Indiana University-Purdue University Indianapolis (IUPUI) / Background: Rehabilitation Robotics (RR) has become a more widely used and better understood treatment intervention and research tool in the last 15 years. Traditional research involves pre and post-test outcomes, making it difficult to analyze changes in behavior during the treatment process. Harnessing kinematics captured throughout each treatment allows motor learning to be quantified and questions of application and dosing to be answered. Objective: The aims of this secondary analysis were: (i) to investigate the impact of treatment presentation during RR on upper extremity movement time (mt) in children with hemiplegic cerebral palsy (CP) and (ii) to investigate the impact of training structure (dose and intensity) on mt in children with CP participating in RR. Methods: Subjects completed 16 intervention sessions of RR (2 x week; 8 weeks) with a total of 1,024 repetitions of movement per session and three assessments: pre, post and 6 month f/u. During each assessment and intervention, subjects completed “one-way record” assessments tracking performance on a planar task without robotic assistance. Kinematics from these records were extracted to assess subject performance over the course of and within sessions. Results: For all participants, a significant decrease in mt was found at post-test and follow-up. No significant differences were found in mt for age, severity or group placement. A significant interaction was found between treatment day, block and group (p = .033). Significant mt differences were found between the three blocks of intervention within individual days (p = .001). Specifically, significant differences were found over the last block of treatment (p = .032) and between successive treatment days (p = .001). Conclusion: The results indicate that for children with CP participating in RR, the number of repetitions per session is important. We hypothesized that children’s performance would plateau during a treatment day as attention waned, the opposite proved to be true. Despite the high-number of repetitions and associated cognitive demand, subjects’ performance actually trended upwards throughout the 1,024 repetitions suggesting that children were able to tolerate and learn from a high volume of repetitions.

An organism’s spatial ecology allows for access to essential resources such as food, mates, and escape from predators. Home range size, or the total area an organism inhabits, varies in relation to numerous factors including seasonality. During the breeding season, home range size increases in males across taxa. In addition, males usually also have larger home range sizes than females. This implicates testosterone (T) as a possible mediator of this relationship. Indeed, T causes an increase in home range size of males in numerous species of lizards. In addition to T causing an increase in home range size, it also causes an increase in coloration, which is used as a signal to deter or elicit aggressive behaviors in lizards. Potentially, contests are less common in natural settings than in the lab due to this signaling despite increased frequency overlap of home ranges in males. The larger the home range size of males, mediated through an increase in T, the more overlap with conspecifics. With this increase in spatial demand, or home range size, there is often a corresponding increase in spatially related brain regions. In reptiles, these brain regions are the medial and dorsal cortices (MC and DC respectively). The increase in cortical brain region size due to an increase in spatial demand may be mediated by an increase in neurogenesis. Proliferation of neurons occurs along the ventricles and radiate to numerous regions in the brain including the MC. With respect to the MC, immature neurons, which express the protein doublecortin (DCX), migrate from the ventricles, through the inner plexiform layer and are integrated into the cell layer. Because DCX is only expressed in recently born, migrating neurons, it can be used to measure neurogenesis. In mammals and birds, neurogenesis and growth of certain brain regions is affected by steroid hormones, including T. Here we tested two hypotheses: (1) T affects the home range size of Sceloporus occidentalis and (2) cortical brain region volumes are related to home range size and/or T which is mediated through changes in rates of neurogenesis. We surgically castrated individuals and implanted subjects with either a T-filled implant or blank implant and then released them at their initial capture sites. In addition to these castrated individuals, subjects not subjected to castration served as unmanipulated controls. Home range size of individuals in the field was quantified using a global positioning system (GPS) unit and later delineating those GPS points using minimum convex polygons (MCPs). We predicted that (1) castrated, T-treated lizards and unmanipulated control lizards would have larger home range sizes than castrated, control lizards c and (2) MC and DC cortices would be larger in volume and contain more DCX-immunoreactive cells in the lizards with the highest circulating T levels and with the largest home range sizes. We found that increased T caused an increase in the number of blue abdominal scales. We found no differences in home range size relating to T. Likewise, T did not affect MC volumes. However, we did observe a decrease in DC volume with increasing plasma levels of T. Because T did not affect home range size, it follows that we did not find an effect of T on MC volume. However, the significant result of T causing a decrease in DC volume implies a possible trade off with regards to energetics and the maintenance of brain region volumes as prior research indicates that T in increases energy expenditure and decreases foraging efforts.

