BACKGROUND: A spinal cord injury (SCI) often results from a traumatic fracture or dislocation of the vertebral structures causing the spinal cord or surrounding nerves to become bruised, crushed or severed. Spinal cord injuries can leave an individual with a range of deficits from nerve impingement to life-threatening complete paralysis. There are hundreds of thousands of Americans living every day with various forms paralysis. Although advancements in acute care and rehabilitative medicine have transpired, individuals with chronic SCIs combat a number of secondary health complications and frequently encounter premature death. LITERATURE REVIEW FINDINGS: The neurologic dysfunction that ensues causes a vast number of secondary health complications including skin breakdown, osteoporosis, diabetes mellitus, dyslipidemia, blood pressure dysfunction, cardiovascular disease and frequently premature death. This comprehensive literature review focuses on these secondary health consequences of chronic spinal cord injuries. Current evidence has presented healthcare providers with guidelines to identify and manage health consequences in the general population. There is a lack of acknowledgement to the SCI population within these guidelines, yet, this subset of patients is, on average, found to have higher rates of osteoporotic fractures, infections, diabetes, dyslipidemia, cardiovascular events and depression due to their sedentary lifestyles. PROPOSED METHODS: The proposed hypothesis of this study states that Primary Healthcare providers will appropriately identify risk factors for secondary illness and proactively manage long-term care for patients with spinal cord injuries after completing CME training. CME seminars will be available for primary healthcare providers to attend at national AAFP, AAPA and AANP conferences. CONCLUSIONS: A SCI can be one of the most life altering experiences as one’s physical, social and psychological welfare are challenged. Beyond these discernible obstacles, lies a life of adverse health consequences linked with significantly reduced lifespans. By educating Physicians, Physician Assistants and Nurse Practitioners about health consequences in the chronic SCI population the care will become centralized and patient-provider relationships will be strengthened. CLINICAL SIGNIFICANCE: In the current medical model, there is a lack of provider education regarding SCI health consequences and subsequently care becomes fragmented to many different subspecialty providers. Educating the primary healthcare providers creates awareness and supports the need for further research in the field of chronic SCI.

BACKGROUND: Multiple System Atrophy –Parkinsonian Type (MSA-P) is a rare, rapidly progressive neurodegenerative disease without any current treatment. Recent research has increased the understanding of brain iron accumulation and its association with neurodegenerative synucleinopathies, like MSA-P. Because of this improved understanding of the disease process, there is potential for new therapies that could benefit patients with MSA-P. Unfortunately, many attempts at finding a new and effective treatments for MSA-P have been unsuccessful. Two drugs that have shown potential in neurodegenerative synucleinopathies associated with brain iron accumulation are iron chelators (Deferiprone) and tyrosine kinase inhibitors (Nilotinib.) METHODS: The proposed study is a multicenter, double blind, randomized control study of Nilotinib and Deferiprone for the treatment of MSA-P. There will be two treatment arms; Nilotinib and a placebo group vs. Nilotinib and Deferiprone. There will be a 24 week treatment phase, followed by a 24 week wash-out phase. All patients will have a baseline evaluation including: a full neurological exam with rating scales (UMSARS, UPDRS, SCOPA, and MOCA) to assess motor and non-motor symptoms of MSA-P. Lab and imaging data will include CBC, CMP, serum iron panel, CSF iron panel and brain SWI-MR scans. Neurological exams and rating scales will be assessed every four weeks while imaging and laboratory data will be assessed at baseline (week 0) at the end of the intervention phase (week 24) and at the end of the follow-up phase (week 48). CONCLUSIONS: Deferiprone and Nilotinib when used together will have a synergistic impact on the symptoms of MSA-P and will be more effective when used together versus when they are used individually. SIGNIFICANCE: Patients with MSA-P have shortened life expectancy as well as severely diminished quality of life due to rapidly progressive neurodegeneration. This trial aims to implementing evidence based treatment for MSA-P that could potentially improve life expectancy as well as quality of life in this patient population.

