Shawn Frost - Academia.edu (original) (raw)

Papers by Shawn Frost

Journal of Neurophysiology, 2003

Although recent neurological research has shed light on the brain's mechanisms of self-repair... more Although recent neurological research has shed light on the brain's mechanisms of self-repair after stroke, the role that intact tissue plays in recovery is still obscure. To explore these mechanisms further, we used microelectrode stimulation techniques to examine functional remodeling in cerebral cortex after an ischemic infarct in the hand representation of primary motor cortex in five adult squirrel monkeys. Hand preference and the motor skill of both hands were assessed periodically on a pellet retrieval task for 3 mo postinfarct. Initial postinfarct motor impairment of the contralateral hand was evident in each animal, followed by a gradual improvement in performance over 1–3 mo. Intracortical microstimulation mapping at 12 wk after infarct revealed substantial enlargements of the hand representation in a remote cortical area, the ventral premotor cortex. Increases ranged from 7.2 to 53.8% relative to the preinfarct ventral premotor hand area, with a mean increase of 36.0 ...

Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability... more Injury of CNS nerve tracts remodels circuitry through dendritic spine loss and hyper-excitability, thus influencing recovery. Due to the complexity of the CNS, a mechanistic understanding of injury-induced synaptic remodeling remains unclear. Using microfluidic chambers to separate and injure distal axons, we show that axotomy causes retrograde dendritic spine loss at directly injured pyramidal neurons followed by retrograde presynaptic hyper-excitability. These remodeling events require activity at the site of injury, axon-to-soma signaling, and transcription. Similarly, directly injured corticospinal neurons in vivo also exhibit a specific increase in spiking following axon injury. Axotomy-induced hyper-excitability of cultured neurons coincides with elimination of inhibitory inputs onto injured neurons, including those formed onto dendritic spines. Netrin-1 downregulation occurs following axon injury and exogenous netrin-1 applied after injury normalizes spine density, presynapti...

Toxicology and Applied Pharmacology, 1983

and ethanol have been reported to inhibit the growth of fibroblasts in cell culture. The objectiv... more and ethanol have been reported to inhibit the growth of fibroblasts in cell culture. The objectives of the present study were to determine whether these compounds could be used to inhibit the growth of fibroblasts in viva, with a bleomycin-induced mouse model of pulmonary fibrosis. DBA/ZJ mice were given a single endotracheal injection of bleomycin, 10 nmol. In addition to bleomycin (BLM), groups of animals received 2% DFMO in drinking water for 4 days prior to BLM and 18 days after (BLM DFMO), 6% ethanol in drinking water for 7 days prior to BLM and 21 days after (BLM E7), 6% ethanol in drinking water for 21 days initiated on the day of BLM intubation (BLM E), or DFMO, E7, and BLM in combination (BLM DFMO E7). Animals died or were killed 2 1 days after bleomycin treatment and lungs were evaluated by histopathologic criteria. DFMO failed to alter the incidence or severity of fibrotic lesions, increased the severity of epithelial metaplasia (p < 0.05), and reduced the lung disease index (from 56.3 to 42.1%. p < 0.05) and mortality from 83.3 to 41.7% (p < 0.025). In contrast to the unsatisfactory response to DFMO, pretreatment with ethanol (BLM E7) reduced the incidence of interstitial fibrosis from 91.3 to 7 1.4% (p < 0.05) and confluent fibrosis from 73.9 to 20.0% (p < 0.005). The severity of lesions was also reduced by ethanol, resulting in an 18.5% decrease in interstitial fibrosis, a 25.9% decrease in epithelial metaplasia, and a 55.4% reduction in the lung disease index (all p < 0.01). However, when ethanol and DFMO were administered in combination, the beneficial effects of ethanol alone were not observed, and only the lung disease index was decreased.

