Reward and Punishment Learning as Predictors of Cognitive Behavioral Therapy Response in Parkinson's Disease Comorbid with Clinical Depression.

Depression is highly comorbid among individuals with Parkinson's Disease (PD), who often experience unique challenges to accessing and benefitting from empirically supported interventions like Cognitive Behavioral Therapy (CBT). Given the role of reward processing in both depression and PD, this study analyzed a subset (N = 25) of participants who participated in a pilot telemedicine intervention of PD-informed CBT, and also completed a Reward- and Punishment-Learning Task (RPLT) at baseline. At the conclusion of CBT, participants were categorized into treatment responders (n = 14) and non-responders (n = 11). Responders learned more optimally from negative rather than positive feedback on the RPLT, while this pattern was reversed in non-responders. Computational modeling suggested group differences in learning rate to negative feedback may drive the observed differences. Overall, the results suggest that a within-subject bias for punishment-based learning might help to predict response to CBT intervention for depression in those with PD.Plain Language Summary Performance on a Computerized Task may predict which Parkinson's Disease Patients benefit from Cognitive Behavioral Treatment of Clinical DepressionWhy was the study done? Clinical depression regularly arises in individuals with Parkinson's Disease (PD) due to the neurobiological changes with the onset and progression of the disease as well as the unique psychosocial difficulties associated with living with a chronic condition. Nonetheless, psychiatric disorders among individuals with PD are often underdiagnosed and likewise undertreated for a variety of reasons. The results of our study have implications about how to improve the accuracy and specificity of mental health treatment recommendations in the future to maximize benefits for individuals with PD, who often face additional barriers to accessing quality mental health treatment.What did the researchers do? We explored whether performance on a computerized task called the Reward- and Punishment-Learning Task (RPLT) helped to predict response to Cognitive Behavioral Therapy (CBT) for depression better than other predictors identified in previous studies. Twenty-five individuals with PD and clinical depression that completed a 10-week telehealth CBT program were assessed for: Demographics (Age, gender, etc.); Clinical information (PD duration, mental health diagnoses, levels of anxiety/depression, etc.); Neurocognitive performance (Memory, processing speed, impulse control, etc.); and RPLT performance.What did the researchers find? A total of 14 participants significantly benefitted from CBT treatment while 11 did not significantly benefit from treatment.There were no differences before treatment in the demographics, clinical information, and neurocognitive performance of those participants who ended up benefitting from the treatment versus those who did not.There were, however, differences before treatment in RPLT performance so that those individuals that benefitted from CBT seemed to learn better from negative feedback.What do the findings mean? Our results suggest that the CBT program benefitted those PD patients with clinical depression that seemed to overall learn best from avoiding punishment rather than obtaining reward which was targeted in CBT by focusing on increasing engagement in rewarding activities. The Reward- and Punishment-Learning Task hence may be a useful tool to help predict treatment response and provide more individualized recommendations on how to best maximize the benefits of psychotherapy for individuals with PD that may struggle to connect to mental health care. Caution is recommended about interpretating these results beyond this study as the overall number of participants was small and the data for this study were collected as part of a previous study so there was no opportunity to include additional measurements of interest.

Low body mass and high-quality sleep maximize the ability of aerobic fitness to promote improved cognitive function in older African Americans.

