Restoring function to damaged neural pathways, or promoting compensatory strategies to overcome dysfunctional neural pathways have been topics of inquiry within motor rehabilitation. This study considers these topics in Parkinsons disease (PD), where disruption within the striatal-thalamic-cortical (STC) circuits can cause impairment in internally guided (IG) movements. A related, but separate externally guided (EG) movement network, recruits the intact cerebellar-thalamic-cortical (CTC) loop to facilitate movement in response to sensory cues, and is effective in remediating motor function. Partnered dance with leading and following roles may be used as proxies for training IG and EG strategies respectively, in PD and can test which strategy is more effective in remediating effects of PD. Leaders determine variables associated with IG and communicate step amplitude, timing, and direction to the follower. Followers use an EG strategy to sense and interpret directional pressure cues from the leader and then enact an appropriate movement response. This study examines how IG and EG training strategy affects STC and CTC circuits and their behavioral outcomes to examine whether compensatory or direct entrainment of neural pathways is more effective in PD. Fifty-eight participants were recruited with mild-moderate PD (stages 1-3) and randomly assigned to EG, IG or non-dance education control group and assessed before and after 12 weeks of biweekly interventions. Participants were assessed with standard cognitive and motor behavioral measures and lay in a Magnetic Resonance Imaging (MRI) scanner while they tapped their foot under two conditions: internal (tapping a learned rhythm: IT) and external (participant taps in response to an assistants felt tap on the participants hand: ET) guidance. The foot-tapping data collected with an accelerometer were evaluated by analyzing the frequency spectrum to calculate amplitude and timing of the foot taps. The functional (fMRI) data were pre-processed (AFNI), registered (MNI), and analyzed for changes in activation using a general linear model in SAS and AFNI. Postintervention, both the EG and the IG groups showed clinically significant changes on disease severity, but the EG group showed improvements on cognitive, motor, and mood variables. The EG group also outperformed the IG group in the in-scanner task performance measured by the foot accelerometer. Imaging data revealed a significant increase in the EG group in the primary motor cortex lower limb region and the parts of the cerebellar circuits, particularly right Cerebellar Lobule VIIIa. The control group showed an increase in activity in the putamen compared to the IG and EG groups that could be due to a different compensatory pathway. All findings were corroborated using a region of interest approach examining the same pathways according to an atlas. Our results indicate that the most effective strategy for the PD participants involved external cues that increased activity in the compensatory CTC pathway, the primary motor region, and significant improvements on almost all behavioral measurements.

mucoid, or mixed populations), the lung lobes in which these variants are found, and regional proinflammatory cytokine production. METHODS/ STUDY POPULATION: We performed BAL on 16 CF patients with clinically stable disease. For each patient, we obtained BAL fluid from the right upper lobe, right middle lobe, right lower lobe, left upper lobe, lingula, and left lower lobe. We plated BAL fluid on nonselective and P.a.-selective medium to quantitate bacteria and to identify P.a. colony subtypes (nonmucoid, mucoid, or mixed). We further used a V-PLEX human cytokine array to quantitate inflammatory cytokine concentrations (IL-1β, TNF-α, IL-6, IL-8, and IL-10) within BAL fluid specimens. Our specimen collection was approved by the local IRB with informed consent and assent obtained from patient volunteers. RESULTS/ANTICIPATED RESULTS: Based on microbiological analysis, each lobar BAL specimen was classified as uninfected with P. a. or infected with nonmucoid, mucoid, or mixed (both nonmucoid and mucoid) P.a. variants. There was no observed propensity of mucoid or nonmucoid variants to be confined to certain lung lobes in our cohort. However, infection with mucoid P.a. variants was associated with higher concentrations of IL-1β (p< 0.001), TNF-α (p< 0.001), IL-8 (p< 0.001), and IL-10 (p< 0.001) within lobar BAL fluid compared with P.a.-free specimens. Specimens with mucoid variants also had greater concentrations of TNF-α (p< 0.01), IL-8 (p< 0.001), and IL-10 (p< 0.05) compared with specimens with only nonmucoid P.a. variants. Patients infected with mixed mucoid and nonmucoid variants showed higher concentrations of TNF-α and IL-10 (p< 0.05) as well as nonsignificant trends for higher concentrations of IL-1β and IL-6 compared to P.a.-free samples. Interestingly, the presence of nonmucoid P.a. variants was inversely correlated with IL-6 (p< 0.05). Total bacterial burden (both P.a. and non-P. a. species) within BAL fluids was positively correlated with higher proinflammatory cytokine concentrations. Additionally, independent of bacterial colonization, the upper lobes (right upper lobe and left upper lobe) of the lungs showed trends towards higher proinflammatory cytokine concentrations compared with the lower lobes (right lower lobe and left lower lobe). DISCUSSION/SIGNIFICANCE OF IMPACT: Our results demonstrate that P.a. variants (mucoid or nonmucoid) appear not to be geographically restricted in ability to colonize any lobe of the CF lung. Moreover, infection with mucoid P.a. (either alone or in mixed populations with nonmucoid variants) is associated with higher inflammatory cytokine concentrations in the CF lung. Given that infection with mucoid P.a. predicts deterioration in pulmonary function, this study provides a rationale for further investigation of cytokines as diagnostic/prognostic correlates of infection and lung disease in CF.

