Impact of SARS-CoV-2 infection during pregnancy on the placenta and fetus.

Pregnant people and their fetuses are vulnerable to adverse health outcomes from coronavirus 2019 disease (COVID-19) due to infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 has been associated with higher rates of maternal mortality, preterm birth, and stillbirth. While SARS-CoV-2 infection of the placenta and vertical transmission is rare, this may be due to the typically longer time interval between maternal infection and testing of the placenta and neonate. Placental injury is evident in cases of SARS-CoV-2-associated stillbirth with massive perivillous fibrin deposition, chronic histiocytic intervillositis, and trophoblast necrosis. Maternal COVID-19 can also polarize fetal immunity, which may have long-term effects on neurodevelopment. Although the COVID-19 pandemic continues to evolve, the impact of emerging SARS-CoV-2 variants on placental and perinatal injury/mortality remains concerning for maternal and perinatal health. Here, we highlight the impact of COVID-19 on the placenta and fetus and remaining knowledge gaps.

Network connectivity and local transcriptomic vulnerability underpin cortical atrophy progression in Parkinson's disease.

Parkinson's disease pathology is hypothesized to spread through the brain via axonal connections between regions and is further modulated by local vulnerabilities within those regions. The resulting changes to brain morphology have previously been demonstrated in both prodromal and de novo Parkinson's disease patients. However, it remains unclear whether the pattern of atrophy progression in Parkinson's disease over time is similarly explained by network-based spreading and local vulnerability. We address this gap by mapping the trajectory of cortical atrophy rates in a large, multi-centre cohort of Parkinson's disease patients and relate this atrophy progression pattern to network architecture and gene expression profiles. Across 4-year follow-up visits, increased atrophy rates were observed in posterior, temporal, and superior frontal cortices. We demonstrated that this progression pattern was shaped by network connectivity. Regional atrophy rates were strongly related to atrophy rates across structurally and functionally connected regions. We also found that atrophy progression was associated with specific gene expression profiles. The genes whose spatial distribution in the brain was most related to atrophy rate were those enriched for mitochondrial and metabolic function. Taken together, our findings demonstrate that both global and local brain features influence vulnerability to neurodegeneration in Parkinson's disease.

Predicting longitudinal brain atrophy in Parkinson's disease using a Susceptible-Infected-Removed agent-based model.

Parkinson's disease is a progressive neurodegenerative disorder characterized by accumulation of abnormal isoforms of alpha-synuclein. Alpha-synuclein is proposed to act as a prion in Parkinson's disease: In its misfolded pathologic state, it favors the misfolding of normal alpha-synuclein molecules, spreads trans-neuronally, and causes neuronal damage as it accumulates. This theory remains controversial. We have previously developed a Susceptible-Infected-Removed (SIR) computational model that simulates the templating, propagation, and toxicity of alpha-synuclein molecules in the brain. In this study, we test this model with longitudinal MRI collected over 4 years from the Parkinson's Progression Markers Initiative (1,068 T1 MRI scans, 790 Parkinson's disease scans, and 278 matched control scans). We find that brain deformation progresses in subcortical and cortical regions. The SIR model recapitulates the spatiotemporal distribution of brain atrophy observed in Parkinson's disease. We show that connectome topology and geometry significantly contribute to model fit. We also show that the spatial expression of two genes implicated in alpha-synuclein synthesis and clearance, SNCA and GBA, also influences the atrophy pattern. We conclude that the progression of atrophy in Parkinson's disease is consistent with the prion-like hypothesis and that the SIR model is a promising tool to investigate multifactorial neurodegenerative diseases over time.

Mitochondrial function-associated genes underlie cortical atrophy in prodromal synucleinopathies.

