

SUMMARY AND CONCLUSIONSO_LIWe investigated the dimensions of output zones affecting specific combinations of forelimb muscles in the precentral "motor" cortex of macaque monkeys. Single-pulse intracortical microstimulation (S-ICMS) was used to evoke subthreshold effects in multiple wrist and finger muscles. S-ICMS consisted of 15 Hz stimulus trains at low intensity (5 A) to avoid spread of effects due to temporal summation and to activate circumscribed foci of cortical cells in the bank of the precentral gyrus. C_LIO_LITo detect subthreshold effects on active muscles, stimuli were delivered during wrist movements against elastic loads, and stimulus-triggered averages of rectified electromyographic (EMG) activity of 12 identified forelimb muscles were compiled. These averages detected statistical increases and decreases in averaged rectified EMG activity termed poststimulus facilitation and poststimulus suppression, respectively (7, 8). The "muscle profile" of a cortical output site was defined as the distribution and relative magnitude of these effects evoked in the recorded muscles. To document the spatial extent of a cortical output zone producing a particular "muscle profile," we delivered S-ICMS at successive sites along electrode tracks in the precentral bank, tangential to and near layer V cells. C_LIO_LIIn some cases the electrodes encountered cortical cells whose post-spike effects on muscles were also documented by spike-triggered averages of EMG activity. Near cells that had post-spike effects, S-ICMS evoked a similar profile of effects on these muscles, over distances of several hundred microns from the location of the cells with post-spike output effects. C_LIO_LIThe locations of tracks were marked by electrolytic lesions at specific depths and were identified in subsequent histological reconstructions. The physiological effects evoked from different sites were correlated with the locations of Nissl-stained cortical cells and corticospinal cells labeled by horseradish peroxidase (HRP) transported from the cervical spinal cord. C_LIO_LIThe "muscle profiles" of poststimulus effects elicited by 5-10 A S-ICMS applied at successive sites were the same for multiple neighboring sites extending over tangential distances of about 1 mm. S-ICMS applied at 300 to 500 m intervals evoked significant poststimulus facilitation or suppression effects over a range of 650-1250 m. Assuming an effective excitation radius of 65 m for 5-A current pulses, the lower limit of the mean tangential dimension of cortical output zones on the precentral bank (n = 17) was estimated to be 800 m. C_LIO_LIA specific muscle could be affected, either singly or in combination with synergist muscles, from aggregate regions of output sites extending about 5 x 4 mm mediolateral x dorsoventral. These regions were comparable in size to output areas containing all the corticomotoneuronal (CM) cells that produced postspike facilitation in that muscle. C_LIO_LIThe cortical entry points of tracks with CM cells producing postspike facilitation in specific muscles were reconstructed for three monkeys. In two monkeys, the flexor and extensor CM cells were thoroughly intermingled; in the third, the flexor CM cells were preferentially located medially and showed less overlap with the region containing extensor CM cells. C_LIO_LIThese results indicate that each motor cortex site represents a different combination of muscles. The effects evoked from cortical sites separated by several hundred microns invariably involved different profiles of muscle activity. The muscle fields of remote CM cells were rarely identical, while the fields of neighboring CM cells were often similar. Given the number of unrecorded muscles, we conclude that primate motor cortex is a mosaic of output sites representing forelimb muscles in different combinations. C_LI

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bioRxiv2025

Cortical potentials evoked by stimulation of cervical vagus vs. auricular nerve: a comparative, parametric study in nonhuman primates

Stimulation of sensory vagal pathways is typically delivered via invasive, cervical vagus nerve stimulation (cVNS) or noninvasive, trans-auricular nerve stimulation (taNS). While both methods are investigated therapeutically, their effects on brain physiology remain poorly understood, hindering mechanistic understanding and stimulus optimization. In 6 awake nonhuman primates, we recorded cortical vagal-evoked potentials (VEPs) from subdural electrodes placed in prefrontal, sensorimotor and parietal cortical areas, in response to cVNS or taNS. Across 478 different taNS and cVNS protocols, we varied stimulation side, intensity, frequency, pulse count, and pulse width (PW) and assessed independent effects on amplitude and latency of early (EC; 30-100 ms), intermediate (IC; 101-200 ms) and late components (LC; 201-500 ms) of VEPs. Fixed and random effects of stimulation parameters and subjects, respectively, on VEP measurements, were assessed using a linear mixed-effects model. Overall, cVNS elicits more robust VEPs than taNS, with larger EC, IC and LC amplitudes in both hemispheres. cVNS-elicited ECs and LCs are largest in PFC and PC areas, whereas ICs are largest in SM areas. On the other hand, taNS generally does not elicit area-specific responses. cVNS-elicited ECs have slower latency than ta-NS elicited ECs. Higher stimulation frequencies and intensities and a longer pulse width elicit larger ECs and ICs for cVNS, and to some extent for taNS. Both short and long cVNS trains elicit stronger ECs, and long trains elicit slower ICs. Earlobe stimulation elicits VEPs that partially overlap with those from taNS. In conclusion, cVNS and taNS elicit cortical VEPs in a manner consistent with distinct engagement of ascending vagal pathways, and with similarities and differences in the effects of stimulation parameters on evoked responses.