ABSTRACTObjectives: Because African Americans are at elevated risk for cognitive decline and Alzheimer's disease, it is important to understand which health and lifestyle factors are most important for reducing this risk. Obesity and poor sleep quality are common in lower-income, urban African Americans and have been linked to cognitive decline in older age. Fortunately, increasing aerobic fitness via regular exercise can improve cognitive function. This study sought to (1) examine the cross-sectional relationship between aerobic fitness and cognitive function in older African Americans, and (2) determine whether body mass index and sleep quality moderated the relationship between aerobic fitness and cognition.Design: 402 older African Americans, ages 60-90 (84% female, mean education level = 14 years) completed neuropsychological testing, computerized behavioral tasks, physical performance measures, and health and lifestyle questionnaires. Hierarchical linear regressions were performed to determine associations between aerobic fitness and cognition and whether body mass index and sleep quality moderate the fitness-cognition relationship while controlling for age, sex, education, depressive symptoms, and literacy.Results: Higher aerobic fitness levels were significantly associated with better executive function. The relationships between fitness and hippocampal-dependent cognitive functions (learning and memory, generalization) were attenuated in those who are obese (body mass index ≥ 30 kg/m2) or rated their sleep quality as poor, ps < .05.Conclusion: Our results suggest that while exercise and associated improvements in aerobic fitness are key for improved cognition, these benefits are maximized in those who maintain low body weight and get sufficient, high quality sleep. Exercise programs for older African Americans will be most effective if they are integrated with education programs that emphasize healthy eating, weight control, and sleep hygiene and conceptualize individuals as part of their broader social and environmental context.

Sleep to remember, sleep to forget: Rapid eye movement sleep can have inverse effects on recall and generalization of fear memories.

Rapid Eye Movement (REM) sleep has been shown to modulate the consolidation of fear memories, a process that may contribute to the development of Post-Traumatic Stress Disorder (PTSD). However, contradictory findings have been reported regarding the direction of this modulation and its differential effects on recall versus generalization. In two complementary experiments, we addressed this by employing sleep deprivation protocols together with a novel fear-conditioning paradigm that required the discrimination between coexisting threat and safety signals. Using skin conductance responses and functional imaging (fMRI), we found two opposing effects of REM sleep: While REM impaired recall of the original threat memories, it improved the ability to generalize these memories to novel situations that emphasized the discrimination between threat and safety signals. These results, as well as previous findings in healthy participants and patients diagnosed with PTSD, could be explained by the degree to which the balance between threat and safety signals for a given stimulus was predictive of threat. We suggest that this account can be integrated with contemporary theories of sleep and fear learning, such as the REM recalibration hypothesis.

Increased dynamic flexibility in the medial temporal lobe network following an exercise intervention mediates generalization of prior learning.

Recent work has conceptualized the brain as a network comprised of groups of sub-networks or modules. "Flexibility" of brain network(s) indexes the dynamic reconfiguration of comprising modules. Using novel techniques from dynamic network neuroscience applied to high-resolution resting-state functional magnetic resonance imaging (fMRI), the present study investigated the effects of an aerobic exercise intervention on the dynamic rearrangement of modular community structure-a measure of neural flexibility-within the medial temporal lobe (MTL) network. The MTL is one of the earliest brain regions impacted by Alzheimer's disease. It is also a major site of neuroplasticity that is sensitive to the effects of exercise. In a two-group non-randomized, repeated measures and matched control design with 34 healthy older adults, we observed an exercise-related increase in flexibility within the MTL network. Furthermore, MTL network flexibility mediated the beneficial effect aerobic exercise had on mnemonic flexibility, as measured by the ability to generalize past learning to novel task demands. Our results suggest that exercise exerts a rehabilitative and protective effect on MTL function, resulting in dynamically evolving networks of regions that interact in complex communication patterns. These reconfigurations may underlie exercise-induced improvements on cognitive measures of generalization, which are sensitive to subtle changes in the MTL.

ABCA7 risk variant in healthy older African Americans is associated with a functionally isolated entorhinal cortex mediating deficient generalization of prior discrimination training.