Isolated rapid eye movement sleep behaviour disorder (iRBD) is a sleep disorder characterized by the loss of rapid eye movement sleep muscle atonia and the appearance of abnormal movements and vocalizations during rapid eye movement sleep. It is a strong marker of incipient synucleinopathy such as dementia with Lewy bodies and Parkinson's disease. Patients with iRBD already show brain changes that are reminiscent of manifest synucleinopathies including brain atrophy. However, the mechanisms underlying the development of this atrophy remain poorly understood. In this study, we performed cutting-edge imaging transcriptomics and comprehensive spatial mapping analyses in a multicentric cohort of 171 polysomnography-confirmed iRBD patients [67.7 ± 6.6 (49-87) years; 83% men] and 238 healthy controls [66.6 ± 7.9 (41-88) years; 77% men] with T1-weighted MRI to investigate the gene expression and connectivity patterns associated with changes in cortical thickness and surface area in iRBD. Partial least squares regression was performed to identify the gene expression patterns underlying cortical changes in iRBD. Gene set enrichment analysis and virtual histology were then done to assess the biological processes, cellular components, human disease gene terms, and cell types enriched in these gene expression patterns. We then used structural and functional neighbourhood analyses to assess whether the atrophy patterns in iRBD were constrained by the brain's structural and functional connectome. Moreover, we used comprehensive spatial mapping analyses to assess the specific neurotransmitter systems, functional networks, cytoarchitectonic classes, and cognitive brain systems associated with cortical changes in iRBD. All comparisons were tested against null models that preserved spatial autocorrelation between brain regions and compared to Alzheimer's disease to assess the specificity of findings to synucleinopathies. We found that genes involved in mitochondrial function and macroautophagy were the strongest contributors to the cortical thinning occurring in iRBD. Moreover, we demonstrated that cortical thinning was constrained by the brain's structural and functional connectome and that it mapped onto specific networks involved in motor and planning functions. In contrast with cortical thickness, changes in cortical surface area were related to distinct genes, namely genes involved in the inflammatory response, and to different spatial mapping patterns. The gene expression and connectivity patterns associated with iRBD were all distinct from those observed in Alzheimer's disease. In summary, this study demonstrates that the development of brain atrophy in synucleinopathies is constrained by specific genes and networks.

Brain atrophy in prodromal synucleinopathy is shaped by structural connectivity and gene expression.

Isolated REM sleep behaviour disorder (iRBD) is a synucleinopathy characterized by abnormal behaviours and vocalizations during REM sleep. Most iRBD patients develop dementia with Lewy bodies, Parkinson's disease or multiple system atrophy over time. Patients with iRBD exhibit brain atrophy patterns that are reminiscent of those observed in overt synucleinopathies. However, the mechanisms linking brain atrophy to the underlying alpha-synuclein pathophysiology are poorly understood. Our objective was to investigate how the prion-like and regional vulnerability hypotheses of alpha-synuclein might explain brain atrophy in iRBD. Using a multicentric cohort of 182 polysomnography-confirmed iRBD patients who underwent T1-weighted MRI, we performed vertex-based cortical surface and deformation-based morphometry analyses to quantify brain atrophy in patients (67.8 years, 84% male) and 261 healthy controls (66.2 years, 75%) and investigated the morphological correlates of motor and cognitive functioning in iRBD. Next, we applied the agent-based Susceptible-Infected-Removed model (i.e. a computational model that simulates in silico the spread of pathologic alpha-synuclein based on structural connectivity and gene expression) and tested if it recreated atrophy in iRBD by statistically comparing simulated regional brain atrophy to the atrophy observed in patients. The impact of SNCA and GBA gene expression and brain connectivity was then evaluated by comparing the model fit to the one obtained in null models where either gene expression or connectivity was randomized. The results showed that iRBD patients present with cortical thinning and tissue deformation, which correlated with motor and cognitive functioning. Next, we found that the computational model recreated cortical thinning (r = 0.51, P = 0.0007) and tissue deformation (r = 0.52, P = 0.0005) in patients, and that the connectome's architecture along with SNCA and GBA gene expression contributed to shaping atrophy in iRBD. We further demonstrated that the full agent-based model performed better than network measures or gene expression alone in recreating the atrophy pattern in iRBD. In summary, atrophy in iRBD is extensive, correlates with motor and cognitive function and can be recreated using the dynamics of agent-based modelling, structural connectivity and gene expression. These findings support the concepts that both prion-like spread and regional susceptibility account for the atrophy observed in prodromal synucleinopathies. Therefore, the agent-based Susceptible-Infected-Removed model may be a useful tool for testing hypotheses underlying neurodegenerative diseases and new therapies aimed at slowing or stopping the spread of alpha-synuclein pathology.

PRESS and Piezo Microsurgery (Bony Lid): A 7-Year Evolution in a Residency Program-Part 2: PRESS-Defined Site Location.

