Influence of Pramipexole on Probability Discounting and Ventral Pallidal Function: Assessments in Parkinsonian-Like Rats

People with neuropathologies who are treated with dopamine agonists may be at risk to develop impulse control disorders. The overall goal of this dissertation project was to expand our knowledge on the neuropsychopharmacology of dopamine agonist-induced impulsivity. At the time this dissertation was being developed, pramipexole was the drug, gambling was the behavior, and Parkinson\u27s disease (PD) was the pathology most widely reported for this phenomenon. Therefore, we first developed a behavioral paradigm (i.e., probability discounting) to measure risk-taking, one aspect of gambling. Utilizing this paradigm, we determine if risk-taking was altered after acute and/or chronic pramipexole treatment. We incorporated an animal model of PD in this study to determine if a PD-like brain state alters the response of pramipexole in the discounting paradigm. The final series of studies focused on determining if a limbic brain region involved in reward-related behaviors is also altered by acute and/or chronic pramipexole exposure. Work from our laboratory and others suggest that the ventral pallidum (VP) would be a region of interest. The VP mediates responses to rewards and VP neural activity integrates predictive, incentive, and reward value information. As studies show that pramipexole can alter aspects of impulsivity, such as risk-taking, and enhance motivational salience of reward-related cues, it is possible that the VP plays a role in mediating effects of pramipexole. Accordingly, we hypothesized that VP neuronal activity is altered by behaviorally relevant doses of pramipexole. We utilized single-cell extracellular electrophysiological techniques to investigate effects of systemic pramipexole on VP neuronal firing rate. Finally, as D3Rs can mediate reward-seeking behavior, we investigated the influence of D3Rs in the ability of pramipexole to alter VP neuronal firing rate using PG01037, a D3R-preferring antagonist. Collectively, my studies demonstrate that acutely administered pramipexole enhances risk-taking in rats and also modulates VP neuronal firing rate; this modulation appears to be mediated by D3R activation. Chronic pramipexole treatment enhances risking-taking compared to acute treatment. Chronic treatment also enhances the potency of PPX to alter VP neuronal firing rate. Finally, these studies suggest that a PD-like brain state does not alter pramipexole-induced alterations in risk-taking

Transcranial magnetic stimulation: potential treatment for co-occurring alcohol, traumatic brain injury and posttraumatic stress disorders

Alcohol use disorder (AUD), mild traumatic brain injury (mTBI), and posttraumatic stress disorder (PTSD) commonly co-occur (AUD + mTBI + PTSD). These conditions have overlapping symptoms which are, in part, reflective of overlapping neuropathology. These conditions become problematic because their co-occurrence can exacerbate symptoms. Therefore, treatments must be developed that are inclusive to all three conditions. Repetitive transcranial magnetic stimulation (rTMS) is non-invasive and may be an ideal treatment for co-occurring AUD + mTBI + PTSD. There is accumulating evidence on rTMS as a treatment for people with AUD, mTBI, and PTSD each alone. However, there are no published studies to date on rTMS as a treatment for co-occurring AUD + mTBI + PTSD. This review article advances the knowledge base for rTMS as a treatment for AUD + mTBI + PTSD. This review provides background information about these co-occurring conditions as well as rTMS. The existing literature on rTMS as a treatment for people with AUD, TBI, and PTSD each alone is reviewed. Finally, neurobiological findings in support of a theoretical model are discussed to inform TMS as a treatment for co-occurring AUD + mTBI + PTSD. The peer-reviewed literature was identified by targeted literature searches using PubMed and supplemented by cross-referencing the bibliographies of relevant review articles. The existing evidence on rTMS as a treatment for these conditions in isolation, coupled with the overlapping neuropathology and symptomology of these conditions, suggests that rTMS may be well suited for the treatment of these conditions together

Psychometric measurement properties of the world health organization disability assessment schedule 2.0 (WHODAS) evaluated among veterans with mild traumatic brain injury and behavioral health conditions