Using high-resolution resting state functional magnetic resonance imaging (fMRI), the present study tested the hypothesis that ABCA7 genetic risk differentially affects intra-medial temporal lobe (MTL) functional connectivity between MTL subfields, versus internetwork connectivity of the MTL with the medial prefrontal cortex (mPFC), in nondemented older African Americans. Although the association of ABCA7 risk variants with Alzheimer's disease (AD) has been confirmed worldwide, its effect size on the relative odds of being diagnosed with AD is significantly higher in African Americans. However, little is known about the neural correlates of cognitive function in older African Americans and how they relate to AD risk conferred by ABCA7. In a case-control fMRI study of 36 healthy African Americans, we observed ABCA7 related impairments in behavioral generalization that was mediated by dissociation in entorhinal cortex (EC) resting state functional connectivity. Specifically, ABCA7 risk variant was associated with EC-hippocampus hyper-synchronization and EC-mPFC hypo-synchronization. Carriers of the risk genotype also had a significantly smaller anterolateral EC, despite our finding no group differences on standardized neuropsychological tests. Our findings suggest a model where impaired cortical connectivity leads to a more functionally isolated EC at rest, which translates into aberrant EC-hippocampus hyper-synchronization resulting in generalization deficits. While we cannot identify the exact mechanism underlying the observed alterations in EC structure and network function, considering the relevance of Aß in ABCA7 related AD pathogenesis, the results of our study may reflect the synergistic reinforcement between amyloid and tau pathology in the EC, which significantly increases tau-induced neuronal loss and accelerates synaptic alterations. Finally, our results add to a growing literature suggesting that generalization of learning may be a useful tool for assessing the mild cognitive deficits seen in the earliest phases of prodromal AD, even before the more commonly reported deficits in episodic memory arise.

Baseline Levels of Rapid Eye Movement Sleep May Protect Against Excessive Activity in Fear-Related Neural Circuitry.

Sleep, and particularly rapid eye movement sleep (REM), has been implicated in the modulation of neural activity following fear conditioning and extinction in both human and animal studies. It has long been presumed that such effects play a role in the formation and persistence of posttraumatic stress disorder, of which sleep impairments are a core feature. However, to date, few studies have thoroughly examined the potential effects of sleep prior to conditioning on subsequent acquisition of fear learning in humans. Furthermore, these studies have been restricted to analyzing the effects of a single night of sleep-thus assuming a state-like relationship between the two. In the current study, we used long-term mobile sleep monitoring and functional neuroimaging (fMRI) to explore whether trait-like variations in sleep patterns, measured in advance in both male and female participants, predict subsequent patterns of neural activity during fear learning. Our results indicate that higher baseline levels of REM sleep predict reduced fear-related activity in, and connectivity between, the hippocampus, amygdala and ventromedial PFC during conditioning. Additionally, skin conductance responses (SCRs) were weakly correlated to the activity in the amygdala. Conversely, there was no direct correlation between REM sleep and SCRs, indicating that REM may only modulate fear acquisition indirectly. In a follow-up experiment, we show that these results are replicable, though to a lesser extent, when measuring sleep over a single night just before conditioning. As such, baseline sleep parameters may be able to serve as biomarkers for resilience, or lack thereof, to trauma.SIGNIFICANCE STATEMENT Numerous studies over the past two decades have established a clear role of sleep in fear-learning processes. However, previous work has focused on the effects of sleep following fear acquisition, thus neglecting the potential effects of baseline sleep levels on the acquisition itself. The current study provides the first evidence in humans of such an effect. Specifically, the results of this study suggest that baseline rapid eye movement (REM) sleep may serve a protective function against enhanced fear encoding through the modulation of connectivity between the hippocampus, amygdala, and the ventromedial PFC. Building on this finding, baseline REM measurements may serve as a noninvasive biomarker for resilience to trauma or, conversely, to the potential development of posttraumatic stress disorder following trauma.

Recruiting Older African Americans to Brain Health and Aging Research Through Community Engagement: Lessons from the African-American Brain Health Initiative at Rutgers University-Newark.

The African-American Brain Health Initiative at Rutgers University-Newark is a university-community partnership combining community engagement, education and training, and brain health research. Partnering with community-based organizations, it promotes brain health literacy, Alzheimer's awareness, brain-healthy lifestyle choices, and participation in brain research for older African Americans in Greater Newark, New Jersey. Our approach to recruitment relies on building trust through long-term relationships; communicating health knowledge through trusted community leaders; recruiting subjects through targeted efforts; and cultivating research participants as ambassadors.