INTRODUCTION: Treatment of a failing endodontic procedure via microsurgical revision presents better outcomes due, in part, to the integration of the surgical operating microscope and cone-beam computed tomography into clinical practice. However, challenges still remain with respect to the operational locations and the techniques required to address them. Posterior sites, with substantial cortical plate thicknesses and sensitive anatomy, present the dichotomy of visualization versus postsurgical regeneration of bone. The bony lid technique bridges the gap between these 2 concepts, and the application of piezosurgery renders a precise and biocompatible osseous incision. The purpose of this article was to outline through case reports the progression of piezo-guided surgery in a resident setting. METHODS: The first 2 evolutions of the technique used a surgeon-defined method for site location. This third and final evolution uses a digital workflow to virtually plan the surgical procedure, integrating Standard Tessellation Language and Digital Imaging and Communication in Medicine files to create 3-dimensional guides with exacting resection locations, levels, and angles. Export of the virtually planned guide in postproduction generates the precision endodontic surgical stent to accurately define the site location and parameters of the procedure. All surgeries were executed using the piezosurgical method with increasing levels of guidance and precision throughout the evolution process. RESULTS: Each step in the technique implementation enabled the resident to assimilate a new technique and skill set while maintaining bone architecture and minimizing volume loss postoperatively. The patient benefits were an increase in intraoperative safety and postoperative comfort. The resident benefits were accelerated regeneration timetables and increases in the confidence level of the resident and the number of scheduled posterior surgical procedures. CONCLUSIONS: The progression from crude on-site measurements to elegant and precise surgical guides enabled the access and manipulations of difficult surgical sites without compromising visibility, postoperative osseous regeneration, or patient comfort.

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability.

Brain atrophy has been reported in the early stages of Parkinson's disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson's disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson's disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson's disease. All brain maps generated here are available on request.

Null effects of levodopa on reward- and error-based motor adaptation, savings, and anterograde interference.

Dopamine signaling is thought to mediate reward-based learning. We tested for a role of dopamine in motor adaptation by administering the dopamine precursor levodopa to healthy participants in two experiments involving reaching movements. Levodopa has been shown to impair reward-based learning in cognitive tasks. Thus, we hypothesized that levodopa would selectively impair aspects of motor adaptation that depend on the reinforcement of rewarding actions. In the first experiment, participants performed two separate tasks in which adaptation was driven either by visual error-based feedback of the hand position or binary reward feedback. We used EEG to measure event-related potentials evoked by task feedback. We hypothesized that levodopa would specifically diminish adaptation and the neural responses to feedback in the reward learning task. However, levodopa did not affect motor adaptation in either task nor did it diminish event-related potentials elicited by reward outcomes. In the second experiment, participants learned to compensate for mechanical force field perturbations applied to the hand during reaching. Previous exposure to a particular force field can result in savings during subsequent adaptation to the same force field or interference during adaptation to an opposite force field. We hypothesized that levodopa would diminish savings and anterograde interference, as previous work suggests that these phenomena result from a reinforcement learning process. However, we found no reliable effects of levodopa. These results suggest that reward-based motor adaptation, savings, and interference may not depend on the same dopaminergic mechanisms that have been shown to be disrupted by levodopa during various cognitive tasks.NEW & NOTEWORTHY Motor adaptation relies on multiple processes including reinforcement of successful actions. Cognitive reinforcement learning is impaired by levodopa-induced disruption of dopamine function. We administered levodopa to healthy adults who participated in multiple motor adaptation tasks. We found no effects of levodopa on any component of motor adaptation. This suggests that motor adaptation may not depend on the same dopaminergic mechanisms as cognitive forms or reinforcement learning that have been shown to be impaired by levodopa.

Denial of Operating Room Access for Pediatric Dental Treatment: A National Survey.

Purpose: U.S. pediatric dentists require access to hospital operating rooms (ORs) to deliver safe and effective dental care to some children but have reported denial of access to ORs for general anesthesia (GA), causing long waiting times, deferral of medically necessary dental care, and unmeasured pain and anxiety for patients. The purpose of this pilot study was to examine the extent and possible underlying causes of operating room access denial. Methods: Public policy advocates (PPAs) of the American Academy of Pediatric Dentistry completed a written or electronic questionnaire about state-specific OR denials during March 2020. Results: Responses from 50 states and the District of Columbia showed 34 PPAs (67 percent) acknowledging OR access problems, with 14 out of 34 (41 percent) reporting a moderate or major problem. Western district PPAs reported the fewest states affected (four out of 11; 36 percent). Hospitals and reimbursement emerged as frequent foci for denials in comment analysis. Conclusions: Operating room access denial is a problem for pediatric dentists in the majority of U.S. states and the District of Columbia; in those states reporting it as a problem, it was considered moderate or major in significance by almost half.