Translational Psychiatry, 2013

The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in th... more The earliest detectable change in Alzheimer's disease (AD) is the buildup of amyloid plaque in the brain. Early detection of AD, prior to irreversible neurological damage, is important for the efficacy of current interventions as well as for the development of new treatments. Although PiB-PET imaging and CSF amyloid are the gold standards for early AD diagnosis, there are practical limitations for population screening. AD-related pathology occurs primarily in the brain, but some of the hallmarks of the disease have also been shown to occur in other tissues, including the retina, which is more accessible for imaging. Retinal vascular changes and degeneration have previously been reported in AD using optical coherence tomography and laser Doppler techniques. This report presents results from analysis of retinal photographs from AD and healthy control participants from the Australian Imaging, Biomarkers and Lifestyle (AIBL) Flagship Study of Ageing. This is the first study to investigate retinal blood vessel changes with respect to amyloid plaque burden in the brain. We demonstrate relationships between retinal vascular parameters, neocortical brain amyloid plaque burden and AD. A number of RVPs were found to be different in AD. Two of these RVPs, venular branching asymmetry factor and arteriolar length-to-diameter ratio, were also higher in healthy individuals with high plaque burden (P ¼ 0.01 and P ¼ 0.02 respectively, after false discovery rate adjustment). Retinal photographic analysis shows potential as an adjunct for early detection of AD or monitoring of AD-progression or response to treatments.

Comparative Biochemistry and Physiology Part B: Biochemistry and Molecular Biology, 1998

In eutherians, patterns of plasma protein levels in blood change during the acute phase response ... more In eutherians, patterns of plasma protein levels in blood change during the acute phase response to trauma and inflammation. Until now, such an acute phase response has not been characterised in a noneutherian species. Here we describe the acute phase response in a marsupial species, the South American polyprotodont marsupial Monodelphis domestica, after brain surgery or injection of lipopolysaccharide. Several days after brain surgery, transthyretin was not detected in plasma. For 48 hr following injection of lipopolysaccharide, the concentration of haptoglobin in plasma increased, that of transthyretin decreased, and the concentration of albumin in plasma did not change significantly. The American polyprotodont marsupials are probably more closely related to the common ancestor marsupial than the Australian marsupials are. It is most likely that the transthyretin gene was not expressed in the liver of this common ancestor. As the transthyretin gene is expressed in the liver of M. domestica, it seems that as soon as transthyretin is synthesised by the liver, it is under negative acute phase control.

2016 IEEE Biomedical Circuits and Systems Conference (BioCAS), 2016

Next, the second SoC has been developed as a first ever miniaturized Brain-Machine-Spinal Cord In... more Next, the second SoC has been developed as a first ever miniaturized Brain-Machine-Spinal Cord Interface (BMSI) for cortical control of ISMS based on the level of spike activity in vivo. The fabricated SoC incorporated two identical four-channel xii modules, each compromising four neural recording channels, a DSP unit for on-the-fly stimulus trigger generation, and four stimulating channels for ISMS. The 3.46 × 3.46 mm 2 BMSI device also integrates a clock generator circuitry and radio frequency frequency-shift-keying (RF-FSK) transmitter for autonomous operation as a stand-alone system. The DSP unit of BMSI generates stimulus triggering based on the level of spike activity on the recording channels with different patterns and controls the ISMS with programmable delay from the last discriminated spike to mimic the natural time-delay existing in the nervous system. Measured results from benchtop testing, in vitro analysis, and biological experiments with anesthetized spinal cord injured rats are presented.

Journal of Neural Engineering, 2020

Objective. The purpose of this study was to determine the effects of spinal cord injury (SCI) on ... more Objective. The purpose of this study was to determine the effects of spinal cord injury (SCI) on spike activity evoked in the hindlimb spinal cord of the rat from cortical electrical stimulation. Approach. Adult, male, Sprague Dawley rats were randomly assigned to a Healthy or SCI group. SCI rats were given a 175 kDyn dorsal midline contusion injury at the level of the T8 vertebrae. At 4 weeks post-SCI, intracortical microstimulation (ICMS) was delivered at several sites in the hindlimb motor cortex of anesthetized rats, and evoked neural activity was recorded from corresponding sites throughout the dorsoventral depths of the spinal cord and EMG activity from hindlimb muscles. Main results. In healthy rats, post-ICMS spike histograms showed reliable, evoked spike activity during a short-latency epoch 10–12 ms after the initiation of the ICMS pulse train (short). Longer latency spikes occurred between ∼20 and 60 ms, generally following a Gaussian distribution, rising above baseline a...