The purpose of this dissertation was to explore methods for generating neuroplastic changes in healthy individuals using transcutaneous spinal cord stimulation (TSCS) and perturbation-based training in order to improve balance performance. This was done to gain an understanding of their effects on healthy individuals, which could then be used in designing treatments for both healthy and motor-impaired subjects. Three studies were undertaken. First, we set out to show that the Robotic Upright Stand Trainer (RobUST) could generate improvements in balance after perturbation balance training (PBT). In this same study, we showed that the assist-as-needed support of RobUST generates postural control improvements. Balance performance metrics including (i) margin of stability (MOS), (ii) metrics based on the center of pressure (COP) and center of mass (COM) excursions, (iii) postural muscle activations, (iv) balance strategy selection (between ankle and hip strategies) were used in this study. Electromyographic data were also collected from 11 subjects who participated in this study. Subjects were split into a RobUST assisted group (FF) and a non-assisted group (NF). An analysis of variance (ANOVA) was carried out to identify the main effects of the two factors, i.e., training and grouping. We also studied the interaction effects between the two factors in the performance variables. After training, the threshold of the forces that destabilize balance increased for all participants. In addition, the area within which they could withstand perturbations without falling also increased. Muscle activation decreased in most muscles for subjects in both groups indicating that subjects improved balance while demonstrating more energetically efficient strategies. The post-training behavior of the two groups differed in the following way: the NF group adapted towards faster reactions to perturbations, greater use of the hip strategy, and more use of the erector spinae muscle, while the FF group adapted towards slower responses and less MOS. These results show that although balance adaptations with RobUST-assisted PBT are not the same as without RobUST, it is still a platform capable of improving balance performance. Second, the effect of TSCS as a means of boosting neuroplasticity and a replacement for epidural stimulation were tested. Eight subjects were given TSCS for 30 mins while lying supine, and their neurophysiological and balance performance measures were tested before and after the intervention. T-tests were used to assess the difference in performance, and it was found that TSCS caused hypopolarisation of the sensory neurons, which increased the synaptic efficacy of sensory afferent–motoneuron synapses. This change was evidenced by increased H-reflex recovery and a leftward shift of the H-reflex recruitment curve. No improvement in fall frequency was observed, although balance adjustments were made that reduced muscle activity. This experiment showed that TSCS could be used to modulate the excitability of the spinal cord in healthy subjects. Third, TSCS was combined with a training intervention in order to study how these two sources of plasticity interact. TSCS was applied to eleven subjects while they underwent a training intervention in which they played a game in virtual reality (VR) while their balance was perturbed by forces applied by RobUST. Balance characteristics were measured both with and without TSCS, before and after the intervention. It was found that TSCS initially caused an increase in muscle activity and an increase in fall frequency for perturbations in the forward direction. With more practice, though, muscle activity decreased. It was postulated that the CNS adjusted to the initial elevated levels of muscle activity caused by TSCS by suppressing muscle activity in order to ensure successful motor control. These results suggest that TSCS can be used to elevate the resting potential of neurons in the dorsal (close to the back of the body) root, making them more easily excited by cortical signals. These changes induced by TSCS can be beneficial to spinal cord injury patients.

