Evaluating the impact of intracortical microstimulation on distant cortical brain regions for neuroprosthetic applications

Enhancing functional motor recovery after localized brain injury is a widely recognized priority in healthcare as disorders of the nervous system that cause motor impairment, such as stroke, are among the most common causes of adult-onset disability. Restoring physiological function in a dysfunctional brain to improve quality of life is a primary challenge in scientific and clinical research and could be driven by innovative therapeutic approaches. Recently, techniques using brain stimulation methodologies have been employed to promote post-injury neuroplasticity for the restitution of motor function. One type of closed-loop stimulation, i.e., activity-dependent stimulation (ADS), has been shown to modify existing functional connectivity within either healthy or injured cerebral cortices and used to increase behavioral recovery following cortical injury. The aim of this PhD thesis is to characterize the electrophysiological correlates of such behavioral recovery in both healthy and injured cortical networks using in vivo animal models. We tested the ability of two different intracortical micro-stimulation protocols, i.e., ADS and its randomized open-loop version (RS), to potentiate cortico-cortical connections between two distant cortical locations in both anaesthetized and awake behaving rats. Thus, this dissertation has the following three main goals: 1) to investigate the ability of ADS to induce changes in intra-cortical activity in healthy anesthetized rats, 2) to characterize the electrophysiological signs of brain injury and evaluate the capability of ADS to promote electrophysiological changes in the damaged network, and 3) to investigate the long-term effects of stimulation by repeating the treatment for 21 consecutive days in healthy awake behaving animals. The results of this study indicate that closed-loop activity-dependent stimulation induced greater changes than open-loop random stimulation, further strengthening the idea that Hebbian-inspired protocols might potentiate cortico-cortical connections between distant brain areas. The implications of these results have the potential to lead to novel treatments for various neurological diseases and disorders and inspire new neurorehabilitation therapies

Activity-driven formation and stabilization of functional spine synapses

Physical changes in neuronal connections, dictated by the neuronal network activity, are believed to be essential for learning and memory. Long-term potentiation (LTP) of synaptic transmission has emerged as a model to study activity-driven plasticity. The majority of excitatory contacts between neurons, called synapses, are found on spines, small dendritic protrusions. LTP is known to trigger the formation and stabilization of new dendritic spines in vitro. Similarly, experience-dependent plasticity in vivo is associated with changes in the number and stability of spines. However, to date, the contribution of excitatory synaptogenesis to the enhanced synaptic transmission after LTP remains elusive. Do new spines form functional synapses with the inputs stimulated during LTP induction and thereby follow Hebbian co-activation rules, or do they connect with random partners? Furthermore, at which time-point are de novo spines functionally integrated into the network? I developed an optical approach to stably and exclusively stimulate the axons of a defined channelrhodopsin-2 (ChR2)-transduced subset of CA3 cell in mature hippocampal slice culture over extended periods of time (up to 24h). I continuously monitored synaptic activation and synaptic structure of CA1 cells dendrites using two-photon imaging. To control the dendritic location where LTP and associated spinogenesis were allowed to take place, I globally blocked Na+-dependent action potential firing and directly evoke neurotransmitter release by local light-evoked depolarization of ChR2-expressing presynaptic boutons (in TTX, 4-AP). I induced optical LTP specifically at this location by combining optogenetic activation with chemical pairing (in low [Mg2+]o, high [Ca2+]o, forskolin, and rolipram). Taking advantage of the NMDA-receptor mediated calcium influx during synaptic activation I assessed the formation of functional synapses using the genetically encoded calcium indicator GCaMP6s. I find that optical LTP led to the generation of new spines, decreased the stability of preexisting spines and increased the stability of new spines. Under optical LTP conditions, a fraction of new spines responded to optical presynaptic stimulation within hours after formation. However, the occurrence of the first synaptic calcium response in de novo spines varied considerably, ranging from 8.5 min to 25 h. Most new spines became responsive within 4 h (1.2 ± 0.9 h, mean ± S.D., n = 16 out of 20), whereas the remainder showed their first response only on the second experimental day (18.2 ± 3.7 h). Importantly, new spines generated under optical LTP were more likely to build functional synapses with light-activated, ChR2-expressing axons than spontaneously formed spines (new responsive spines under optical LTP: 64 ± 4 %; control 1: 0%; control 2: 13 ± 4 %; control 3: 11 ± 4 %). Furthermore, new spines that were responsive to optical presynaptic stimulation were less prone to be eliminated after overnight incubation than new spines that failed to respond (% overnight spine survival; 81 ± 3 % new responsive spines; 58 ± 4 % of new unresponsive spines). In summary, the results from my thesis demonstrate that synapses can form rapidly in an input-specific manner