neuroscience↗

bioRxiv2025

SYNAPTIC INTERACTIONS IN PRIMATE MOTOR CORTEX: RELATIONS BETWEEN CONNECTIVITY AND INTRACORTICAL LOCATION

To investigate intracortical microcircuits within primate motor cortical areas, we documented pairs of neurons whose synaptic interactions were identified by spike-triggered averaging (STA) of intracellularly recorded membrane potentials and whose relative location was histologically identified. Average synchronous excitation potentials (ASEPs) were the most commonly observed feature in STAs between neuron pairs in all cortical layers (about 70%). This synchrony spread broadly for distances of more than 4 mm, gradually decreasing in amplitude and probability with cell separation. Excitatory postsynaptic potentials (EPSPs) were observed among 9% of the neuron pairs, whose separation extended for distances of more than 4 mm. The peak amplitudes of EPSPs were inversely correlated with cell separation. Most source neurons were located in layer II-III or layer V, while the postsynaptic target neurons had wide laminar distribution. The probability of finding excitatory connections was not uniform within the cortical space. The connectivity between neuron pairs was relatively dense within 1.0 mm, and became sparse for distances between 1.0 and 2.0 mm, and showed a second peak for distance between 2.0 and 4.0 mm. Inhibitory postsynaptic potentials (IPSPs) and/or average synchronous inhibitory potentials (ASIPs) were observed for 10% of neuron pairs. Most of these were separated by less than 1.0 mm, suggesting that their influence was restricted within their own and neighboring columns. The major source neurons that provide these inhibitory effects were located within layer II-III. We conclude that excitatory synaptic effects (ASEPs and EPSPs) are widely distributed and omni-directional within primate motor cortex, while inhibitory connections (ASIPs and IPSPs) are restricted within columnar dimensions, and are predominantly directed from superficial to deeper layers. The appearance of independent zones that had no functional connectivity with neighboring columns indicates that primate motor cortical areas may not be organized in a uniform way. This would support the sparse coding theory and multiple representations of cortical output in the motor cortex.

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bioRxiv2024

Flexible modeling of large-scale neural network stimulation: electrical and optical extensions to The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX)

BackgroundComputational models that predict effects of neural stimulation can be used as a preliminary tool to inform in-vivo research, reducing the costs, time, and ethical considerations involved. However, current models do not support the diverse neural stimulation techniques used in-vivo, including the expanding selection of electrodes, stimulation modalities, and stimulation paradigms. New MethodTo develop a more comprehensive software, we created several extensions to The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX), the MATLAB-based neural stimulation tool from Newcastle University. VERTEX simulates input currents in a large population of multi-compartment neurons within a small cortical slice to model electric field stimulation, while recording local field potentials (LFPs) and spiking activity. Our extensions to its existing electric field stimulation framework include allowing multiple pairs of parametrically defined electrodes and biphasic, bipolar stimulation delivered at programmable delays. To support the growing use of optogenetic approaches for targeted neural stimulation, we introduced a feature that models optogenetic stimulation through an additional VERTEX input function that converts irradiance to currents at optogenetically responsive neurons. Finally, we added extensions to allow complex stimulation protocols including paired-pulse, spatiotemporal patterned, and closed-loop stimulation. ResultsWe demonstrated our novel features using VERTEXs built-in functionalities, with results in alignment with other models and experimental work. ConclusionsOur extensions provide an all in one platform to efficiently and systematically test diverse, targeted, and individualized stimulation patterns.

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bioRxiv2023

Synchrony and amplitude modulation of cortical activity in humans performing manipulative visuomotor tasks