In this two-part study, I investigated whether the cyclic-adenosine monophosphate response element-binding (CREB) protein has the potential to be clinically modulated as a therapeutic target for the treatment of neurodegenerative diseases. Part one consisted of a systematic review that was conducted on select articles gathered through a stepwise method to explore (1) the relationship between diseased, neurodegenerative brains and levels of active, phosphorylated CREB (pCREB), (2) increased activation of CREB as a treatment for neurodegenerative symptoms, and (3) a potential therapeutic drug for neurodegenerative diseases that can target CREB signaling. The results of the systematic review showed evidence that suggested excitotoxic concentrations of N-methyl-D-aspartate (NMDA) results in decreased pCREB levels, while decreased pCREB levels were associated with impaired cognition and behavior, increased cell death, as well as decreased CRE-gene transcription and long-term potentiation (LTP). Part two consisted of a systematic review and meta-analysis on clinical trials that used the phosphodiesterase type IV inhibitor, roflumilast, on healthy and schizophrenic patients. It was found that 100 µM roflumilast was able to improve verbal learning in healthy and schizophrenic subjects (ES = 64). Initial evidence indicates that future research on neurodegenerative diseases should further investigate CREB’s potential to be clinically modulated and research investigating PDE4 inhibitor drug therapy for the treatment of neurodegeneration should be expanded upon further in subsequent studies.

No description available.

The primary motor cortex (M1) contains a somatotopic progression with highly overlapping areas outputting to muscles of the upper limb. This organization is modified by muscle activity and neurological injury such as spinal cord injury (SCI). To date, bilateral M1 organization in controls and SCI has been minimally explored, and no study has examined the cortical territory that directs output to multiple muscles thought to be involved in movement synergies. An initial study was conducted to characterize the bilateral organization and representational overlap for muscles of the upper limb in incomplete spinal cord injury relative to uninjured individuals. Differences in symmetry and amount of overlapping territory were observed between groups, possibly reflecting differences in synergistic muscle use. The second study examined transcallosal communication between the two motor cortices and its role in dynamically modulating motor representations during unilateral contraction. The depth of interhemispheric inhibition (IHI) was examined in a muscle of the right hand by delivering a conditioning stimulus to ipsilateral M1 followed by a test stimulus to contralateral M1. Reduced IHI corresponded to larger cortical territory, a relationship that existed for both contralateral and ipsilateral contraction. These data demonstrate that the magnitude of IHI in a hand muscle predicts the size of the cortical territory occupied by that muscle. We present a mechanistic model to explain these findings that further elucidate the role of interhemispheric communication in shaping motor output. This interaction between transcallosal inhibition and motor output may act as a component to experience-dependent plasticity within M1. By targeting this interaction, it may be possible to facilitate motor learning and performance or promote recovery of function following neurological injury. Further study examining the role of various intracortical circuits on representational plasticity and modulation of these interactions may yield advances in both basic and clinical neuroscience. / Thesis / Master of Science (MSc)

Associative plasticity, which involves modification of synaptic strength by coactivation of two synaptic inputs, has been demonstrated in many species. Here I explore whether it is possible to induce associative plasticity within a corticocortical pathway in the human brain using a novel protocol that activates two brain areas repeatedly with double-site transcranial magnetic stimulation (TMS). The pathway between ventral premotor cortex (PMv) and primary motor cortex (M1) which computes hand movements for precision grasp was manipulated. First, I selectively potentiated physiological connectivity between the stimulated brain areas. The effects as assessed with paired-pulse TMS were in accordance with principles of spike timing-dependent plasticity (STDP), pathwayspecific and showed a different pattern of expression during rest and during performance of a naturalistic prehension task. Furthermore, I demonstrated that effects evolved rapidly, lasted for up to three hours and were reversible. In a follow-up study, the protocol‘s effects on network interactions were investigated using functional magnetic resonance imaging (fMRI), specifically focussing on functional connectivity of network nodes within the wider parietofrontal circuit controlling reaching-and-grasping. The study demonstrated that functional connectivity was causally modified between stimulated nodes and that those changes in coupling also affected parallel, functionally-related pathways. Comparison of neurophysiological (paired-pulse TMS) and functional (fMRI) connectivity between individuals revealed a linear relationship of these connectivity indices; the first can assess the physiological nature of the interaction, whereas the latter can elucidate global network effects, making the techniques complementary. Neurophysiological interactions of ipsilesional and contralesional PMv-M1 were tested in chronic subcortical stroke patients during grasping. Patients showed a diminished facilitatory influence of ipsilesional PMv on M1 compared to healthy controls which might contribute to their motor disability. Application of paired-associative TMS “normalised“ the reduced effective influence of ipsilesional PMv on M1 and this effect correlated with the patient‘s potential to improve their dexterity.