Cognitive function involves the interplay of functionally-separate regions of the human brain. Of critical importance to neuroscience research is to accurately measure the activity and communication between these regions. The MEG imaging modality is well-suited to capturing functional cortical communication due to its high temporal resolution, on the millisecond scale. However, localizing the sources of cortical activity from the sensor measurements is an ill-posed problem, where different solutions trade-off between spatial accuracy, correcting for linear mixing of cortical signals, and computation time. Linear mixing, in particular, affects the reliability of many connectivity measures. We present a MATLAB-based pipeline that we developed to correct for linear mixing and compute time-varying connectivity (phase synchrony, Granger Causality) between cortically-defined regions interfacing with established toolboxes for MEG data processing (Minimum Norm Estimation Toolbox, Brainstorm, Fieldtrip). In Chapter 1, we present a new method for localizing cortical activation while controlling cross-talk on the cortex. In Chapter 2, we apply a nonparametric statistical test for measuring phase locking in the presence of cross-talk. Chapters 3 and 4 describe the application of the pipeline to MEG data collected from subjects performing a visual object motion detection task. Chapter 5 focuses on real-time MEG (rt-MEG) neurofeedback which is the real-time measurement of brain activity and its self-regulation through feedback. Typically neurofeedback modulates directly brain activation for the purpose of training sensory, motor, emotional or cognitive functions. Direct measures, however, are not suited to training dynamic measures of brain activity, such as the speed of switching between tasks, for example. We developed a novel rt-MEG neurofeedback method called state-based neurofeedback, where brain activity states related to subject behavior are decoded in real-time from the MEG sensor measurements. The timing related to maintaining or transitioning between decoded states is then presented as feedback to the subject. In a group of healthy subjects we applied the state-based neurofeedback method for training the time required for switching spatial attention from one side of the visual field to the other (e.g. left side to right side) following a brief presentation of a visual cue. In Chapter 6, we used our pipeline to investigate training-related changes in cortical activation and network connectivity in each subject. Our results suggested that the rt-MEG neurofeedback training resulted in strengthened beta-band connectivity prior to the switch of spatial attention, and strengthened gamma-band connectivity during the switch. There were two goals of this dissertation: First was the development of the MATLAB-based pipeline for computing time-evolving functional connectivity analysis in MEG and its application to visual motion perception. The second goal was the development of a real-time MEG neurofeedback method to train the dynamics of brain states and its application to a group of healthy subjects. / 2019-11-02T00:00:00Z

Despite evidence linking the serotoninergic (5-HT) dorsal raphe nucleus (DRN) with the regulation of sleep-wake states, lesions of serotoninergic DRN neurons in rats minimally alter sleep-wake cycle. The lesion studies are however difficult to interpret given possible compensation mechanisms, lack of specificity of the toxins to induce the lesion, and incomplete cell loss. The DRN is heterogeneous and contains 5-HT, dopaminergic, GABAergic, and glutamatergic neurons. Thus, cell-type specific approaches are needed to define the individual contribution of DRN cell populations, including serotoninergic DRN neurons, to sleep-wake cycle control. Here we employed a conditional chemogenetic approach to selectively and acutely activate serotoninergic DRN neurons and analyzed behavioral and electrographic outcomes. Male serotonin reuptake transporter (SERT)-Cre driver mice were stereotaxically injected with a Cre-dependent adeno-associated viral (AAV) vector expressing an excitatory chemogenetic system (AAV-FLEX-hM3Dq-mCherry) into the DRN. The mice were then surgically implanted with EEG/EMG recording electrodes to monitor sleep-wake cycle. Injections of the hM3Dq ligand, clozapine-N-oxide (CNO; 0.3mg/kg, i.p.) were given at 9:00am (a time of high sleep pressure in the nocturnal mouse) and 6:00pm (a time of low sleep pressure in the mouse). Changes in behavioral state were determined from EEG/EMG and behavioral analysis from video monitoring. Eutopic expression of Cre and hM3Dq in the SERT-Cre mouse was confirmed using standard histological techniques. Administration of CNO at 9:00am produced a significant increase in NREM sleep during the first post injection hour and a significant reduction in latency to sleep. In addition, we report no statistically significant reduction in anxiety following acute and selective activation of serotoninergic DRN neurons in two anxiety-related behavioral tests, the open field and the elevated plus maze. While these results suggest that activation of serotoninergic neurons in the DRN may not produce anxiolytic effects, further studies will be required to confirm this. / 2019-07-03T00:00:00Z