A Prodromal Brain-Clinical Pattern of Cognition in Synucleinopathies.

OBJECTIVE: Isolated (or idiopathic) rapid eye movement sleep behavior disorder (iRBD) is associated with dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Biomarkers are lacking to predict conversion to a dementia or a motor-first phenotype. Here, we aimed at identifying a brain-clinical signature that predicts dementia in iRBD. METHODS: A brain-clinical signature was identified in 48 patients with polysomnography-confirmed iRBD using partial least squares between brain deformation and 27 clinical variables. The resulting variable was applied to 78 patients with iRBD followed longitudinally to predict conversion to a synucleinopathy, specifically DLB. The deformation scores from patients with iRBD were compared with 207 patients with PD, DLB, or prodromal DLB to assess if scores were higher in DLB compared to PD. RESULTS: One latent variable explained 31% of the brain-clinical covariance in iRBD, combining cortical and subcortical deformation and subarachnoid/ventricular expansion to cognitive and motor variables. The deformation score of this signature predicted conversion to a synucleinopathy in iRBD (p = 0.036, odds ratio [OR] = 2.249; 95% confidence interval [CI] = 1.053-4.803), specifically to DLB (OR = 4.754; 95% CI = 1.283-17.618, p = 0.020) and not PD (p = 0.286). Patients with iRBD who developed dementia had scores similar to clinical and prodromal patients with DLB but higher scores compared with patients with PD. The deformation score also predicted cognitive performance over 1, 2, and 4 years in patients with PD. INTERPRETATION: We identified a brain-clinical signature that predicts conversion in iRBD to more severe/dementing forms of synucleinopathy. This pattern may serve as a new biomarker to optimize patient care, target risk reduction strategies, and administer neuroprotective trials. ANN NEUROL 2021;89:341-357.

Impact of geriatrics elective courses at three colleges of pharmacy: Attitudes toward aging and eldercare.

INTRODUCTION: One in five Americans will be 65 years and older by 2030. Training student pharmacists to provide quality eldercare as healthcare professionals is essential. The objective of the study was to assess pharmacy students' attitudes toward aging and eldercare before and after a geriatrics-focused elective course. METHODS: The University of Arizona Aging and Health Care (UA AHC) survey was modified for pharmacy and administered pre and post to students enrolled in a geriatrics elective course at three United States (US) colleges of pharmacy. Pre and post means were calculated to examine attitudinal changes after course participation. Factor analysis was performed to examine construct validity by identifying the dimensions being measured. RESULTS: Sixteen of 37 questions differed significantly from pre-course to post-course demonstrating improved attitudes after course participation. Students also reported an awareness of how older adults are viewed and treated. Factor analysis identified seven factors with a range of behaviors, skills, training, and attitudes perceived to be important in geriatric care. Two factors, importance of learning about geriatric care and experience/comfort with older adults, showed significant changes confirming positive impact of the course. CONCLUSIONS: Geriatrics-focused elective courses in three colleges of pharmacy had a positive impact on students' perceived importance of learning about geriatric care and experience/comfort with elders. Further research to adapt and validate the UA AHC survey to pharmacy education is needed. The identification of the skills and attitudes necessary to meet the growing needs of older adults is necessary for pharmacy curriculum implementation and practice.

Biomarkers of Parkinson's disease: Striatal sub-regional structural morphometry and diffusion MRI.