IFCN-endorsed practical guidelines for clinical magnetoencephalography (MEG)

Magnetoencephalography (MEG) records weak magnetic fields outside the human head and thereby provides millisecond-accurate information about neuronal currents supporting human brain function. MEG and electroencephalography (EEG) are closely related complementary methods and should be interpreted together whenever possible. This manuscript covers the basic physical and physiological principles of MEG and discusses the main aspects of state-of-the-art MEG data analysis. We provide guidelines for best practices of patient preparation, stimulus presentation, MEG data collection and analysis, as well as for MEG interpretation in routine clinical examinations. In 2017, about 200 whole-scalp MEG devices were in operation worldwide, many of them located in clinical environments. Yet, the established clinical indications for MEG examinations remain few, mainly restricted to the diagnostics of epilepsy and to preoperative functional evaluation of neurosurgical patients. We are confident that the extensive ongoing basic MEG research indicates potential for the evaluation of neurological and psychiatric syndromes, developmental disorders, and the integrity of cortical brain networks after stroke. Basic and clinical research is, thus, paving way for new clinical applications to be identified by an increasing number of practitioners of MEG. (C) 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V.Peer reviewe

Applications of EMG in Clinical and Sports Medicine

This second of two volumes on EMG (Electromyography) covers a wide range of clinical applications, as a complement to the methods discussed in volume 1. Topics range from gait and vibration analysis, through posture and falls prevention, to biofeedback in the treatment of neurologic swallowing impairment. The volume includes sections on back care, sports and performance medicine, gynecology/urology and orofacial function. Authors describe the procedures for their experimental studies with detailed and clear illustrations and references to the literature. The limitations of SEMG measures and methods for careful analysis are discussed. This broad compilation of articles discussing the use of EMG in both clinical and research applications demonstrates the utility of the method as a tool in a wide variety of disciplines and clinical fields

Closed-loop approaches for innovative neuroprostheses

The goal of this thesis is to study new ways to interact with the nervous system in case of damage or pathology. In particular, I focused my effort towards the development of innovative, closed-loop stimulation protocols in various scenarios: in vitro, ex vivo, in vivo

Optical-Electrode: The Next Generation Brain-Machine Interface

Brain machine interfaces, or brain computer interfaces, are attracting ever increasing research interests for their promising application prospects. A number of methods and devices were proposed on this topic, but all have inherent limits particularly concerning spatial density and signal resolution. An optical-electrode is hereby proposed to overcome these limitations by transducing the electrical signal into an optical signal using liquid crystal cells. In addition, photovoltaic stimulation capabilities were added to form an integrated bidirectional interface. A recording subsystem and a stimulating subsystem were proposed for driving the sensing and stimulation parts respectively, and their benchtop characterisations were carried out. Noise performances in the recording subsystem were analysed and optimised. To provide initial validation, animal studies were conducted on rabbit sciatic nerves (in vivo and ex vivo) and on cardiac tissues (ex vivo). The recorded signals and stimulated responses were compared with those made by commonly used traditional electrical systems under the same experimental conditions. Compound action potentials, although showing differences on delays and morphology over traditional methods, were successfully recorded and evoked. The charge balance ability was also demonstrated in the experiments. Finally, a 'zero mode' photodetector is introduced, which is specifically suitable for the recording subsystem and can potentially improve the noise performance. The works in this thesis will contribute to the next iteration of the technology, i.e. help the creation of high density arrays in the form of integrated chips

Southwest Research Institute assistance to NASA in biomedical areas of the technology

Significant applications of aerospace technology were achieved. These applications include: a miniaturized, noninvasive system to telemeter electrocardiographic signals of heart transplant patients during their recuperative period as graded situations are introduced; and economical vital signs monitor for use in nursing homes and rehabilitation hospitals to indicate the onset of respiratory arrest; an implantable telemetry system to indicate the onset of the rejection phenomenon in animals undergoing cardiac transplants; an exceptionally accurate current proportional temperature controller for pollution studies; an automatic, atraumatic blood pressure measurement device; materials for protecting burned areas in contact with joint bender splints; a detector to signal the passage of animals by a given point during ecology studies; and special cushioning for use with below-knee amputees to protect the integrity of the skin at the stump/prosthesis interface

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 127, April 1974

This special bibliography lists 279 reports, articles, and other documents introduced into the NASA scientific and technical information system in March 1974