It is well established that physical exercise and cardiovascular fitness are beneficial for brain health. Cardiovascular fitness can attenuate both the neurobiological and cognitive consequences of age-related declines. Epidemiological studies provided converging evidence that exercise has a positive effect on mental health in individuals suffering from neurological disorders, and can reduce the risk for developing Mild Cognitive Impairment (MCI) and Alzheimer’s disease (AD). Although there is a large amount of evidence from animal research suggesting a relationship between aerobic exercise and medial temporal lobe neuroplasticity, the majority of human literature that studied the effect of exercise on cognition have focused on executive control, attention networks along with other prefrontal and posterior parietal -mediated cognitive functions, but not on hippocampus mediated memory function. In a cross-sectional study using established behavioral tasks known to recruit the hippocampus and entorhinal cortex (EC) and structural MRI in healthy older adults, we tested the hypothesis that (1) aerobic fitness levels are positively associated with hippocampus dependent memory task performance. (2) aerobic fitness levels are positively associated with the structure of the hippocampus and EC. (3) the volume of hippocampus and thickness of EC are associated with behavioral tasks performance. In addition, we examined the relationship of aerobic fitness with brain regions known to show cortical thinning that predict AD dementia. Healthy older adult (age 55-85 years) underwent a standard graded submaximal treadmill test to determine cardio-respiratory fitness (Modified-Balke protocol, VO2max). Freesurfer MRI analytic software was used to calculate cortical thickness and volume of T1-weighted MR images. Greater aerobic fitness was associated with greater volumes in the left and right hippocampus before controlling for multiple comparisons but not with EC thickness. Aerobic fitness did not correlate with behavioral task performance. Furthermore, there was a significant negative correlation between fitness level and right supramarginal gyrus, a brain area known to show cortical thinning in AD. Our results indicate that higher fitness level is positively associated with hippocampal volume and may be protective against loss of hippocampal volume with aging. These data extend prior work on the cerebral effects of aerobic exercise and fitness to the medial temporal lobe in healthy older adults thus providing compelling evidence for a relationship between aerobic fitness and structure of the medial temporal lobe memory system. Future studies are needed to examine causal relationships between these variables.

Damage to the orbitofrontal cortex (OFC) is often accompanied by disorders in personality, mood and social behavior. The purpose of this thesis was to study the cellular composition and architecture of this very complex and functionally important area. The posterior part of the OFC (pOFC) has the most multimodal circuits of the OFC and robust connections with the amygdala, a key center of the brain for emotions. Moreover, because cortico-cortical connections can be predicted on the basis of architectonic features, analyzing the cytoarchitecture of this area is important in order to understand its connections and functions. Previous descriptions show that the architecture throughout the OFC varies along two major gradients of laminar differentiation. These gradients show that the size of layer IV decreases medially and posteriorly and that the most medial and posterior areas lack layer IV and are agranular. In this study we analyzed the transitional dysgranular cortex, which has a narrow layer IV, and lies between the anterior granular cortices, with well-developed layer IV, and the posterior agranular areas. For that purpose, three regions of interest (ROIs) along the mediolateral axis of the transitional pOFC were delineated: lateral, central, and medial. We used unbiased systematic sampling in our ROIs to estimate the densities of neurons, astrocytes, oligodendrocytes and microglia. We also estimated the densities of three classes of inhibitory neurons that are identified by the expression of calcium-binding proteins (calretinin, parvalbumin, and calbindin). We also found that neurons labeled for calretinin are the most common inhibitory neuron class. The density of calretinin labeled neurons in the transitional dysgranular part of pOFC also increases from medial to lateral at a comparable rate to the entire population of neurons. Parvalbumin and calbindin neuron densities also increase from medial to lateral, but the difference is less pronounced. Our findings show that, despite the density gradient from medial to lateral, the proportion of CR, PV, and CB neurons is comparable across the three ROIs. This shows that there is a balance of excitation and inhibition along the transitional dysgranular part of the pOFC, which is functionally important because it has been shown to be affected in disorders like autism.

