Assessing changes in whole-brain structural connectivity in the unilateral 6-hydroxydopamine rat model of Parkinson's disease using diffusion imaging and tractography.

Parkinson's disease (PD) is a multifactorial, progressive neurodegenerative disease that has a profound impact on those it afflicts. Its hallmark pathophysiology is characterized by degeneration of dopaminergic (DA) neurons in the midbrain which trigger a host of motor and non-motor symptoms. Many preclinical research efforts utilize unilateral lesion models to assess the neural mechanisms of PD and explore new therapeutic approaches because these models produce similar motor symptoms to those of PD patients.

Wearable peripheral nerve stimulator reduces essential tremor symptoms through targeted brain modulation.

Background: Essential tremor (ET), the most common movement disorder in adults, presents with involuntary shaking of the upper extremities during postural hold and kinetic tasks linked to dysfunction in the cerebello-thalamo-cortical network. Recently, transcutaneous afferent patterned stimulation (TAPS), applied through a wrist-worn device, has emerged as a non-invasive treatment for medication-refractory ET. However, its mechanism remains unclear.

Trigeminal or peripheral nerve stimulation improves functional outcomes of nerve recovery in a rodent forelimb gap repair model.

Background: The hypothesis of this study was that trigeminal nerve stimulation (TNS) or peripheral nerve stimulation (PNS) could improve functional outcomes of peripheral nerve injury in a rat forelimb model when compared to control rats not receiving electrical stimulation (ES). While PNS is known to improve outcomes after nerve surgery, the role of TNS has not been explored.

Methods: Lewis rats were trained to perform a reach and grasp task before receiving a 2 mm gap repair of the ulnar and median nerves and randomized into four treatment groups: (1) sham injury, (2) nerve injury with sham ES, (3) nerve injury with PNS, and (4) nerve injury with TNS.

Quantifying changes in local basal ganglia structural connectivity in the 6-hydroxydopamine model of Parkinson's Disease using correlational tractography.

In recent years, tractography based on diffusion magnetic resonance imaging (dMRI) has become a popular tool for studying microstructural changes resulting from brain diseases like Parkinson's Disease (PD). Quantitative anisotropy (QA) is a parameter that is used in deterministic fiber tracking as a measure of connection between brain regions. It remains unclear, however, if microstructural changes caused by lesioning the median forebrain bundle (MFB) to create a Parkinsonian rat model can be resolved using tractography based on ex-vivo diffusion MRI.

Vagus nerve stimulation in the non-human primate: implantation methodology, characterization of nerve anatomy, target engagement and experimental applications.

Background: Vagus nerve stimulation (VNS) is a FDA approved therapy regularly used to treat a variety of neurological disorders that impact the central nervous system (CNS) including epilepsy and stroke. Putatively, the therapeutic efficacy of VNS results from its action on neuromodulatory centers via projections of the vagus nerve to the solitary tract nucleus. Currently, there is not an established large animal model that facilitates detailed mechanistic studies exploring how VNS impacts the function of the CNS, especially during complex behaviors requiring motor action and decision making.

Spatially selective stimulation of the pig vagus nerve to modulate target effect versus side effect.

Electrical stimulation of the cervical vagus nerve using implanted electrodes (VNS) is FDA-approved for the treatment of drug-resistant epilepsy, treatment-resistant depression, and most recently, chronic ischemic stroke rehabilitation. However, VNS is critically limited by the unwanted stimulation of nearby neck muscles-a result of non-specific stimulation activating motor nerve fibers within the vagus. Prior studies suggested that precise placement of small epineural electrodes can modify VNS therapeutic effects, such as cardiac responses.

Neural Correlates of Multisensory Integration for Feedback Stabilization of the Wrist.

Robust control of action relies on the ability to perceive, integrate, and act on information from multiple sensory modalities including vision and proprioception. How does the brain combine sensory information to regulate ongoing mechanical interactions between the body and its physical environment? Some behavioral studies suggest that the rules governing multisensory integration for action may differ from the maximum likelihood estimation rules that appear to govern multisensory integration for many perceptual tasks. We used functional magnetic resonance (MR) imaging techniques, a MR-compatible robot, and a multisensory feedback control task to test that hypothesis by investigating how neural mechanisms involved in regulating hand position against mechanical perturbation respond to the presence and fidelity of visual and proprioceptive information.