Synchrony of oscillatory brain activity has been postulated to be a binding mechanism for cognitive and motor functions. Spectral analysis of human electrocorticogram (ECoG) in sensorimotor cortex has shown that power density of gamma band activity (30-60 Hz) increased and that of alpha-beta band activity (10-20 Hz) decreased during performance of manipulative visuomotor tasks, indicating that amplitude modulation of the gamma band activity occurred in relation to the task performance. Amplitude modulation may provide evidence for synchrony of local neuronal assembly. However, it does not implement the binding mechanisms for distributed networks that are necessary for cognitive and motor functions. To prove that oscillatory activity mediates a binding mechanism, phase modulation of oscillatory activity in a wide range area should be shown. We performed coherence analysis of the ECoG signals in sensorimotor cortex to study if synchrony of the gamma band activity between these areas occurs in relation to manipulative task performance. The ECoGs were recorded from 14 sites in sensorimotor cortex including hand-arm areas with subdural grid electrodes in four subjects. Coherence estimates in all pair-wise sites were calculated in different frequency bands with 10 Hz widths from 10 to 80 Hz. In all subjects, coherence estimates increased in the lower gamma band (20-50 Hz) during the performance of the manipulative tasks. But coherence in the alpha-beta band (10-20 Hz) also increased even though amplitude modulation did not occur in this frequency band. Coherence estimates increased in site pairs within and between sensory and motor areas, many separated by intervening sites. This interregional synchrony of the alpha-beta and the lower gamma activities may play a role in integration of sensorimotor information. Task-dependent increases in coherence estimates, i.e., greater increases during performance of the manipulative tasks than during the simple tasks, suggest another role of synchrony in attention mechanism. Time-series coherence analysis showed that phase modulation occurred in different timings for activities in the alpha-beta and the lower gamma bands. For the activity in higher gamma band (50-80 Hz), power density increased but coherence estimates decreased. Thus, only amplitude modulation occurred in this frequency band. Altogether these results suggest that oscillatory activities in different frequency bands may reflect different functional roles by modulating neural activity in different ways.

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bioRxiv2022

Paired stimulation for spike-timing dependent plasticity quantified with single neuron responses in primate motor cortex

Spike-timing dependent plasticity (STDP) is an extensively studied topic. Previous studies have demonstrated stimulus induced targeted STDP both in vitro and in vivo, but a more consistent and robust method is required. We hypothesized there were two reasons contributing to the inconsistent results previously reported: 1. the measure of connectivity is poorly understood, and 2. the timing of stimulation is static or has low temporal specificity. To test our hypotheses, we applied paired stimulation to the primary motor cortex of awake primates. Single unit responses to stimulation were used as measures of connectivity, and we applied inter-stimulus intervals (ISIs) from {+/-}0.1 to {+/-}50 ms with sub-millisecond intervals. The excitatory single unit response resulted in very consistent changes after conditioning that was dependent on the ISI. Negative ISIs resulted in depression similar to classic STDP, but positive ISI also often resulted in depression. Normalizing the ISIs to the timing of the excitatory response revealed that potentiation only occurred if the second stimulus arrived before the response. Stimuli occurring around the time of the response often resulted in depression as strong as negative ISIs. We additionally tracked the changes in cortico-cortical evoked potentials (CCEPs), a commonly used measure of connectivity in plasticity experiments. CCEP changes showed a similar but more variable dependence to ISI. These results show that the classic STDP curve may be more difficult to induce due to interactions between excitatory and inhibitory circuitry, and that CCEPs may not be the ideal measure of changes in strength of connectivity.

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bioRxiv2022

Local field potentials and single unit dynamics in motor cortex of unconstrained macaques during different behavioral states

Different sleep states have been shown to be vital for a variety of brain function, including learning, memory, and skill consolidation. However, our understanding of neural dynamics during sleep and the role of prominent LFP frequency bands remain incomplete. To elucidate such dynamics and changes between different behavioral states we collected multichannel LFP and spike data in primary motor cortex of unconstrained macaques for up to 24 hours using the Neurochip3. Each 8 second bin of time was classified into awake and moving (Move), awake and at rest (Rest), REM sleep (REM), or non-REM sleep (NREM) by using dimensionality reduction and clustering on the average spectral density and the acceleration of the head. LFP power showed high delta during NREM, high theta during REM, and high beta when the animal was awake. Cross-frequency phase-amplitude coupling typically showed higher coupling for deeper sleep between all pairs of frequency bands. Two notable exceptions were high delta-high gamma and theta-high gamma coupling during Move, and high theta-beta coupling during REM. Sorted single units showed decreased firing rate with deeper sleep, though with higher "bursty" patterns during NREM compared to other states. Spike-LFP synchrony showed high delta synchrony during Move, and higher coupling with all other frequency bands with deeper sleep. These results altogether are consistent with previous findings showing reactivation of cortical circuitry during sleep, which may be moderated by delta band LFP.