Parkinson's disease (PD) is a progressive neurological disorder that has no reliable biomarkers. The aim of this study was to explore the potential of semi-automated sub-regional analysis of the striatum with magnetic resonance imaging (MRI) to distinguish PD patients from controls (i.e., as a diagnostic biomarker) and to compare PD patients at different stages of disease. With 3 Tesla MRI, diffusion- and T1-weighted scans were obtained on two occasions in 24 PD patients and 18 age-matched, healthy controls. PD patients completed one session on and the other session off dopaminergic medication. The striatum was parcellated into seven functionally disparate sub-regions. The segmentation was guided by reciprocal connections to distinct cortical regions. Volume, surface-based morphometry, and integrity of white matter connections were calculated for each striatal sub-region. Test-retest reliability of our volume, morphometry, and white matter integrity measures across scans was high, with correlations ranging from r = 0.452, p < 0.05 and r = 0.985, p < 0.001. Global measures of striatum such as total striatum, nucleus accumbens, caudate nuclei, and putamen were not significantly different between PD patients and controls, indicating poor sensitivity of these measures, which average across sub-regions that are functionally heterogeneous and differentially affected by PD, to act as diagnostic biomarkers. Further, these measures did not correlate significantly with disease severity, challenging their potential to serve as progression biomarkers. In contrast, a) decreased volume and b) inward surface displacement of caudal-motor striatumthe region first and most dopamine depleted in PDdistinguished PD patients from controls. Integrity of white matter cortico-striatal connections in caudal-motor and adjacent striatal sub-regions (i.e., executive and temporal striatum) was reduced for PD patients relative to controls. Finally, volume of limbic striatum, the only striatal sub-region innervated by the later-degenerating ventral tegmental area in PD, was reduced in later-stage compared to early stage PD patients a potential progression biomarker. Segmenting striatum based on distinct cortical connectivity provided highly sensitive MRI measures for diagnosing and staging PD.

Independent effects of age and levodopa on reversal learning in healthy volunteers.

The dopamine overdose hypothesis has provided an important theoretical framework for understanding cognition in Parkinson's disease. It posits that effects of dopaminergic therapy on cognition in Parkinson's disease depend on baseline dopamine levels in brain regions that support different functions. Although functions performed by more severely dopamine-depleted brain regions improve with medication, those associated with less dopamine deficient areas are actually worsened. It is presumed that medication-related worsening of cognition owes to dopamine overdose. We investigated whether age-related changes in baseline dopamine levels would modulate effects of dopaminergic therapy on reward learning in healthy volunteers. In a double-blind, crossover design, healthy younger and older adults completed a probabilistic reversal learning task after treatment with 100/25 mg of levodopa/carbidopa versus placebo. Older adults learned more poorly than younger adults at baseline, being more likely to shift responses after misleading punishment. Levodopa worsened stimulus-reward learning relative to placebo to the same extent in both groups, irrespective of differences in baseline performance and expected dopamine levels. When order effects were eliminated, levodopa induced response shifts after reward more often than placebo. Our results reveal independent deleterious effects of age group and exogenous dopamine on reward learning, suggesting a more complex scenario than predicted by the dopamine overdose hypothesis.

Effects of levodopa on stimulus-response learning versus response selection in healthy young adults.

Dopaminergic therapy has been shown to worsen some cognitive functions, particularly learning, in Parkinson's disease (PD). This has been attributed to dopamine overdose of brain regions that are relatively dopamine replete. Dopamine dosages are titrated to the severely depleted dorsal striatum (DS). According to this account, dopaminergic therapy should worsen cognitive functions in healthy young adults who have normal dopamine levels. As a critical test of the dopamine overdose hypothesis, we tested the effect of levodopa on learning stimulus-response associations and on performing stimulus-specific responses once these associations were learned. In a randomized, double-blind, placebo-controlled, between-subjects design, 40 healthy young adults completed a stimulus-response learning task on either levodopa or placebo. Half of the participants received 100mg of levodopa and 25mg of carbidopa whereas the other half received an equal volume of placebo. In Session 1, participants learned to associate abstract images with specific key-press responses through trial and error with outcome feedback. In Session 2, participants performed stimulus-specific selections to abstract images they had previously learned in Session 1. Participants treated with levodopa compared to those on placebo demonstrated unambiguously less efficient acquisition of stimulus-response associations. The groups did not differ in their ability to enact stimulus-specific selections once they were learned, however, even though these responses were not overlearned. This pattern of findings is entirely consistent with the effect of levodopa on cognition in PD. The deleterious effects of levodopa on learning seem independent of PD pathology. These results have important implications for understanding mechanisms of cognitive dysfunction in PD and caution about the potential for cognitive deficits in patients treated with levodopa for other indications.

Pramipexole Increases Go Timeouts but Not No-go Errors in Healthy Volunteers.