Visualization of Pig Vagus Nerve "Vagotopy" Using Ultrasound.

Placement of the clinical vagus nerve stimulating cuff is a standard surgical procedure based on anatomical landmarks, with limited patient specificity in terms of fascicular organization or vagal anatomy. As such, the therapeutic effects are generally limited by unwanted side effects of neck muscle contractions, demonstrated by previous studies to result from stimulation of (1) motor fibers near the cuff in the superior laryngeal and (2) motor fibers within the cuff projecting to the recurrent laryngeal. Conventional non-invasive ultrasound, where the transducer is placed on the surface of the skin, has been previously used to visualize the vagus with respect to other landmarks such as the carotid and internal jugular vein.

Improving the Selectivity of an Osseointegrated Neural Interface: Proof of Concept For Housing Sieve Electrode Arrays in the Medullary Canal of Long Bones.

Sieve electrodes stand poised to deliver the selectivity required for driving advanced prosthetics but are considered inherently invasive and lack the stability required for a chronic solution. This proof of concept experiment investigates the potential for the housing and engagement of a sieve electrode within the medullary canal as part of an osseointegrated neural interface (ONI) for greater selectivity toward improving prosthetic control. are that (A) the addition of a sieve interface to a cuff electrode housed within the medullary canal of the femur as part of an ONI would be capable of measuring efferent and afferent compound nerve action potentials (CNAPs) through a greater number of channels; (B) that signaling improves over time; and (C) that stimulation at this interface generates measurable cortical somatosensory evoked potentials through a greater number of channels.

Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve.

Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time.

Clinically-derived vagus nerve stimulation enhances cerebrospinal fluid penetrance.

Introduction: Vagus nerve stimulation (VNS) is an FDA-approved neuromodulatory treatment used in the clinic today for epilepsy, depression, and cluster headaches. Moreover, evidence in the literature has led to a growing list of possible clinical indications, with several small clinical trials applying VNS to treat conditions ranging from neurodegenerative diseases to arthritis, anxiety disorders, and obesity. Despite the growing list of therapeutic applications, the fundamental mechanisms by which VNS achieves its beneficial effects are poorly understood.

A system identification analysis of optogenetically evoked electrocorticography and cerebral blood flow responses.

Objective: The main objective of this research was to study the coupling between neural circuits and the vascular network in the cortex of small rodents from system engineering point of view and generate a mathematical model for the dynamics of neurovascular coupling. The model was adopted to implement closed-loop blood flow control algorithms.

Approach: We used a combination of advanced technologies including optogenetics, electrocorticography, and optical coherence tomography to stimulate selected populations of neurons and simultaneously record induced electrocorticography and hemodynamic signals.

Propagating Motor Cortical Dynamics Facilitate Movement Initiation.

Voluntary movement initiation involves the modulations of large groups of neurons in the primary motor cortex (M1). Yet similar modulations occur during movement planning when no movement occurs. Here, we show that a sequential spatiotemporal pattern of excitability propagates across M1 prior to the movement initiation in one of two oppositely oriented directions along the rostro-caudal axis.

Functional vagotopy in the cervical vagus nerve of the domestic pig: implications for the study of vagus nerve stimulation.

Objective: Given current clinical interest in vagus nerve stimulation (VNS), there are surprisingly few studies characterizing the anatomy of the vagus nerve in large animal models as it pertains to on-and off-target engagement of local fibers. We sought to address this gap by evaluating vagal anatomy in the pig, whose vagus nerve organization and size approximates the human vagus nerve.

Approach: Here we combined microdissection, histology, and immunohistochemistry to provide data on key features across the cervical vagus nerve in a swine model, and compare our results to other animal models (mouse, rat, dog, non-human primate) and humans.