No description available.

Aside from preventing traumatic brain injuries (TBIs) altogether, treatment options for TBI typically focus on the secondary biochemical processes that occur in response to the primary mechanical insult. These secondary injuries can lead to apoptosis and necrosis in the days and weeks that follow a TBI. Therefore, finding a treatment that can prevent, reduce, and repair secondary damage is instrumental in the recovery of TBI patients. The flavonoid 7,8-dihydroxyflavone (7,8-DHF) has been identified as a TrkB agonist that mimics the effects of brain derived neurotrophin factor (BDNF). Upon binding to the TrkB receptor, signaling cascades are initiated that can promote neuronal survival and neural differentiation. The use of 7,8-DHF in the treatment of TBI is favorable due to its long half-life and ability to pass the blood-brain barrier (BBB). In this study, we evaluated the dosage time frame of 7,8-DHF that would allow for the greatest impact in recovery after a focal TBI. Adult Sprague-Dawley rats were subjected to a moderate cortical impact injury and administered a 5mg/kg dose of 7,8-DHF i.p. for five days starting on day 0, 2, 3, or 5 post injury. Sensorimotor function was evaluated with beam walk and rotarod test. Morris Water Maze (MWM) and fear conditioning test were used to analyze cognitive function. Biotinylated dextran amine (BDA) was injected into the contralateral cerebral cortex 14 days after injury and animals were sacrificed 28 dpi. Brain sections were processed for Giemsa histological staining to assess cortical lesion volume and the total number of surviving neurons. Parallel sections were processed for BDA staining to assess changes of axon sprouting in the injured cortex. VGlut-1 staining of the hippocampus was used to identify presynaptic plasticity. We found that the administration of 7,8- DHF starting at one hour after TBI could provide protection against motor and cognitive dysfunction. Histological examination showed a significant reduction of cortical lesion volume and higher number of survival neurons in the injured hippocampus when 7,8-DHF administration began one hour and two days after injury. BDA staining of intracortical axon sprouting and VGlut-1 staining of the hippocampus highlighted a trend that 7,8-DHF administration starting day five post brain injury may enhance neuronal plasticity. Collectively, the results indicate that 7,8-DHF can provide the better neuronal protection when administration begins one hour after TBI.

Olfactory receptor neurons (ORNs) maintain the ability to regenerate. These neurons reside in the olfactory epithelium and project axons that connect to the olfactory bulbs. Despite the diffuse distribution of ORNs in the olfactory epithelium, they converge at discrete glomeruli in the olfactory bulb. In the P2 IRES tau-lacZ mouse, the P2 ORN subtype has been previously mapped to two glomeruli, using X-gal staining. To determine if age affects ORN regeneration, left olfactory nerve transections were performed on P2 mice from immature (five-weeks old) and mature (1 6-weeks old) groups. Following recovery, the olfactory bulbs were processed to observe ORN regeneration. A significant difference was seen in the number and mapping of full P2 glomeruli between lesioned and control olfactory bulbs, but not between the age groups. This suggests that age differences between the two groups in this study were not large enough to affect the regeneration of P2 ORNs.