©, This work was authored as part of the Contributor\u27s official duties as an Employee of the United States Government and is therefore a work of the United States Government. In accordance with 17 U.S.C. 105, no copyright protection is available for such works under U.S. Law. Purpose: Examine the psychometric properties of the World Health Organization Disability Assessment Schedule 2.0 among U.S. Iraq/Afghanistan Veterans with a combination of mild traumatic brain injury and behavioral health conditions using Rasch analysis. Methods: 307 Veterans were classified as either combat control (n = 141), or one of three clinical groups: mild traumatic brain injury (n = 10), behavioral health conditions (n = 24), or both (n = 128). Data from the three clinical groups were used to establish step and item calibrations serving as anchors when including the control group. Results: Measurement precision was excellent (person separation reliability = 0.93). Ordering of item calibrations formed a logical hierarchy. Test items were off-target (too easy) for the clinical groups. Principal component analysis indicated unidimensionality although 4/36 items misfit the measurement model. No meaningful differential item functioning was detected. There was a moderate effect size (Hedge’s g = 1.64) between the control and clinical groups. Conclusions: The World Health Organization Disability Assessment Schedule was suitable for our study sample, distinguishing 4 levels of functional ability. Although items may be easy for some Veterans with mild traumatic brain injury and/or behavioral health conditions, the World Health Organization Disability Assessment Schedule can be used to capture disability information for those with moderate to severe disability.Implications for rehabilitation Persistent functional disability is seen in military and civilian populations with mild traumatic brain injury which often co-occurs with behavioral health conditions. A comprehensive measure of disability is needed to distinguish between levels of disability to inform clinical decisions for individual patients and to detect treatment effects between groups in research. Results of this analysis indicate the World Health Organization Disability Assessment Schedule items are sufficiently unidimensional to evaluate level of disability in the moderate and severe range among persons with mild traumatic brain injury with and without behavioral health conditions. Further examination of the psychometric properties of the World Health Organization. Disability Assessment Schedule is necessary before measurement of disability is recommended for those with less than moderate levels of disability

A pilot trial examining the merits of combining amantadine and repetitive transcranial magnetic stimulation as an intervention for persons with disordered consciousness after TBI

Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. Objective: Report pilot findings of neurobehavioral gains and network changes observed in persons with disordered consciousness (DoC) who received repetitive transcranial magnetic stimulation (rTMS) or amantadine (AMA), and then rTMS+AMA. Participants: Four persons with DoC 1 to 15 years after traumatic brain injury (TBI). Design: Alternate treatment-order, within-subject, baseline-controlled trial. Main Measures: For group and individual neurobehavioral analyses, predetermined thresholds, based on mixed linear-effects models and conditional minimally detectable change, were used to define meaningful neurobehavioral change for the Disorders of Consciousness Scale-25 (DOCS) total and Auditory-Language measures. Resting-state functional connectivity (rsFC) of the default mode and 6 other networks was examined. Results: Meaningful gains in DOCS total measures were observed for 75% of treatment segments and auditory-language gains were observed after rTMS, which doubled when rTMS preceded rTMS+AMA. Neurobehavioral changes were reflected in rsFC for language, salience, and sensorimotor networks. Between networks interactions were modulated, globally, after all treatments. Conclusions: For persons with DoC 1 to 15 years after TBI, meaningful neurobehavioral gains were observed after provision of rTMS, AMA, and rTMS+AMA. Sequencing and combining of treatments to modulate broad-scale neural activity, via differing mechanisms, merits investigation in a future study powered to determine efficacy of this approach to enabling neurobehavioral recovery

Neural Connectivity Changes Facilitated by Familiar Auditory Sensory Training in Disordered Consciousness: A TBI Pilot Study

© Copyright © 2020 Bender Pape, Livengood, Kletzel, Blabas, Guernon, Bhaumik, Bhaumik, Mallinson, Weaver, Higgins, Wang, Herrold, Rosenow and Parrish. For people with disordered consciousness (DoC) after traumatic brain injury (TBI), relationships between treatment-induced changes in neural connectivity and neurobehavioral recovery have not been explored. To begin building a body of evidence regarding the unique contributions of treatments to changes in neural network connectivity relative to neurobehavioral recovery, we conducted a pilot study to identify relationships meriting additional examination in future research. To address this objective, we examined previously unpublished neural connectivity data derived from a randomized clinical trial (RCT). We leveraged these data because treatment efficacy, in the RCT, was based on a comparison of a placebo control with a specific intervention, the familiar auditory sensory training (FAST) intervention, consisting of autobiographical auditory-linguistic stimuli. We selected a subgroup of RCT participants with high-quality imaging data (FAST n = 4 and placebo n = 4) to examine treatment-related changes in brain network connectivity and how and if these changes relate to neurobehavioral recovery. To discover promising relationships among the FAST intervention, changes in neural connectivity, and neurobehavioral recovery, we examined 26 brain regions and 19 white matter tracts associated with default mode, salience, attention, and language networks, as well as three neurobehavioral measures. Of the relationships discovered, the systematic filtering process yielded evidence supporting further investigation of the relationship among the FAST intervention, connectivity of the left inferior longitudinal fasciculus, and auditory-language skills. Evidence also suggests that future mechanistic research should focus on examining the possibility that the FAST supports connectivity changes by facilitating redistribution of brain resources. For a patient population with limited treatment options, the reported findings suggest that a simple, yet targeted, passive sensory stimulation treatment may have altered functional and structural connectivity. If replicated in future research, then these findings provide the foundation for characterizing the unique contributions of the FAST intervention and could inform development of new treatment strategies. For persons with severely damaged brain networks, this report represents a first step toward advancing understanding of the unique contributions of treatments to changing brain network connectivity and how these changes relate to neurobehavioral recovery for persons with DoC after TBI. Clinical Trial Registry: NCT00557076, The Efficacy of Familiar Voice Stimulation During Coma Recovery (http://www.clinicaltrials.gov)