Associative diaschisis and skilled rehabilitation-induced behavioral recovery following focal ischemic infact

132 leaves : ill. ; 28 cm.The time course of peri-infarct diaschisis following a focal ischemic infarct and the effects of delayed rehabilitation on behavioral and functional recovery were examined. Intracortical microstimulation (ICMS) was used to derive topographical maps of forelimb representations within the rat motor cortex and ischemia was induced via bipolar coagulation of surface vasculature. At one hour there was a dramatic expansion of reprentations in control but not ischemic animals. A significant loss of forelimb representations within peri-infarct dysfunction indicates the need for immediate administration of therapeutic interventions following an ischemic event. These results indicate that the timing of rehabilitation does not effect functional and behavioral recovery but does support the need for rehabilitative interventions of facilitate these types of recovery

The cognitive neuroscience of prehension: recent developments

Prehension, the capacity to reach and grasp, is the key behavior that allows humans to change their environment. It continues to serve as a remarkable experimental test case for probing the cognitive architecture of goal-oriented action. This review focuses on recent experimental evidence that enhances or modifies how we might conceptualize the neural substrates of prehension. Emphasis is placed on studies that consider how precision grasps are selected and transformed into motor commands. Then, the mechanisms that extract action relevant information from vision and touch are considered. These include consideration of how parallel perceptual networks within parietal cortex, along with the ventral stream, are connected and share information to achieve common motor goals. On-line control of grasping action is discussed within a state estimation framework. The review ends with a consideration about how prehension fits within larger action repertoires that solve more complex goals and the possible cortical architectures needed to organize these actions

Investigating a combination therapy of robot-driven rehabilitation techniques with viral delivery of brain-derived neurotrophic factor in treating adult spinal cord injury

A complete spinal cord injury (SCI) disrupts the normal architecture of the central nervous system, resulting in severe and irreversible impairment of the healthy functions of the body. SCI physically interrupts the neural networks used to relay descending motor information from and ascending sensory information to supraspinal structures in the brain separating circuits in spinal cord from brain supervision and recruitment. Depending on the location of the injury, complete SCI can lead to paraplegia or quadriplegia. In the injured individual, the loss of autonomy and mobility can severely decrease quality of life, as well as negatively impact health outcomes. As a result, locomotor rehabilitation is an area of interest for research for its potential translational benefits in the clinic. In previous work in our lab studying the rat model for SCI, we have demonstrated the efficacy of robotic technology in the rehabilitation of adult rats transected as neonates (NTX), which are unique in their ability to produce autonomous stepping after complete SCI without intervention. Using robotic assistance at the pelvis in our trunk-based rehabilitation paradigm, we have significantly improved locomotor function in such animals. Viewing the NTX model, thus, as a signpost for what is possible in recovery when using our robot in animals that can step after SCI, we have also shown that our robot can be used to drive epidural stimulation (ES) in the rat transected as an adult (ATX) to promote stepping patterns and increase body weight support. Recently, the use of neurotrophins, such as brain-derived neurotrophic factor (BDNF) has been investigated as a means to induce stepping and locomotor behaviors in the ATX model to varying levels of success. We believe that there are potentially synergistic benefits to combining our robot rehabilitation techniques with the use of BDNF to rehabilitate ATX animals. This thesis addresses this idea in depth. We first investigated how BDNF and our robot-assisted treadmill training might interact in the ATX model. Next, we added robot-driven epidural stimulation to the treatment regimen to further understand how the therapies might interact in rehabilitation. Finally, to elucidate the mechanisms underlying locomotor recovery following injury, we used intracortical microstimulation (ICMS) to map the motor cortex of successfully rehabilitated animals. Our results suggest that BDNF and robot technologies can be combined successfully to provide robust stepping patterns, characterized by body weight support and plantar stepping in the ATX model for rats. Furthermore, we show that epidural stimulation can be used to mitigate pathological sequelae that come from BDNF use. Finally, our work shows how active stepping using BDNF and robot rehabilitation in the ATX model may induce significant reorganization of the trunk motor cortex, providing more clues to the relationship between the cortex and the spinal cord in motor control and muscle synergy development.Ph.D., Biomedical Engineering -- Drexel University, 201

A possible role for sPLA2 in oligodendrocyte death and spinal cord injury.