PM & R : the journal of injury, function, and rehabilitation, 2016

astrocytoma included, yielding 22 total patients. The tumor was resected in 18 patients and un-re... more astrocytoma included, yielding 22 total patients. The tumor was resected in 18 patients and un-resected in 4. A random number generator was used to select comparison groups of 26 stroke patients and 20 traumatic brain injury (TBI) patients who were admitted during the same period. Interventions: Not applicable. Main Outcome Measures: Functional independence measure (FIM) change between admission and discharge, FIM efficiency, percentage of therapy days that 3-hour rule was not met, major complication rate, and rate of transfer out of acute rehabilitation unit. Results: Average FIM change by group was GBM 16.5, stroke 22.6 (P¼.116), and TBI 24.8 (P¼.048). FIM efficiency by group was GBM 1.04, stroke 1.62 (P¼.089), TBI 2.24 (P¼.003). Percent of therapy days that 3-hour rule was not met by group was GBM 28.3%, stroke 13.2% (P¼.014), TBI 15.3% (P¼.042). Major complication rate by group was GBM 0.59, stroke 0.27 (P¼.094), and TBI 0.65 (P¼.808). Rate of transfer out of rehabilitation unit was 0.23 for GBM group, 0.25 for stroke (P¼.777), and 0.15 for TBI (P¼.812). Conclusions: GBM patients demonstrated functional improvement during acute rehabilitation; however, their rate and magnitude of improvement was significantly less than TBI patients and trended towards significance compared to stroke patients. Additionally, the participation of GBM patients was significantly less than stroke and TBI patients. This may be helpful for providers, therapists, and patients when guiding expectations. In addition, decisions regarding delay of chemotherapy treatments for pursuit of an acute rehabilitation course may be made with a better understanding of potential functional outcomes.

Stroke; a journal of cerebral circulation, 2015

New insights into the brain's ability to reorganize after injury are beginning to suggest nov... more New insights into the brain's ability to reorganize after injury are beginning to suggest novel restorative therapy targets. Potential therapies include pharmacological agents designed to promote axonal growth. The purpose of this study was to test the efficacy of one such drug, GSK249320, a monoclonal antibody that blocks the axon outgrowth inhibition molecule, myelin-associated glycoprotein, to facilitate recovery of motor skills in a nonhuman primate model of ischemic cortical damage. Using a between-groups repeated-measures design, squirrel monkeys were randomized to 1 of 2 groups: an experimental group received intravenous GSK249320 beginning 24 hours after an ischemic infarct in motor cortex with repeated dosages given at 1-week intervals for 6 weeks and a control group received only the vehicle at matched time periods. The primary end point was a motor performance index based on a distal forelimb reach-and-retrieval task. Neurophysiological mapping techniques were used to...

2014 IEEE 57th International Midwest Symposium on Circuits and Systems (MWSCAS), 2014

ABSTRACT

2014 36th Annual International Conference of the IEEE Engineering in Medicine and Biology Society, 2014

Nearly 6 million people in the United States are currently living with paralysis in which 23% of ... more Nearly 6 million people in the United States are currently living with paralysis in which 23% of the cases are related to spinal cord injury (SCI). Miniaturized closed-loop neural interfaces have the potential for restoring function and mobility lost to debilitating neural injuries such as SCI by leveraging recent advancements in bioelectronics and a better understanding of the processes that underlie functional and anatomical reorganization in an injured nervous system. This paper describes our current progress towards developing a miniaturized brain-machine-spinal cord interface (BMSI) that is envisioned to convert in real time the neural command signals recorded from the brain to electrical stimuli delivered to the spinal cord below the injury level. Specifically, the paper reports on a corticospinal interface integrated circuit (IC) as a core building block for such a BMSI that is capable of low-noise recording of extracellular neural spikes from the cerebral cortex as well as muscle activation using intraspinal microstimulation (ISMS) in a rat with contusion injury to the thoracic spinal cord. The paper further presents results from a neurobiological study conducted in both normal and SCI rats to investigate the effect of various ISMS parameters on movement thresholds in the rat hindlimb. Coupled with proper signal-processing algorithms in the future for the transformation between the cortically recorded data and ISMS parameters, such a BMSI has the potential to facilitate functional recovery after an SCI by re-establishing corticospinal communication channels lost due to the injury.

Journal of Neuroscience, 2005

Previously, we showed that the ventral premotor cortex (PMv) underwent neurophysiological remodel... more Previously, we showed that the ventral premotor cortex (PMv) underwent neurophysiological remodeling after injury to the primary motor cortex (M1). In the present study, we examined cortical connections of PMv after such lesions. The neuroanatomical tract tracer biotinylated dextran amine was injected into the PMv hand area at least 5 months after ischemic injury to the M1 hand area. Comparison of labeling patterns between experimental and control animals demonstrated extensive proliferation of novel PMv terminal fields and the appearance of retrogradely labeled cell bodies within area 1/2 of the primary somatosensory cortex after M1 injury. Furthermore, evidence was found for alterations in the trajectory of PMv intracortical axons near the site of the lesion. The results suggest that M1 injury results in axonal sprouting near the ischemic injury and the establishment of novel connections within a distant target. These results support the hypothesis that, after a cortical injury, such as occurs after stroke, cortical areas distant from the injury undergo major neuroanatomical reorganization. Our results reveal an extraordinary anatomical rewiring capacity in the adult CNS after injury that may potentially play a role in recovery.