OBJECTIVES/SPECIFIC AIMS: Parkinson’s disease (PD) is a condition that affects over a million Americans, and despite current medical therapies, the progression of the disease results in impaired generation of internally timed or guided (IG) movements. To address this loss of motor function, previous rehabilitation therapies have focused on remediating the affected striatal-thalamic-cortical circuits (STC), primarily thought to be responsible in generating timed motor patterns. However, given the disease leads to the cell death of dopaminergic cells that are essential for proper STC function, we propose a motor therapy aimed at utilizing a compensatory parallel cerebellar-thalamic-cortical (CTC) pathway, recruited to perform externally guided (EG) movements, in which gait initiation is driven from sensory input. Our previous study has shown efficacy in our novel argentine tango therapy and improves behavioral measures above the relevant MCID threshold, but it has not been established that the CTC are in the causal pathway that are responsible for these changes. Using neural measures from task fMRI, we have begun to characterize networks that have changed and quantify any associations with behavioral metrics. METHODS/STUDY POPULATION: Patients were randomly assigned to an IG (n=18), EG (n=18), or education contact control (n=14). Participants were assessed preintervention and postintervention for behavioral motor and cognitive measures and neurophysiologically with task based fMRI. In the task, participants performed a foot tapping task under both IG (tap their foot in previously learned rhythm) or EG (tap immediately after receiving a tactile cue on their hand) conditions. The fMRI data were preprocessed using AFNI and registered to MNI standard space. The brainnetome atlas was applied and the average time series of each region of interest (ROI) was used to increase the signal to noise ratio. The activation of these ROI with respect to the stimulus was modeled using GLM, and we estimated the area under the curve during the task blocks. A 1-way ANOVA analysis on these betas were performed between the pre and the post intervention time points and the ROIs that were above a significance of 0.95 were identified and corrected for multiple comparisons. The change in beta in all ROIs for each individual were calculated and then correlated with the changes in the behavioral data, to see which changes in ROI areas matched the best with the behavioral changes. RESULTS/ANTICIPATED RESULTS: The EG group showed significant changes only in the EG task in 2 areas—inferior frontal gyrus and inferior temporal sulcus. Correlating to the cognitive behavioral measures show reduced error from the Inferior frontal gyrus (corr>0.5) best reflect changes in observed. There were no changes to either the STC or the CTC pathways. The IG group showed no changes behaviorally and showed no changes neurally as well. The control group showed no changes behaviorally, but neuronally certain DMN nodes, such as the precuneus and inferior temporal regions showed a significant change for both tasks. DISCUSSION/SIGNIFICANCE OF IMPACT: Addressing the damaged STC pathway directly through IG therapy may not be effective. The EG therapy may not be able to enhance the STC pathway. However, the therapy appears to utilize new areas in the frontal regions and correlates with positively with changes in spatial memory and balance tasks. Contrary to our hypothesis the CTC circuit was not upregulated for performance of the IG or EG task, but therapy may have enhanced recruitment of other cognitively engaged areas. The educational control group interestingly showed changes in the DMN network, which has been shown to be linked to attention during tasks blocks.