Optical interrogation and manipulation of neural dynamics is a cornerstone of systems neuroscience. Genetic targeting enable delivering fluorescent indicators and opsins to specific neural subpopulations. Optic probes can fluorescently sense and convey calcium, voltage, and neurotransmitter dynamics. This optical toolkit enables recording and perturbing cellular-resolution activity in thousands of neurons across a field of view. Yet these techniques are limited by the light scattering properties of tissues. The cutting edge of microscopy, three-photon imaging, can record from intact tissues at depths up to 1 mm, but requires head-fixed experimental paradigms. To access deeper layers and non-cortical structures, researchers rely on optical implants, such as GRIN lenses or prisms, or the removal of superficial tissue. In this thesis, we introduce a novel implant for interfacing with deep brain regions constructed from bundles of hundreds or thousands of dissociated, small diameter (<8 µm) optical fibers. During insertion into the tissue, the fibers move independently, splaying through the target region. Each fiber achieves near total internal reflection, acting as a bidirectional optical interface with a small region of tissue near the fiber aperture. The small diameter and flexibility of the fibers minimize tissue response, preserving local connectivity and circuit dynamics. Histology and immunohistochemistry from implants into zebra finch basal ganglia (depth 2.9 mm) show the splaying of the fibers and the presence of NeuN-stained cells in close proximity to the fiber tips. By modeling the optical properties of the fibers and tissue, we simulate the interface properties of a bundle of fibers. Overlap in the sensitivity between nearby fibers allows application of blind source separation to extract individual neural traces. We describe a nonnegative independent component analysis algorithm especially suited to the interface. Finally, experimental data from implants in transgenic mice yield proof of principle recordings during both cortical spreading depolarization and forepaw stimulation. Collectively, the data presented here paint a compelling picture of splaying microfibers as a deep brain interface capable of sampling or perturbing neural activity at hundreds or thousands of points throughout a 3D volume of tissue while eliciting less response than existing optical implants.

<p> The etiology of Alzheimer&rsquo;s disease involves the presymptomatic development and progression of amyloid-&beta; and tau in healthy aging. Amyloid-&beta; and tau are naturally occurring proteins that can form abnormal aggregates&mdash;amyloid-&beta; plaques and neurofibrillary tangles&mdash;which constitute the pathological hallmarks of Alzheimer&rsquo;s disease. The initial formation of these aggregates occurs decades before the onset of cognitive symptoms, in individuals otherwise considered to be healthy and unimpaired. This dissertation hinges on <i> in-vivo</i> PET imaging of amyloid-&beta; and tau in humans using PIB-PET and AV1451-PET to explore this presymptomatic phase of Alzheimer&rsquo;s disease&mdash;when pathology is present without detectable symptoms. I place particular emphasis on amyloid-&beta; pathology&mdash;understanding the factors that underlie vulnerability to amyloid-&beta; as well as identifying the initial sources and progressive spread of amyloid-&beta; pathology in healthy aging. My focus on amyloid-&beta; is consistent with the predominant framework for Alzheimer&rsquo;s disease, the amyloid cascade hypothesis, which contends that amyloid-&beta; initiates a slow and ultimately deadly chain of events that results, decades later, in deteriorating memory and breakdown of cognition. In recognition that Alzheimer&rsquo;s disease does not reflect a focal disorder, but rather network failure of large-scale brain systems, I adapt a network-based framework to account for the role of the complex interdependencies between distributed brain regions&mdash;of glucose metabolism from FDG-PET, of brain activity from resting-state functional MRI, and of amyloid-&beta; from PIB-PET. Examining metabolic brain networks, I reveal widespread, highly systematic reorganization of glucose metabolism in old age&mdash;well beyond what has been revealed using other methods&mdash;that is more heterogeneous in those possessing both substantial amyloid-&beta; and genetic risk for Alzheimer&rsquo;s disease. Further, I demonstrate that the topology of early-life &ldquo;metabolic inefficiency&rdquo;&mdash;a novel metric that removes the potential association of glucose metabolism with highly connected hubs&mdash;explains the topology of amyloid-&beta; in healthy aging. Finally, I provide evidence that very early amyloid-&beta; accumulation, in those without substantial amyloid-&beta; pathology, is multifocal and broadly distributed across brain networks&mdash;consistent with shared tissue vulnerability, not transneuronal spread, being the driving force of accumulation of amyloid-&beta; pathology. These findings support the notion that shared tissue vulnerability of a metabolic origin drives widespread, systematic accumulation of amyloid-&beta; in healthy aging. Future work should uncover the nature and origin of metabolic tissue vulnerability to amyloid-&beta;, exploring the complex chain of events that drive widespread age-related reorganization&mdash;especially of cerebral glucose metabolism&mdash;and its links other age-related changes and the onset of pathological accumulation of amyloid-&beta;.</p><p>