Motor-symptom laterality affects acquisition in Parkinson's disease: A cognitive and functional magnetic resonance imaging study.

BACKGROUND AND OBJECTIVES: Asymmetric onset of motor symptoms in PD can affect cognitive function. We examined whether motor-symptom laterality could affect feedback-based associative learning and explored its underlying neural mechanism by functional magnetic resonance imaging in PD patients. METHODS: We recruited 63 early-stage medication-naïve PD patients (29 left-onset medication-naïve patients, 34 right-onset medication-naïve patients) and 38 matched normal controls. Subjects completed an acquired equivalence task (including acquisition, retention, and generalization) and resting-state functional magnetic resonance imaging scans. Learning accuracy and response time in each phase of the task were recorded for behavioral measures. Regional homogeneity was used to analyze resting-state functional magnetic resonance imaging data, with regional homogeneity lateralization to evaluate hemispheric functional asymmetry in the striatum. RESULTS: Left-onset patients made significantly more errors in acquisition (feedback-based associative learning) than right-onset patients and normal controls, whereas right-onset patients performed as well as normal controls. There was no significant difference among these three groups in the accuracy of either retention or generalization phase. The three groups did not show significant differences in response time. In the left-onset group, there was an inverse relationship between acquisition errors and regional homogeneity in the right dorsal rostral putamen. There were no significant regional homogeneity changes in either the left or the right dorsal rostral putamen in right-onset patients when compared to controls. CONCLUSIONS: Motor-symptom laterality could affect feedback-based associative learning in PD, with left-onset medication-naïve patients being selectively impaired. Dysfunction in the right dorsal rostral putamen may underlie the observed deficit in associative learning in patients with left-sided onset.© 2016 International Parkinson and Movement Disorder Society.

Deficits in hippocampal-dependent transfer generalization learning accompany synaptic dysfunction in a mouse model of amyloidosis.

Elevated ß-amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimer's disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the "transfer" of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative "transfer learning" task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle ß-amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.

The influence of sleep on emotional and cognitive processing is primarily trait- (but not state-) dependent.

Human studies of sleep and cognition have established thatdifferent sleep stages contribute to distinct aspects of cognitive and emotional processing. However, since the majority of these findings are based on single-night studies, it is difficult to determine whether such effects arise due to individual, between-subject differences in sleep patterns, or from within-subject variations in sleep over time. In the current study, weinvestigated the longitudinal relationship between sleep patterns and cognitive performance by monitoring both in parallel, daily, for a week. Using two cognitive tasks - one assessing emotional reactivity to facial expressions and the other evaluating learning abilities in a probabilistic categorization task - we found that between-subjectdifferences in the average time spent in particular sleep stages predicted performance in these tasks far more than within-subject daily variations. Specifically, the typical time individualsspent in Rapid-Eye Movement (REM) sleep and Slow-Wave Sleep (SWS) was correlated to their characteristic measures of emotional reactivity, whereas the typical time spent in SWS and non-REM stages 1 and 2 was correlated to their success in category learning. These effects were maintained even when sleep properties werebased onbaseline measures taken prior to the experimental week. In contrast, within-subject daily variations in sleep patterns only contributed to overnight difference in one particular measure of emotional reactivity. Thus, we conclude that the effects of natural sleep onemotional cognition and categorylearning are more trait-dependent than state-dependent, and suggest ways to reconcile these results with previous findings in the literature.

Love to win or hate to Lose? Asymmetry of dopamine D2 receptor binding predicts sensitivity to reward versus punishment.

