Indiana University-Purdue University Indianapolis (IUPUI) / A histological marker of Parkinson’s disease (PD) is the loss of synapses located on striatal medium spiny neurons (MSNs) as a result of dopaminergic nigral cell depletion. The dendritic spines that give MSNs their name have a well-characterized structure and are the main regions of post-synaptic input. It has been shown that spines have altered functionality and morphology in many neurodegenerative diseases. Spine morphology, and potentially function, is dictated by an array of structural proteins and their associations with other proteins in a region dubbed the post-synaptic density (PSD). Spinophilin and neurofilament medium (NF-M) are two proteins that are enriched in the PSD and have potential implications in PD. Interestingly, preliminary data show that there is a decrease in the NF-M-spinophilin interaction in animal models of PD. Here it is shown that these two proteins interact in brain tissue and when overexpressed in a mammalian cell system. Moreover, we have begun to determine mechanisms that regulate this interaction. It is known that there is a misregulation of protein phosphatases and kinases in many neurodegenerative diseases. Moreover, the phosphorylation state of a protein can regulate its association with other proteins. Therefore, we hypothesize that the phosphorylation state of either protein affects the interaction between spinophilin and NF-M. Furthermore, we have conducted experiments utilizing protein phosphatases and kinases that are known to modulate the phosphorylation state of NF-M and/or spinophilin. Data show that both kinase and phosphatase activity and/or expression modulates the NF-M-spinophilin interaction in heterologous cell lines. Through the use of MS/MS analysis, we have begun to map specific phosphorylation sites that may play a role in regulating this interaction. Currently, we are elucidating the specific effects of these post-translational modifications on regulating the spinophilin-NF-M interaction. These data will enhance our knowledge of spinophilin’s interactions and how these interactions are altered in neurological disorders such as PD.

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Low back pain is a leading cause of disability and is associated with whole-body vibration exposure in industrial workers and military personnel. The pathophysiological mechanisms by which whole-body vibration causes low back pain have been studied in vivo, but there is little data that improve diagnosis of low back pain. The overall objective of this research was to elucidate diagnostic biomarkers associated with whole-body vibration. Hence, a rat model for vibration-induced inflammatory responses was developed. Von Frey filaments were used to determine the withdrawal threshold of the hind paw as a surrogate behavioral marker for pain. The concentration of nerve growth factor in the serum was measured every four days using an assay as a potential diagnostic biomarker for low back pain. In the first study, whole-body vibration was applied using a modified commercially available device at 8 or 12 Hz every other day for two weeks, following which animals recovered for one week. At the conclusion of the study, intervertebral discs were graded histologically for degeneration. The nerve growth factor concentration increased threefold in the 8 Hz group and twofold in the 12 Hz group and returned to baseline by the end of the recovery period for 12 Hz, but not 8 Hz. Mechanical sensitivity appeared to change over time due to habituation and not any effect of vibration and was inconclusive. There was no difference in intervertebral disc degeneration scores between groups. In the second study, rats were vibrated at 8 Hz every other day for two or four weeks. The concentrations of nine cytokines were determined in the longissimus muscle, spleen, and thymus using a multiplex assay. These cytokines were ranked according to their ability to differentiate vibrated and non-vibrated animals, and classification models were compared. Nerve growth factor serum concentration peaked on day 13, then returned to baseline on day 17. The withdrawal threshold in vibrated animals decreased throughout the study indicating greater sensitivity to the stimulus, a surrogate for increased pain. Several longissimus muscle and spleen cytokines were important in distinguishing vibrated animals from non-vibrated, while thymus cytokines and weeks of exposure were not significant.