Parkinson's disease (PD) is characterized by motor symptoms, such as resting tremor, bradykinesia and rigidity, but also features non-motor complications. PD patients taking dopaminergic therapy, such as levodopa but especially dopamine agonists (DAs), evidence an increase in impulse control disorders (ICDs), suggesting a link between dopaminergic therapy and impulsive pursuit of pleasurable activities. However, impulsivity is a multifaceted construct. Motor impulsivity refers to the inability to overcome automatic responses or cancel pre-potent responses. Previous research has suggested that PD patients, on dopaminergic medications, have decreased motor impulsivity. Whether effects on impulsivity are main effects of dopaminergic therapies or are specific to PD is unclear. Using a Go No-go task, we investigated the effect of a single dose of the DA pramipexole on motor impulsivity in healthy participants. The Go No-go task consisted of Go trials, for which keystroke responses were made as quickly as possible, and lesser frequency No-go trials, on which motor responses were to be inhibited. We hypothesized that pramipexole would decrease motor impulsivity. This would manifest as: (a) fewer No-go errors (i.e., fewer responses on trials in which a response ought to have been inhibited); and (b) more timed-out Go trials (i.e., more trials on which the deadline elapsed before a decision to make a keystroke occurred). Healthy volunteers were treated with either 0.5 mg of pramipexole or a standard placebo (randomly determined). During the 2-h wait period, they completed demographic, cognitive, physiological and affective measures. The pramipexole group had significantly more Go timeouts (p < 0.05) compared to the placebo group though they did not differ in percent of No-go errors. In contrast to its effect on pursuit of pleasurable activities, pramipexole did not increase motor impulsivity. In fact, in line with findings in PD and addiction, dopaminergic therapy might increase motor impulse control. In these patient groups, by enhancing function of the dorsal striatum (DS) of the basal ganglia in contrast to its effect on impulsive pursuit of pleasurable activities. These findings have implications for use and effects of pramipexole in PD as well as in other conditions (e.g., restless leg, dystonia, depression, addiction-related problems).

Pramipexole Impairs Stimulus-Response Learning in Healthy Young Adults.

Dopaminergic therapy has paradoxical effects on cognition in Parkinson's disease (PD) patients, with some functions worsened and others improved. The dopamine overdose hypothesis is proposed as an explanation for these opposing effects of medication taking into account the varying levels of dopamine within different brain regions in PD. The detrimental effects of medication on cognition have been attributed to exogenous dopamine overdose in brain regions with spared dopamine levels in PD. It has been demonstrated that learning is most commonly worsened by dopaminergic medication. The current study aimed to investigate whether the medication-related learning impairment exhibited in PD patients is due to a main effect of medication by evaluating the dopamine overdose hypothesis in healthy young adults. Using a randomized, double-blind, placebo-controlled design, 40 healthy young undergraduate students completed a stimulus-response learning task. Half of the participants were treated with 0.5 mg of pramipexole, a dopamine agonist, whereas the other half were treated with a placebo. We found that stimulus-response learning was significantly impaired in participants on pramipexole relative to placebo controls. These findings are consistent with the dopamine overdose hypothesis and suggest that dopaminergic medication impairs learning independent of PD pathology. Our results have important clinical implications for conditions treated with pramipexole, particularly PD, restless leg syndrome, some forms of dystonia, and potentially depression.

Guideline summary review: an evidence-based clinical guideline for the diagnosis and treatment of adult isthmic spondylolisthesis.