Spinal cord injury (SCI) can be divided into two distinct stages, an initial mechanical impact and a later secondary injury resulting from a cascade of cytokines triggering a spreading demyelination and apoptosis of neurons and glia within the spinal cord. It is believed that blockade of this secondary injury could improve functional and histological recovery following SCI. Here we propose that sPLA2 might be one of the crucial mediators of the secondary injury. To test this possibility we first elucidated that the mRNA and protein of several isozymes of sPLA2 are present in the rodent spinal cord and that the group II enzymes are upregulated following SCI with a peak expression at 4 hours. Next, we showed that injuring differentiated cultures of oligodendrocyte precursor cells with H2O2 or TNFa and IL-1ß induces sPLA2 expression and pharmacological inhibition with a sPLA2 inhibitor, S3319, creates partial reversal of this injury. We further showed that a nanogram injection of sPLA2 into the naÏve dorsolateral funiculus of the cervical spinal cord is sufficient to produce demyelination, axonopathy, and glial death as well as a dose dependent loss of function as measured by pellet retrieval. Finally we showed that inhibition of sPLA2 by either i.p. injections of S3319 or a frame shift mutation in the sPLA2-IIA gene creates functional improvements in overground locomotion and bladder function. The functional recovery correlates well with increased white matter sparing and oligodendrocyte numbers within in the spinal cord, increased axon numbers at the lesion epicenter, and decreased inflammation and lesion cavity volume. These findings suggest that sPLA2 may play an important role in secondary SCI and that its blockade could facilitate recovery following SCI

Parietal maps of visual signals for bodily action planning

The posterior parietal cortex (PPC) has long been understood as a high-level integrative station for computing motor commands for the body based on sensory (i.e., mostly tactile and visual) input from the outside world. In the last decade, accumulating evidence has shown that the parietal areas not only extract the pragmatic features of manipulable objects, but also subserve sensorimotor processing of others’ actions. A paradigmatic case is that of the anterior intraparietal area (AIP), which encodes the identity of observed manipulative actions that afford potential motor actions the observer could perform in response to them. On these bases, we propose an AIP manipulative action-based template of the general planning functions of the PPC and review existing evidence supporting the extension of this model to other PPC regions and to a wider set of actions: defensive and locomotor actions. In our model, a hallmark of PPC functioning is the processing of information about the physical and social world to encode potential bodily actions appropriate for the current context. We further extend the model to actions performed with man-made objects (e.g., tools) and artifacts, because they become integral parts of the subject’s body schema and motor repertoire. Finally, we conclude that existing evidence supports a generally conserved neural circuitry that transforms integrated sensory signals into the variety of bodily actions that primates are capable of preparing and performing to interact with their physical and social world

Development of Low-Frequency Repetitive Transcranial Magnetic Stimulation as a Tool to Modulate Visual Disorders: Insights from Neuroimaging

Repetitive transcranial magnetic stimulation (rTMS) has become a popular neuromodulation technique, increasingly employed to manage several neurological and psychological conditions. Despite its popular use, the underlying mechanisms of rTMS remain largely unknown, particularly at the visual cortex. Moreover, the application of rTMS to modulate visual-related disorders is under-investigated. The goal of the present research was to address these issues. I employ a multitude of neuroimaging techniques to gain further insight into neural mechanisms underlying low-frequency (1 Hz) rTMS to the visual cortex. In addition, I begin to develop and refine clinical low-frequency rTMS protocols applicable to visual disorders as an alternative therapy where other treatment options are unsuccessful or where there are simply no existing therapies. One such visual disorder that can benefit from rTMS treatment is the perception of visual hallucinations that can occur following visual pathway damage in otherwise cognitively healthy individuals. In Chapters 23, I investigate the potential of multiday low-frequency rTMS to the visual cortex to alleviate continuous and disruptive visual hallucinations consequent to occipital injury. Combining rTMS with magnetic resonance imaging techniques reveals functional and structural cortical changes that lead to the perception of visual hallucinations; and rTMS successfully attenuates these anomalous visual perceptions. In Chapters 45, I compare the effects of alternative doses of low-frequency rTMS to the visual cortex on neurotransmitter levels and intrinsic functional connectivity to gain insight into rTMS mechanisms and establish the most effective protocol. Differential dose-dependent effects are observed on neurotransmitter levels and functional connectivity that suggest the choice of protocol critically depends on the neurophysiological target. Collectively, this work provides a basic framework for the use of low-frequency rTMS and neuroimaging in clinical application for visual disorders

Cortical and Subcortical Mechanisms of Pleasure and Motivation.