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Shoulder impingement is the most common cause of shoulder pain. It is often described as mechanical irritation of the tendons of the rotator cuff or long head of the biceps due to compression against either the structures of the subacromial arch or the glenoid and glenoid labrum. Various treatment options exist to address impingement, and recent studies suggest thoracic spine manipulation may be a useful option. The purpose of this study was to assess changes in range of motion (ROM), pain and shoulder function both immediately post- and 7 to 10 days after receiving thoracic spine manipulations. We also attempted to identify changes in scapular kinematics and shoulder muscle activity associated with thoracic spine manipulation in subjects with shoulder impingement. Thirty subjects between the ages of 18 and 45 with signs of shoulder impingement participated in this repeated measures study. All subjects received both a mid-thoracic spine and a cervicothoracic junction manipulation. Changes in pain were assessed using an 11 point numeric pain rating scale. Subjects reported pain with performance of provocative testing (Jobes Empty Can, Hawkins-Kennedy and Neer's tests for impingement) as well as with performance of cervical rotation, thoracic spine flexion and extension and weighted humeral elevation. Shoulder elevation force production pre- and post- manipulation was assessed using hand-held dynamometry. Additionally, subjects completed the Penn Shoulder Score (PSS) and the Sports and Performing Arts Module of the Disabilities of the Arm, Shoulder and Hand (DASH) Questionnaire to assess shoulder pain and function 7 to 10 days post thoracic spine manipulation. Electromagnetic sensors tracked three-dimensional scapular and clavicular kinematics as well as cervical, thoracic and humerothoracic ROM. Surface electromyography data were collected from the infraspinatus, serratus anterior, and the upper, middle and lower trapezius muscles with loaded humerothoracic elevation. A repeated measures analysis of variance (ANOVA) was used to compare scapular orientation and muscle activity at 30, 60, 90 ad 120 degrees of humerothoracic elevation before and after spinal manipulation. Paired t - tests revealed significant decreases in pain [(Jobes 2.6 ± 1.1, Neer's 2.6 ± 1.3, Hawkins-Kennedy 2.8 ± 1.3; p<0.001 for all three tests) (weighted shoulder elevation 2.0 ± 1.5, p<0.001; cervical rotation 0.4 ± .9, p=0.039)] as well as improvements in shoulder function (Force production 5.5±3.1, PSS 7.7 ± 9.4 and DASH 16.4 ± 13.2; p<0.001 for each). No significant changes in any of the ROM assessments were observed. No changes in scapular or clavicular kinematics were observed, with the exception of small decrease in scapular upward rotation (p = .04). A small but significant increase in middle trapezius activity (p = .03) was detected; however, no other significant differences in muscle activity were observed following manipulation. Moreover, paired t-tests revealed no significant differences in muscle onset times after manipulation. The findings of this study indicate that thoracic spine manipulation may be an effective intervention to treat pain associated with shoulder impingement; however, the improvements associated with thoracic spine manipulation are not likely explained by changes in scapular kinematics or shoulder muscle activity. Thoracic spine manipulation did not substantially alter scapular kinematics or motor control at the shoulder. / Physical Therapy

For years, the human back has puzzled researchers with the complex behaviors it presents. Principally, the internal forces produced by back muscles have not been determined accurately. Two different approaches have historically been taken to predict muscle forces. The first relies on electromyography (EMG), while the second attempts to predict muscle responses using mathematical models. Three such predictive models are compared here. The models are Sum of Cubed Intensities, Artificial Neural Networks, and Distributed Moment Histogram. These three models were adapted to run using recently published descriptions of the lower back anatomy. To evaluate their effectiveness, the models were compared in terms of their fit to a muscle activation database including 14 different muscles. The database was collected as part of this experiment, and included 8 participants (4 male and 4 female) with similar height and weight. The participants resisted loads applied to their torso via a harness. Results showed the models performed poorly (average R2's in the 0.40's), indicating that further improvements are needed in our current low back muscle activation modeling techniques. Considerable discrepancies were found between internal moments (at L3/L4) determined empirically and measured with a force plate, indicating that the maximum muscle stress selected and/or the anatomy used were faulty. The activation pattern database collected also fills a gap in the literature by considering static loading patterns that had not been systematically varied before. / Master of Science