Humans show consistent differences in the extent to which their behavior reflects a bias toward appetitive approach-related behavior or avoidance of aversive stimuli [Elliot, A. J. Approach and avoidance motivation. In A. J. Elliot (Ed.), Handbook of approach and avoidance motivation (pp. 3-14). New York: Psychology Press, 2008]. We examined the hypothesis that in healthy participants this motivational bias (assessed by self-report and by a probabilistic learning task that allows direct comparison of the relative sensitivity to reward and punishment) reflects lateralization of dopamine signaling. Using [F-18]fallypride to measure D2/D3 binding, we found that self-reported motivational bias was predicted by the asymmetry of frontal D2 binding. Similarly, striatal and frontal asymmetries in D2 dopamine receptor binding, rather than absolute binding levels, predicted individual differences in learning from reward versus punishment. These results suggest that normal variation in asymmetry of dopamine signaling may, in part, underlie human personality and cognition.

Hippocampal BOLD response during category learning predicts subsequent performance on transfer generalization.

To test a prediction of our previous computational model of cortico-hippocampal interaction (Gluck and Myers [1993, 2001]) for characterizing individual differences in category learning, we studied young healthy subjects using an fMRI-adapted category-learning task that has two phases, an initial phase in which associations are learned through trial-and-error feedback followed by a generalization phase in which previously learned rules can be applied to novel associations (Myers et al. [2003]). As expected by our model, we found a negative correlation between learning-related hippocampal responses and accuracy during transfer, demonstrating that hippocampal adaptation during learning is associated with better behavioral scores during transfer generalization. In addition, we found an inverse relationship between Blood Oxygenation Level Dependent (BOLD) activity in the striatum and that in the hippocampal formation and the orbitofrontal cortex during the initial learning phase. Conversely, activity in the dorsolateral prefrontal cortex, orbitofrontal cortex and parietal lobes dominated over that of the hippocampal formation during the generalization phase. These findings provide evidence in support of theories of the neural substrates of category learning which argue that the hippocampal region plays a critical role during learning for appropriately encoding and representing newly learned information so that that this learning can be successfully applied and generalized to subsequent novel task demands.

Strategies for Recruiting Older Black Men into Aging and Alzheimer's Research.

BACKGROUND: Despite their high risks for Alzheimer's disease, older Black men are minimally represented in Alzheimer's research and clinical trials. The absence of older Black men in Alzheimer's research limits our ability to characterize the changes associated with cognitive impairments in older Black men-a key health disparity concern. METHODS: Drawing on lessons we learned from years of community-based participatory research in Newark, NJ, we highlight recruitment strategies developed alongside community partners to guide our enrollment and retention efforts for Black men. RESULTS: We identified seven recruitment strategies: provide indirect health education through social programming, target older men through the younger men in their lives, go beyond Black churches, use older Black men as trained community ambassadors, enlist the women in Black men's lives, frame research participation as a legacy to leave their sons, and use past and current Black men participants as role models. CONCLUSIONS: These recruitment strategies help us address many barriers to recruiting older Black men. They can be easily implemented by researchers conducting aging and brain health research or interested in working with older Black men and under-represented populations.

Higher Number of Children is Associated with Increased Risk of Generalization Deficits in Older African American Women.

OBJECTIVES: The objectives of this project were to: (1) examine the relationship between the number of biological children and hippocampal-dependent cognitive performance among older African American women and (2) determine the influence of socioeconomic status (i.e., age, education, marital status, median household income), if any, on this relationship. METHODS: 146 cognitively unimpaired African American women aged 60 and older were recruited from the greater Newark area and reported their number of biological children, marital status, educational level, and age. We retrieved median household income from census tract data based on the participants' addresses. Participants' cognitive performance was assessed using the Rey Auditory Verbal Learning Test (RAVLT) long delay recall and a Rutgers generalization task (Concurrent Discrimination and Transfer Task). RESULTS: As the number of biological children a woman has had increases, the number of generalization errors also increased, indicating poorer hippocampal-dependent cognitive performance when controlling for age, education, marital status, and median household income. There was no significant relationship between the number of children and performance on a standardized neuropsychological measure of episodic memory (RAVLT), although education was a significant covariate. DISCUSSION: Generalization tasks may better capture early changes in cognitive performance in older African American women who have had children than standardized neuropsychological assessments. This finding may be explained by the fluctuations in estrogen associated with having children. Future studies should explore how these findings can be applied to protecting cognitive function and preventing AD in older African American women who have had children.