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bioRxiv2022

Responses of cortical neurons to intracortical microstimulation in awake primates

Intracortical microstimulation (ICMS) is commonly used in many experimental and clinical paradigms; however, its effects on the activation of neurons are still not completely understood. To document the responses of cortical neurons in non-human primates to stimulation, we recorded single unit activity while delivering single-pulse stimulation via Utah arrays implanted in primary motor cortex of three macaque monkeys. Stimuli between 5-50 A delivered to single channels reliably evoked spikes in neurons recorded throughout the array with delays of up to 12 milliseconds. ICMS pulses also induced a period of inhibition lasting up to 150 ms that typically followed the initial excitatory response. Higher current amplitudes led to a greater probability of evoking a spike and extended the duration of inhibition. The likelihood of evoking a spike in a neuron was dependent on the spontaneous firing rate as well as the delay between its most recent spike time and stimulus onset. Tonic repetitive stimulation between 2 and 20 Hz often modulated both the probability of evoking spikes and the duration of inhibition, although high frequency stimulation in particular was more likely to change both responses. On a trial-by-trial basis, whether a stimulus evoked a spike did not affect the subsequent inhibitory response; however, their changes over time were frequently positively or negatively correlated. Our results document the complex dynamics of cortical neural responses to electrical stimulation that need to be considered when utilizing ICMS for scientific and clinical applications. Significance statementIntracortical microstimulation (ICMS) is commonly used to probe the cortex, and previous studies have characterized the responses of single neurons to ICMS. However, these studies typically explored the averaged effects of ICMS throughout each experimental session, rather than by a trial-by-trial basis for each stimulation pulse. By shifting the approach, we explored the dependence of neural responses to ICMS on the spontaneous neural activity as well as the dynamics of responses over time due to repetitive stimulation. Our results highlight how the responses of neurons to ICMS are likely the result of interactions between local excitatory and inhibitory cortical circuits. These results will help inform the design of ICMS for both basic research and clinically relevant stimulation protocols.

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bioRxiv2021

Movement-Dependent Electrical Stimulation for Volitional Strengthening of Cortical Connections in Behaving Monkeys

Correlated activity of neurons can lead to long-term strengthening or weakening of the connections between them. In addition, the behavioral context, imparted by execution of physical movements or the presence of a reward, can modulate the plasticity induced by Hebbian mechanisms. In the present study, we have combined behavior and induced neuronal correlations to strengthen connections in the motor cortex of adult behaving monkeys. Correlated activity was induced using an electrical-conditioning protocol in which stimuli gated by voluntary movements were used to produce co-activation of neurons at motor-cortical sites involved in those movements. Delivery of movement-dependent stimulation resulted in small increases in the strength of associated cortical connections immediately after conditioning. Remarkably, when paired with further repetition of the movements that gated the conditioning stimuli, there were substantially larger gains in the strength of cortical connections, that occurred in a use-dependent manner, without delivery of additional conditioning stimulation. In the absence of such movements, little change was observed in the strength of motor-cortical connections. Performance of the motor behavior in the absence of conditioning also did not produce any changes in connectivity. Our results show that combining movement-gated stimulation with further natural use of the "conditioned" pathways after stimulation ends can produce use-dependent strengthening of connections in adult primates, highlighting an important role for behavior in cortical plasticity. Our data also provide strong support for combining movement-gated stimulation with use-dependent physical rehabilitation for strengthening connections weakened by a stroke or spinal-cord injury. Significance StatementWe describe an electrical-conditioning protocol in adult behaving monkeys in which stimuli gated by voluntary movements were used to strengthen connections between motor-cortical neurons involved in those movements. Movement-gated stimulation created a plastic landscape in which repetition of the movements that gated conditioning stimuli produced strengthening of cortical connections, in a use-dependent manner, long after stimulation had ended, a finding that is both novel and unique. In the absence of such behavior, little change was observed in the strength of connections. Similarly, movements alone did not produce any changes in connectivity. Our data highlight a critical role for behavior in plasticity and provide strong support for combining movement-gated stimulation with use-dependent rehabilitation for strengthening connections weakened by injury or disease.

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bioRxiv2020

An integrate-and-fire spiking neural network model simulating artificially induced cortical plasticity

We describe an integrate-and-fire (IF) spiking neural network that incorporates spike-timing dependent plasticity (STDP) and simulates the experimental outcomes of four different conditioning protocols that produce cortical plasticity. The original conditioning experiments were performed in freely moving non-human primates with an autonomous head-fixed bidirectional brain-computer interface. Three protocols involved closed-loop stimulation triggered from (a) spike activity of single cortical neurons, (b) EMG activity from forearm muscles, and (c) cycles of spontaneous cortical beta activity. A fourth protocol involved open-loop delivery of pairs of stimuli at neighboring cortical sites. The IF network that replicates the experimental results consists of 360 units with simulated membrane potentials produced by synaptic inputs and triggering a spike when reaching threshold. The 240 cortical units produce either excitatory or inhibitory post-synaptic potentials in their target units. In addition to the experimentally observed conditioning effects, the model also allows computation of underlying network behavior not originally documented. Furthermore, the model makes predictions about outcomes from protocols not yet investigated, including spike-triggered inhibition, gamma-triggered stimulation and disynaptic conditioning. The success of the simulations suggests that a simple voltage-based IF model incorporating STDP can capture the essential mechanisms mediating targeted plasticity with closed-loop stimulation.

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