Amber Jacobs

Assessing the role of dopamine in limb and cranial-oromotor control in a rat model of Parkinson's disease

UNLABELLED Parkinsons disease (PD) is a neurodegenerative disorder primarily characterized by sensorimotor dysfunction. The neuropathology of PD includes a loss of dopamine (DA) neurons of the nigrostriatal pathway. Classic signs of the disease include rigidity, bradykinesia, and postural instability. However, as many as 90% of patients also experience significant deficits in speech, swallowing (including mastication), and respiratory control. Oromotor deficits such as these are underappreciated, frequently emerging during the early, often hemi-Parkinson, stage of the disease. In this paper, we review tests commonly used in our labs to model early and hemi-Parkinson deficits in rodents. We have recently expanded our tests to include sensitive models of oromotor deficits. This paper discusses the most commonly used tests in our lab to model both limb and oromotor deficits, including tests of forelimb-use asymmetry, postural instability, vibrissae-evoked forelimb placing, single limb akinesia, dry pasta handling, sunflower seed shelling, and acoustic analyses of ultrasonic vocalizations and pasta biting strength. In particular, we lay new groundwork for developing methods for measuring abnormalities in the acoustic patterns during eating that indicate decreased biting strength and irregular intervals between bites in the hemi-Parkinson rat. Similar to limb motor deficits, oromotor deficits, at least to some degree, appear to be modulated by nigrostriatal DA. Finally, we briefly review the literature on targeted motor rehabilitation effects in PD models. LEARNING OUTCOMES Readers will: (a) understand how a unilateral lesion to the nigrostriatal pathway affects limb use, (b) understand how a unilateral lesion to the nigrostriatal pathway affects oromotor function, and (c) gain an understanding of how limb motor deficits and oromotor deficits appear to involve dopamine and are modulated by training.

Methodological issues for designing and conducting a multicenter, international clinical trial in Acute Stroke: Experience from ARTSS-2 trial

BACKGROUND We describe innovations in the study design and the efficient data coordination of a randomized multicenter trial of Argatroban in Combination with Recombinant Tissue Plasminogen Activator for Acute Stroke (ARTSS-2). METHODS ARTSS-2 is a 3-arm, multisite/multiregional randomized controlled trials (RCTs) of two doses of Argatroban injection (low, high) in combination with recombinant tissue plasminogen activator (rt-PA) in acute ischemic stroke patients and rt-PA alone. We developed a covariate adaptive randomization program that balanced the study arms with respect to study site as well as hemorrhage after thrombolysis (HAT) score and presence of distal internal carotid artery occlusion (DICAO). We used simulation studies to validate performance of the randomization program before making any adaptations during the trial. For the first 90 patients enrolled in ARTSS-2, we evaluated performance of our randomization program using chi-square tests of homogeneity or extended Fishers exact test. We also designed a four-step partly Bayesian safety stopping rule for low and high dose Argatroban arms. RESULTS Homogeneity of the study arms was confirmed with respect to distribution of study site (UK sites vs. US sites, P=0.98), HAT score (0-2 vs. 3-5, P=1.0), and DICAO (N/A vs. No vs. Yes, P=0.97). Our stopping thresholds for safety of low and high dose Argatroban were not crossed. Despite challenges, data quality was assured. CONCLUSIONS We recommend adaptive designs for randomization and Bayesian safety stopping rules for multisite Phase I/II RCTs for maintaining additional flexibility. Efficient data coordination could lead to improved data quality.

Telemedicine-guided remote enrollment of patients into an acute stroke trial

Enrollment into acute stroke clinical trials is limited to experienced tertiary centers with emergency research infrastructure. Feasibility of remote enrollment via telemedicine into an acute thrombolytic clinical trial has never been demonstrated.

Comparison Between a Standardized Questionnaire and Expert Clinicians for Capacity Assessment in Stroke Clinical Trials

Research into treatments for acute strokes has dramatically increased in the last decade. Accordingly, the need for testing through randomized clinical trials has also increased. Because of the unique combination of factors that are common in acute stroke–related research, including narrow treatment windows, ethical concerns regarding research with acute stroke populations, and capacity for informed consent, stroke clinical trial enrollment levels have remained stagnant. Given the devastating consequences of acute stroke, researchers are intensifying their efforts to recruit and enroll larger sample sizes in clinical trials.1 Capacity to consent to medical treatment or medical research is closely related to cognitive functioning, which is frequently impaired in stroke.2 Medical decision-making capacity (MDC) requires the ability to understand and appreciate diagnostic, treatment, and research information and risks and ability to express a choice that is based on adequate reasoning. The treating physician is responsible for the assessment of a patient’s decision-making capacity and clinically estimate their patient’s ability to provide informed consent.3 Many physicians request additional consultative assistance to assess cognitive capacity for consent from psychiatry or neuropsychology, which are considered to be the clinical gold standards4 or they perform standardized capacity questionnaires to aid the assessment of capacity.5,6 One such tool, the aid-to-capacity evaluation (ACE) had 80% to 89% agreement with expert clinicians in 1 study and inter-rater reliability reported as ĸ=0.79 for medical hospitalized patients.7,8 The ACE has been validated and found to be one of the best available instruments to assist clinicians in making judgments on MDC.4 It is designed to be used by trained nonclinicians and takes ≈10 minutes to perform.4 For patients who lack capacity medical decisions are deferred to a surrogate decision maker. Surrogate decision makers in acute stroke are able to accurately predict …