Experimental Basis for Creating an Osseointegrated Neural Interface for Prosthetic Control: A Pilot Study in Rabbits.

Introduction: While debate persists over how to best prevent or treat amputation neuromas, the more pressing question of how to best marry residual nerves to state-of-the-art robotic prostheses for naturalistic control of a replacement limb has come to the fore. One potential solution involves the transposition of terminal nerve ends into the medullary canal of long bones, creating the neural interface within the bone. Nerve transposition into bone is a long-practiced, clinically relevant treatment for painful neuromas.

Cuff and sieve electrode (CASE): The combination of neural electrodes for bi-directional peripheral nerve interfacing.

Background: A number of peripheral nerve interfaces for nerve stimulation and recording exist for the purpose of controlling neural prostheses, each with a set of advantages and disadvantages. The ultimate goal of neural prostheses is a seamless bi-directional communication between the peripheral nervous system and the prosthesis. Here, we developed an interfacing electrode array, the "cuff and sieve electrodes" (CASE), integrating microfabricated cuff and sieve electrodes to a single unit, to decrease the weaknesses faced by these electrode designs in isolation.

Methodology for creating a chronic osseointegrated neural interface for prosthetic control in rabbits.

Background: Chronic stability and high degrees of selectivity are both essential but somewhat juxtaposed components for creating an implantable bi-directional PNI capable of controlling of a prosthetic limb. While the more invasive implantable electrode arrays provide greater specificity, they are less stable over time due to compliance mismatch with the dynamic soft tissue environment in which the interface is created.

New Method: This paper takes the surgical approach of transposing nerves into bone to create neural interface within the medullary canal of long bones, an osseointegrated neural interface, to provide greater stability for implantable electrodes.

An Injectable Neural Stimulation Electrode Made from an In-Body Curing Polymer/Metal Composite.

Implanted neural stimulation and recording devices hold vast potential to treat a variety of neurological conditions, but the invasiveness, complexity, and cost of the implantation procedure greatly reduce access to an otherwise promising therapeutic approach. To address this need, a novel electrode that begins as an uncured, flowable prepolymer that can be injected around a neuroanatomical target to minimize surgical manipulation is developed. Referred to as the Injectrode, the electrode conforms to target structures forming an electrically conductive interface which is orders of magnitude less stiff than conventional neuromodulation electrodes.

μECoG Recordings Through a Thinned Skull.

The studies described in this paper for the first time characterize the acute and chronic performance of optically transparent thin-film micro-electrocorticography (μECoG) grids implanted on a thinned skull as both an electrophysiological complement to existing thinned skull preparation for optical recordings/manipulations, and a less invasive alternative to epidural or subdurally placed μECoG arrays. In a longitudinal chronic study, μECoG grids placed on top of a thinned skull maintain impedances comparable to epidurally placed μECoG grids that are stable for periods of at least 1 month. Optogenetic activation of cortex is also reliably demonstrated through the optically transparent μECoG grids acutely placed on the thinned skull.

Flexible, multichannel cuff electrode for selective electrical stimulation of the mouse trigeminal nerve.

The trigeminal nerve (cranial nerve V), along with other cranial nerves, has in recent years become a popular target for bioelectric medicine due to its direct access to neuromodulatory centers. Trigeminal nerve stimulation is currently being evaluated as an adjunctive treatment for various neurodegenerative and neuropsychiatric diseases despite the mechanism of action being in question. In this work, we describe the development and validation of a novel neural interface for the infraorbital branch of the trigeminal nerve utilizing a thin film (TF) nerve cuff containing multiple electrode sites allowing for more selective stimulation of the nerve.

Strategies for interfacing with the trigeminal nerves in rodents for bioelectric medicine.

Background: Bioelectric medicine seeks to modulate neural activity via targeted electrical stimulation to treat disease. Recent clinical evidence supports trigeminal nerve stimulation as a bioelectric treatment for several neurological disorders; however, the mechanisms of trigeminal nerve stimulation and potential side effects remain largely unknown. The goal of this study is to optimize the methodology and reproducibility of neural interface implantation for mechanistic studies in rodents.