Hypertension is associated with reduced resting-state medial temporal lobe dynamic network flexibility in older African Americans.

Hypertension disproportionately affects African Americans and is a risk factor for Alzheimer's disease (AD). We investigated the relationship of blood pressure (BP) with medial temporal lobe (MTL) dynamic network flexibility (a novel AD biomarker) and cognitive generalization in older African Americans. In a cross-sectional study, 37 normotensive (systolic BP <130 mmHg, 82.5% F, 64.4 ± 4.9 years; 14.3 ± 2.1 years of education) versus 79 hypertensive (systolic BP ≥130 mmHg, 79.5% F, 66.8 ± 4.1 years; 14.0 ± 0.2 years of education) participants were enrolled. All participants completed a 10-min resting-state functional magnetic resonance imaging scan to assess MTL dynamic network flexibility and two generalization tasks to assess cognition. Anthropometrics and aerobic fitness (via 6-min walk test) were also determined. There was no difference in BMI (29.7 ± 6.4 vs. 31.9 ± 6.3 kg/m2, p = 0.083) or aerobic fitness (15.5 ± 2.6 vs. 15.1 ± 2.6 mL/kg/min; p = 0.445) between normotensive and hypertensive groups. However, normotensive participants had higher MTL dynamic network flexibility compared to hypertensive participants (0.42 ± 0.23 vs. 0.32 ± 0.25 mL, p = 0.040), and this was associated with higher mean arterial blood pressure (r = -0.21, p = 0.036). Therefore, hypertensive older African Americans demonstrated lower MTL dynamic network flexibility compared to their normotensive counterparts independent of BMI and aerobic fitness. Further studies are required to determine how blood pressure mediates AD risk in African Americans.

Enhanced avoidance learning in behaviorally inhibited young men and women.

Behavioral inhibition (BI) is a temperamental tendency to avoid or withdraw from novel social and nonsocial situations, and has been shown to predispose individuals to anxiety disorders. However, adequate means to assess individual differences in avoidance learning in humans are presently limited. Here, we tested whether individuals with high self-reported BI show faster associative learning on a purely cognitive task and whether such inhibited individuals are more prone to avoid aversive outcomes. In Experiment 1, we tested 74 healthy undergraduate students (mean age 19.5 years; 55.4% female) on a computer-based probabilistic classification task, where participants were asked to classify four distinct visual stimuli into two categories. Two stimuli were associated with reward (point gain) and two were associated with punishment (point loss). In Experiment 2, 79 participants from the same population (mean age 19.8 years; 62% female) were tested on a novel modification of the same task, where they also had the option to opt out of responding on each trial, thus avoiding any chance of being punished (or rewarded) on that trial. Results show that inhibited participants demonstrated better associative learning in Experiment 1, while exhibiting a greater tendency to opt out in Experiment 2 (repeated-measures analysis of variance, main effects of BI, both p < 0.05). These results indicate that the facilitated classically conditioned learning previously observed in inhibited individuals can be extended to a cognitive task, and also highlight a specific preference in inhibited individuals for withdrawal ("opting out") as a response strategy, when multiple strategies are available to avoid punishment.

{alpha}-Synuclein gene duplication impairs reward learning.

alpha-Synuclein (SNCA) plays an important role in the regulation of dopaminergic neurotransmission and neurodegeneration in Parkinson disease. We investigated reward and punishment learning in asymptomatic carriers of a rare SNCA gene duplication who were healthy siblings of patients with Parkinson disease. Results revealed that healthy SNCA duplication carriers displayed impaired reward and intact punishment learning compared with noncarriers. These results demonstrate that a copy number variation of the SNCA gene is associated with selective impairments on reinforcement learning in asymptomatic carriers without the motor symptoms of Parkinson disease.

Dissociating the cognitive effects of levodopa versus dopamine agonists in a neurocomputational model of learning in Parkinson's disease.