Neurorehabilitation and Neural Repair, 2007

Background. Small lesions to rostral versus caudal portions of the hand representation in the pri... more Background. Small lesions to rostral versus caudal portions of the hand representation in the primary motor cortex (M1) produce different behavioral deficits. The goal of the present study was to determine if rehabilitative training has similar effects on functional topography of the spared M1 after rostral versus previously reported caudal M1 lesions. Methods. Following a lesion to the rostral M1 hand area, monkeys were trained for 1 h/day for 30 days to retrieve food pellets from small wells using their impaired hand. Electrophysiological maps of the M1 were derived in anesthetized monkeys before infarct and after rehabilitative training using intracortical microstimulation. Results. After a lesion to the rostral M1 and rehabilitative training, the size of the spared hand representation decreased 1.2%. This change is not statistically different from the 9% increase seen after caudal M1 lesion and rehabilitative training ( P > 0.2). Conclusion. Postlesion training spares peri-in...

Neurological Research, 2003

Stroke is often characterizedby incomplete recovery and chronic motor impairments. A nonhuman pri... more Stroke is often characterizedby incomplete recovery and chronic motor impairments. A nonhuman primate model of cortical ischemia was used to evaluate the feasibility of using device-assistedcortical stimulation combined with rehabilitative training to enhance behavioral recovery and cortical plasticity. Following preinfarct training on a unimanual motor task, maps of movement representations in primary motor cortex were derived. Then, an ischemic infarct was produced which destroyed the hand representation. Several weeks later, a second cortical map was derived to guide implantation of a surface electrode over periinfarct motor cortex. After several months of spontaneous recovery, monkeys underwent subthreshold electrical stimulation combined with rehabilitative training for several weeks. Post-therapy behavioral performance was tracked for several additional months. A third cortical map was derived several weeks post-therapy to examine changes in motor representations. Monkeys showed signi cant improvements in motor performance (success, speed, and ef ciency) following therapy, which persisted for several months. Cortical mapping revealed large-scale emergence of new hand representations in peri-infarct motor cortex, primarily in cortical tissue underlying the electrode. Results support the feasibility of using a therapy approach combining peri-infarct electricalstimulation with rehabilitative training to alleviate chronic motor de cits and promote recovery from cortical ischemic injury.

Journal of Neurosurgery: Spine, 2013

Object The purpose of the present study was to determine the feasibility of using a common labora... more Object The purpose of the present study was to determine the feasibility of using a common laboratory rat strain for reliably locating cortical motor representations of the hindlimb. Methods Intracortical microstimulation techniques were used to derive detailed maps of the hindlimb motor representations in 6 adult Fischer-344 rats. Results The organization of the hindlimb movement representation, while variable across individual rats in topographic detail, displayed several commonalities. The hindlimb representation was positioned posterior to the forelimb motor representation and posterolateral to the motor trunk representation. The areal extent of the hindlimb representation across the cortical surface averaged 2.00 ± 0.50 mm2. Superimposing individual maps revealed an overlapping area measuring 0.35 mm2, indicating that the location of the hindlimb representation can be predicted reliably based on stereotactic coordinates. Across the sample of rats, the hindlimb representation wa...

Journal of Neurophysiology, 2008

Neuroimaging studies in stroke survivors have suggested that adaptive plasticity occurs following... more Neuroimaging studies in stroke survivors have suggested that adaptive plasticity occurs following stroke. However, the complex temporal dynamics of neural reorganization after injury make the interpretation of functional imaging studies equivocal. In the present study in adult squirrel monkeys, intracortical microstimulation (ICMS) techniques were used to monitor changes in representational maps of the distal forelimb in the supplementary motor area (SMA) after a unilateral ischemic infarct of primary motor (M1) and premotor distal forelimb representations (DFLs). In each animal, ICMS maps were derived at early (3 wk) and late (13 wk) postinfarct stages. Lesions resulted in severe deficits in motor abilities on a reach and retrieval task. Limited behavioral recovery occurred and plateaued at 3 wk postinfarct. At both early and late postinfarct stages, distal forelimb movements could still be evoked by ICMS in SMA at low current levels. However, the size of the SMA DFL changed after ...