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In recent decades, vagus nerve stimulation (VNS) therapy has become widely used for clinical applications including epilepsy, depression, and enhancing the effects of rehabilitation. However, several questions remain regarding optimization of this therapy to maximize clinical outcomes. Although stimulation parameters such as pulse width, amplitude, and frequency are well studied, the timing of stimulation delivery both acutely (with respect to disease events) and chronically (over the timeline of a disease's progression) has generally received less attention. Leveraging such information would provide a framework for the implementation of next generation closed-loop VNS therapies. In this mini-review, we summarize a number of VNS therapies and discuss (1) general timing considerations for these applications and (2) open questions that could lead to further therapy optimization.

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Objective.The common marmoset has been increasingly used in neural interfacing studies due to its smaller size, easier handling, and faster breeding compared to Old World non-human primate (NHP) species. While assessment of cortical anatomy in marmosets has shown strikingly similar layout to macaques, comprehensive assessment of electrophysiological properties underlying forelimb reaching movements in this bridge species does not exist. The objective of this study is to characterize electrophysiological properties of signals recorded from the marmoset primary motor cortex (M1) during a reach task and compare with larger NHP models such that this smaller NHP model can be used in behavioral neural interfacing studies.Approach and main results.Neuronal firing rates and local field potentials (LFPs) were chronically recorded from M1 in three adult, male marmosets. Firing rates, mu + beta and high gamma frequency bands of LFPs were evaluated for modulation with respect to movement. Firing rate and regularity of neurons of the marmoset M1 were similar to that reported in macaques with a subset of neurons showing selectivity to movement direction. Movement phases (rest vs move) was classified from both neural spiking and LFPs. Microelectrode arrays provide the ability to sample small regions of the motor cortex to drive brain-machine interfaces (BMIs). The results demonstrate that marmosets are a robust bridge species for behavioral neuroscience studies with motor cortical electrophysiological signals recorded from microelectrode arrays that are similar to Old World NHPs.Significance. As marmosets represent an interesting step between rodent and macaque models, successful demonstration that neuron modulation in marmoset motor cortex is analogous to reports in macaques illustrates the utility of marmosets as a viable species for BMI studies.

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OBJECTIVE: Spinal cord injury remains an ailment with no comprehensive cure, and affected patients suffer from a greatly diminished quality of life. This large population could significantly benefit from prosthetic technologies to replace missing limbs, reanimate nonfunctional limbs, and enable new modes of technologies to restore muscle control and function. While cortically driven brain machine interfaces have achieved great success in interfacing with an external device to restore lost functions, interfacing with the spinal cord can provide an additional site to record motor control signals, which can have its own advantages, despite challenges from using a smaller non-human primate (NHP) model. The goal of this study is to develop such a spinal cord neural interface to record motor signals from the high cervical levels of the spinal cord in a common marmoset (Callithrix jacchus) model. Approach and main results. Detailed methods are discussed for this smaller NHP model that includes behavioral training, surgical methods for electrode placement, connector placement and wire handling, electrode specifications and modifications for accessing high cervical level interneurons and motorneurons. The study also discusses the methods and challenges involved in behavioral multi-channel extracellular recording from the marmoset spinal cord, including the major recording failure mechanisms encountered during the study. SIGNIFICANCE: Marmosets provide a good step between rodent and larger NHP models due to their small size, ease of handling, cognitive abilities, and similarities to other primate motor systems. The study shows the feasibility of recording spinal cord signals and using marmosets as a smaller NHP model in behavioral neuroscience studies. Interfacing with the spinal cord in chronically implanted animals can provide useful information about how motor control signals within the spinal cord are transformed to cause limb movements.

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Current neuroprosthetics rely on stable, high quality recordings from chronically implanted microelectrode arrays (MEAs) in neural tissue. While chronic electrophysiological recordings and electrode failure modes have been reported from rodent and larger non-human primate (NHP) models, chronic recordings from the marmoset model have not been previously described. The common marmoset is a New World primate that is easier to breed and handle compared to larger NHPs and has a similarly organized brain, making it a potentially useful smaller NHP model for neuroscience studies. This study reports recording stability and signal quality of MEAs chronically implanted in behaving marmosets. Six adult male marmosets, trained for reaching tasks, were implanted with either a 16-channel tungsten microwire array (five animals) or a Pt-Ir floating MEA (one animal) in the hand-arm region of the primary motor cortex (M1) and another MEA in the striatum targeting the nucleus accumbens (NAcc). Signal stability and quality was quantified as a function of array yield (active electrodes that recorded action potentials), neuronal yield (isolated single units during a recording session), and signal-to-noise ratio (SNR). Out of 11 implanted MEAs, nine provided functional recordings for at least three months, with two arrays functional for 10 months. In general, implants had high yield, which remained stable for up to several months. However, mechanical failure attributed to MEA connector was the most common failure mode. In the longest implants, signal degradation occurred, which was characterized by gradual decline in array yield, reduced number of isolated single units, and changes in waveform shape of action potentials. This work demonstrates the feasibility of longterm recordings from MEAs implanted in cortical and deep brain structures in the marmoset model. The ability to chronically record cortical signals for neural prosthetics applications in the common marmoset extends the potential of this model in neural interface research.

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BACKGROUND: The common marmoset (Callithrix jacchus) has been proposed as a suitable bridge between rodents and larger primates. They have been used in several types of research including auditory, vocal, visual, pharmacological and genetics studies. However, marmosets have not been used as much for behavioral studies. NEW METHOD: Here we present data from training 12 adult marmosets for behavioral neuroscience studies. We discuss the husbandry, food preferences, handling, acclimation to laboratory environments and neurosurgical techniques. In this paper, we also present a custom built "scoop" and a monkey chair suitable for training of these animals. RESULTS: The animals were trained for three tasks: 4 target center-out reaching task, reaching tasks that involved controlling robot actions, and touch screen task. All animals learned the center-out reaching task within 1-2 weeks whereas learning reaching tasks controlling robot actions task took several months of behavioral training where the monkeys learned to associate robot actions with food rewards. COMPARISON TO EXISTING METHOD: We propose the marmoset as a novel model for behavioral neuroscience research as an alternate for larger primate models. This is due to the ease of handling, quick reproduction, available neuroanatomy, sensorimotor system similar to larger primates and humans, and a lissencephalic brain that can enable implantation of microelectrode arrays relatively easier at various cortical locations compared to larger primates. CONCLUSION: All animals were able to learn behavioral tasks well and we present the marmosets as an alternate model for simple behavioral neuroscience tasks.

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