BACKGROUND/AIMS: Levodopa and dopamine agonists have different effects on the motor, cognitive, and psychiatric aspects of Parkinson's disease (PD). METHODS: Using a computational model of basal ganglia (BG) and prefrontal cortex (PFC) dopamine, we provide a theoretical synthesis of the dissociable effects of these dopaminergic medications on brain and cognition. Our model incorporates the findings that levodopa is converted by dopamine cells into dopamine, and thus activates prefrontal and striatal D(1) and D(2) dopamine receptors, whereas antiparkinsonian dopamine agonists directly stimulate D(2) receptors in the BG and PFC (although some have weak affinity to D(1) receptors). RESULTS: In agreement with prior neuropsychological studies, our model explains how levodopa enhances, but dopamine agonists impair or have no effect on, stimulus-response learning and working memory. CONCLUSION: Our model explains how levodopa and dopamine agonists have differential effects on motor and cognitive processes in PD.

High-Quality Sleep Mitigates ABCA7-Related Generalization Deficits in Healthy Older African Americans.

BACKGROUND: Both sleep deficiencies and Alzheimer's disease (AD) disproportionately affect older African Americans. Genetic susceptibility to AD further compounds risk for cognitive decline in this population. Aside from APOE ɛ4, ABCA7 rs115550680 is the strongest genetic locus associated with late-onset AD in African Americans. While sleep and ABCA7 rs115550680 independently influence late-life cognitive outcomes, we know too little about the interplay between these two factors on cognitive function. OBJECTIVE: We investigated the interaction between sleep and ABCA7 rs115550680 on hippocampal-dependent cognitive function in older African Americans. METHODS: One-hundred fourteen cognitively healthy older African Americans were genotyped for ABCA7 risk (n = 57 carriers of risk "G" allele; n = 57 non-carriers), responded to lifestyle questionnaires, and completed a cognitive battery. Sleep was assessed via a self-reported rating of sleep quality (poor, average, good). Covariates included age and years of education. RESULTS: Using ANCOVA, we found that carriers of the risk genotype who reported poor or average sleep quality demonstrated significantly poorer generalization of prior learning-a cognitive marker of AD-compared to their non-risk counterparts. Conversely, there was no genotype-related difference in generalization performance in individuals who reported good sleep quality. CONCLUSION: These results indicate that sleep quality may be neuroprotective against genetic risk for AD. Future studies employing more rigorous methodology should investigate the mechanistic role of sleep neurophysiology in the pathogenesis and progression of AD associated with ABCA7. There is also need for the continued development of non-invasive sleep interventions tailored to racial groups with specific AD genetic risk profiles.

Altered learning and transfer abilities in Korsakoff's syndrome depending on task complexity.

Korsakoff's syndrome (KS) is characterized by episodic memory impairment due to damage to the medial diencephalic structures. Although commonly associated with chronic alcoholism, starvation due to the hunger strike is one of its nonalcoholic causes. Learning the stimulus-response associations and transferring the just-learned associations to novel combinations were previously tested by specific tasks in memory-impaired patients with hippocampal, basal forebrain, and basal ganglia damage. To add to this previous research, we aimed to use the same tasks in a group of patients with hunger strike-related KS presenting a stable isolated amnestic profile. Twelve patients with hunger strike-related KS and matched healthy controls were tested in two tasks varying in task complexity. Each task included two phases: the initial phase is feedback-based learning of (simple vs. complex) stimulus-response associations, and the following phase is transfer generalization (in the presence vs. absence of feedback). On a task involving simple associations, five patients with KS failed to learn the associations, while the other seven patients showed intact learning and transfer. On the other task involving more complex associations, seven patients showed slower learning and failed at transfer generalization, whereas the other five patients failed even at the acquisition phase. These findings of a task-complexity-related impairment on associative learning and transfer represent a distinct pattern from the spared learning but impaired transfer previously observed on these tasks in patients with medial temporal lobe amnesia.