BACKGROUND CONTEXT: The North American Spine Society's (NASS) Evidence-Based Clinical Guideline for the Diagnosis and Treatment of Adult Isthmic Spondylolisthesis features evidence-based recommendations for diagnosing and treating adult patients with isthmic spondylolisthesis. The guideline is intended to reflect contemporary treatment concepts for symptomatic isthmic spondylolisthesis as reflected in the highest quality clinical literature available on this subject as of June 2013. NASS' guideline on this topic is the only guideline on adult isthmic spondylolisthesis accepted in the Agency for Healthcare Research and Quality's National Guideline Clearinghouse. PURPOSE: The purpose of the guideline is to provide an evidence-based educational tool to assist spine specialists when making clinical decisions for adult patients with isthmic spondylolisthesis. This article provides a brief summary of the evidence-based guideline recommendations for diagnosing and treating patients with this condition. STUDY DESIGN: This is a guideline summary review. METHODS: This guideline is the product of the Adult Isthmic Spondylolisthesis Work Group of NASS' Evidence-Based Clinical Guideline Development Committee. The methods used to develop this guideline are detailed in the complete guideline and technical report available on the NASS website. In brief, a multidisciplinary work group of spine care specialists convened to identify clinical questionsto address in the guideline. The literature search strategy was developed in consultation with medical librarians. Upon completion of the systematic literature search, evidence relevant to the clinical questions posed in the guideline was reviewed. Work group members utilized NASS evidentiary table templates to summarize study conclusions, identify study strengths and weaknesses, and assign levels of evidence. Work group members participated in webcasts and in-person recommendation meetings to update and formulate evidence-based recommendations and incorporate expert opinion when necessary. The draft guidelines were submitted to an internal peer review process and ultimately approved by the NASS Board of Directors. Upon publication, the Adult Isthmic Spondylolisthesis guideline was accepted into the National Guideline Clearinghouse and will be updated approximately every 5 years. RESULTS: Thirty-one clinical questions were addressed, and the answers are summarized in this article. The respective recommendations were graded according to the levels of evidence of the supporting literature. CONCLUSIONS: The evidence-based clinical guideline has been created using techniques of evidence-based medicine and best available evidence to aid practitioners in the diagnosis and treatment of adult patients with isthmic spondylolisthesis. The entire guideline document, including the evidentiary tables, literature search parameters, literature attrition flowchart, suggestions for future research, and all of the references, is available electronically on the NASS website at https://www.spine.org/ResearchClinicalCare/QualityImprovement/ClinicalGuidelines.aspx and will remain updated on a timely schedule.

Levodopa impairs probabilistic reversal learning in healthy young adults.

RATIONALE: Dopaminergic therapy improves some cognitive functions and worsens others in patients with Parkinson's disease (PD). These paradoxical effects are explained by the dopamine overdose hypothesis, which proposes that effects of dopaminergic therapy on a cognitive function is determined by the baseline dopamine levels in brain regions mediating that function. OBJECTIVES: We directly tested this prevalent hypothesis, evaluating the effects of levodopa on stimulus-reward learning in healthy young adults, who presumably have optimal baseline dopamine levels and dopamine regulation. METHODS: Twenty-six healthy, young adults completed a probabilistic reversal learning task in a randomized, double-blind, placebo-controlled, crossover design. Participants completed one session on levodopa 100 mg/carbidopa 25 mg and another session on placebo. RESULTS: We found that levodopa impaired reversal learning relative to placebo. Further analyses revealed that levodopa impaired learning from both punishment and reward. CONCLUSIONS: Exogenous dopamine impairs stimulus-reward learning, independent of PD pathology and prior to sensitization through repeated exposure, in healthy adults with normal cognition and baseline dopamine function. Our findings support the dopamine overdose hypothesis and caution clinicians about detrimental effects of levodopa in all clinical populations (e.g., early PD, restless leg syndrome) regardless of baseline cognitive and dopaminergic system function.

Dopaminergic therapy affects learning and impulsivity in Parkinson's disease.

OBJECTIVE: The aim was to examine the effect of dopaminergic medication on stimulus-response learning versus performing decisions based on learning. METHOD: To see the effect of dopaminergic therapy on stimulus-response learning and response selection, participants with Parkinson's disease (PD) were either tested on and/or off their prescribed dose of dopaminergic therapy during different testing days. Forty participants with PD and 34 healthy controls completed the experiment on consecutive days. On Day 1, participants learned to associate abstract images with spoken, "right" or "left" responses via feedback (Session 1). On Day 2, participants recalled these responses (Session 2) and indicated the location (i.e., right or left of center) of previously studied images intermixed with new images (Session 3). RESULTS: Participants with PD off medication learned stimulus-response associations equally well compared to healthy controls. Learning was impaired by dopaminergic medication. Regardless of medication status, patients recalled the stimulus-response associations from Day 1 as well as controls. In Session 3 off medication, patients demonstrated enhanced facilitation relative to controls and patients on medication, when the stimulus location was congruent with the spoken response that was learned for the stimulus in Session 1. INTERPRETATION: Learning in PD was comparable to that of healthy controls off medication. Learning was worsened by dopaminergic therapy in PD. We interpret greater facilitation in participants with PD off medication for congruent responses as evidence of greater impulsivity. This motor or reflexive impulsivity was normalized by medication in PD. These findings shed light on the cognitive profile of PD and have implications for dopaminergic treatment.