So far, investigations into the neural basis of affect have revealed discrete, anatomically localized sites called hedonic “hotspots” in nucleus accumbens (NAc) and ventral pallidum (VP) that are able to modulate the hedonic impact of a reward. Here, I further examined the localization and neurochemical specificity of the hotspots, as well as explored new potential sites of interest to more clearly establish a hedonic circuit. In Chapter 2, I focused on the NAc hotspot, testing the effects of mu, delta, or kappa opioid receptor stimulation on hedonic and motivated behaviors. I found that while all three opioid receptor subtypes could reliably enhance hedonic ‘liking’ in the hotspot, they all had unique effects on motivated food intake. In Chapter 3, I extended the neurochemical investigation to include orexin and acetylcholine systems within NAc. I found that like the opioids, orexin stimulations only enhanced hedonic impact in the rostral hotspot, but enhanced food intake throughout shell. By contrast, blockade of acetylcholine muscarinic receptors caused a broad shift toward ‘disgust’, reducing appetitive behaviors and enhancing aversive ones. In Chapter 4, I sought to determine whether any cortical sites were capable of modulating hedonic impact or motivation, especially orbitofrontal cortex (OFC) and insula. I found that both of these areas contained localized hedonic hotspots that were sensitive to mu or orexin stimulations. The OFC hotspot was localized to the rostral 2/3 of OFC, and the insula hotspot was localized to the far caudal 1/3. I also found a single large hedonic coldspot that started in caudolateral OFC and extended into anterior and mid insula. Lastly, in Chapter 4, I found that selectively stimulation of lateral hypothalamic inputs into the VP hotspot could enhance hedonic ‘liking’ reactions to sucrose, as well as intake of palatable M&Ms. By contrast, local VP stimulation only increased hedonic ‘liking’ reactions, and local LH stimulation only increased food intake. Collectively, these experiments expand the neurochemical repertoire of the hotspots, as well as expand the hedonic circuit to include cortical and hypothalamic mechanisms for generating affect, carrying important implications for the treatment of affective disorders like depression or bipolar.PhDPsychologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/133381/1/castrod_1.pd

Activation of the pro-resolving receptor Fpr2 attenuates inflammatory microglial activation

Poster number: P-T099 Theme: Neurodegenerative disorders & ageing Activation of the pro-resolving receptor Fpr2 reverses inflammatory microglial activation Authors: Edward S Wickstead - Life Science & Technology University of Westminster/Queen Mary University of London Inflammation is a major contributor to many neurodegenerative disease (Heneka et al. 2015). Microglia, as the resident immune cells of the brain and spinal cord, provide the first line of immunological defence, but can become deleterious when chronically activated, triggering extensive neuronal damage (Cunningham, 2013). Dampening or even reversing this activation may provide neuronal protection against chronic inflammatory damage. The aim of this study was to determine whether lipopolysaccharide (LPS)-induced inflammation could be abrogated through activation of the receptor Fpr2, known to play an important role in peripheral inflammatory resolution. Immortalised murine microglia (BV2 cell line) were stimulated with LPS (50ng/ml) for 1 hour prior to the treatment with one of two Fpr2 ligands, either Cpd43 or Quin-C1 (both 100nM), and production of nitric oxide (NO), tumour necrosis factor alpha (TNFα) and interleukin-10 (IL-10) were monitored after 24h and 48h. Treatment with either Fpr2 ligand significantly suppressed LPS-induced production of NO or TNFα after both 24h and 48h exposure, moreover Fpr2 ligand treatment significantly enhanced production of IL-10 48h post-LPS treatment. As we have previously shown Fpr2 to be coupled to a number of intracellular signaling pathways (Cooray et al. 2013), we investigated potential signaling responses. Western blot analysis revealed no activation of ERK1/2, but identified a rapid and potent activation of p38 MAP kinase in BV2 microglia following stimulation with Fpr2 ligands. Together, these data indicate the possibility of exploiting immunomodulatory strategies for the treatment of neurological diseases, and highlight in particular the important potential of resolution mechanisms as novel therapeutic targets in neuroinflammation. References Cooray SN et al. (2013). Proc Natl Acad Sci U S A 110: 18232-7. Cunningham C (2013). Glia 61: 71-90. Heneka MT et al. (2015). Lancet Neurol 14: 388-40

Neuroplasticity of Ipsilateral Cortical Motor Representations, Training Effects and Role in Stroke Recovery

This thesis examines the contribution of the ipsilateral hemisphere to motor control with the aim of evaluating the potential of the contralesional hemisphere to contribute to motor recovery after stroke. Predictive algorithms based on neurobiological principles emphasize integrity of the ipsilesional corticospinal tract as the strongest prognostic indicator of good motor recovery. In contrast, extensive lesions placing reliance on alternative contralesional ipsilateral motor pathways are associated with poor recovery. Within the predictive algorithms are elements of motor control that rely on contributions from ipsilateral motor pathways, suggesting that balanced, parallel contralesional contributions can be beneficial. Current therapeutic approaches have focussed on the maladaptive potential of the contralesional hemisphere and sought to inhibit its activity with neuromodulation. Using Transcranial Magnetic Stimulation I seek examples of beneficial plasticity in ipsilateral cortical motor representations of expert performers, who have accumulated vast amounts of deliberate practise training skilled bilateral activation of muscles habitually under ipsilateral control. I demonstrate that ipsilateral cortical motor representations reorganize in response to training to acquisition of skilled motor performance. Features of this reorganization are compatible with evidence suggesting ipsilateral importance in synergy representations, controlled through corticoreticulopropriospinal pathways. I demonstrate that ipsilateral plasticity can associate positively with motor recovery after stroke. Features of plastic change in ipsilateral cortical representations are shown in response to robotic training of chronic stroke patients. These findings have implications for the individualization of motor rehabilitation after stroke, and prompt reappraisal of the approach to therapeutic intervention in the chronic phase of stroke