<p> Current understanding within the field of neuroscience regarding why the brain requires significant periods of sleep rests upon the existence of extremely stereotypical patterns of oscillatory neural activity found in almost all mammals. Within these characteristic patterns of wide-scale neural activity occurs crossregional synchronization of oscillations of various frequencies and this coupling is fundamental to the process of memory consolidation. Specifically, high-frequency oscillations, or ripples, in the hippocampal formation are required for the conversion of short-term to long-term memory. These ripples couple to two slower oscillations found in the cortex, delta waves and spindles. The author describes here his contributions to the field of memory consolidation showing that hippocampal ripples in aged rats are of decreased frequency during sleep but not during wake. In addition, it is well documented that with age, behavioral and neural sleep parameters decrease while the incidence of neurodegenerative diseases increases. The author will discuss unpublished findings of behavioral sleep disturbances and changes in cortical sleep oscillations preceding motor impairment in a LRRK2 mouse model of Parkinson&rsquo;s disease (PD), and explore herein putative links between age-related changes in neural oscillations and the predilection towards neurodegeneration.</p><p>

abstract: Audiovisual (AV) integration is a fundamental component of face-to-face communication. Visual cues generally aid auditory comprehension of communicative intent through our innate ability to “fuse” auditory and visual information. However, our ability for multisensory integration can be affected by damage to the brain. Previous neuroimaging studies have indicated the superior temporal sulcus (STS) as the center for AV integration, while others suggest inferior frontal and motor regions. However, few studies have analyzed the effect of stroke or other brain damage on multisensory integration in humans. The present study examines the effect of lesion location on auditory and AV speech perception through behavioral and structural imaging methodologies in 41 left-hemisphere participants with chronic focal cerebral damage. Participants completed two behavioral tasks of speech perception: an auditory speech perception task and a classic McGurk paradigm measuring congruent (auditory and visual stimuli match) and incongruent (auditory and visual stimuli do not match, creating a “fused” percept of a novel stimulus) AV speech perception. Overall, participants performed well above chance on both tasks. Voxel-based lesion symptom mapping (VLSM) across all 41 participants identified several regions as critical for speech perception depending on trial type. Heschl’s gyrus and the supramarginal gyrus were identified as critical for auditory speech perception, the basal ganglia was critical for speech perception in AV congruent trials, and the middle temporal gyrus/STS were critical in AV incongruent trials. VLSM analyses of the AV incongruent trials were used to further clarify the origin of “errors”, i.e. lack of fusion. Auditory capture (auditory stimulus) responses were attributed to visual processing deficits caused by lesions in the posterior temporal lobe, whereas visual capture (visual stimulus) responses were attributed to lesions in the anterior temporal cortex, including the temporal pole, which is widely considered to be an amodal semantic hub. The implication of anterior temporal regions in AV integration is novel and warrants further study. The behavioral and VLSM results are discussed in relation to previous neuroimaging and case-study evidence; broadly, our findings coincide with previous work indicating that multisensory superior temporal cortex, not frontal motor circuits, are critical for AV integration. / Dissertation/Thesis / Masters Thesis Communication Disorders 2017