Increased mean diffusivity of the caudal motor SNc identifies patients with REM sleep behaviour disorder and Parkinson's disease.

Idiopathic rapid eye movement sleep behaviour disorder (iRBD)-a Parkinson's disease (PD) prodrome-might exhibit neural changes similar to those in PD. Substantia nigra pars compacta (SNc) degeneration underlies motor symptoms of PD. In iRBD and early PD (ePD), we measured diffusion MRI (dMRI) in the caudal motor SNc, which overlaps the nigrosome-1-the earliest-degenerating dopaminergic neurons in PD-and in the striatum. Nineteen iRBD, 26 ePD (1.7 ± 0.03 years), and 46 age-matched healthy controls (HCs) were scanned at Western University, and 47 iRBD, 115 ePD (0.9 ± 0.01 years), and 56 HCs were scanned through the Parkinson's Progression Markers Initiative, using 3T MRI. We segmented the SNc and striatum into subregions using automated probabilistic tractography to the cortex. We measured mean diffusivity (MD) and fractional anisotropy (FA) along white-matter bundles and subregional surfaces. We performed group-level and classification analyses. Increased caudal motor SNc surface MD was the only iRBD-HCs and ePD-HCs difference replicating across datasets (padj < 0.05). No iRBD-ePD differences emerged. Caudal motor SNc surface MD classified patient groups from HCs at the single-subject level with good-to-excellent balanced accuracy in an independent sample (0.91 iRBD and 0.86 iRBD and ePD combined), compared to fair performance for total SNc surface MD (0.72 iRBD and ePD). Caudal motor SNc surface MD correlated significantly with MDS-UPDRS-III scores in ePD patients. Using dMRI and automated segmentation, we detected changes suggesting altered microstructural integrity in iRBD and ePD in the nigrostriatal subregion known to degenerate first in PD. Surface MD of the caudal motor SNc presents a potential measure for inclusion in neuroimaging biomarkers of iRBD and PD.

Alprazolam Reduces Freezing of Gait (FOG) and Improves FOG-Related Gait Deficiencies.

Background: Freezing of gait (FOG) is an intractable motor symptom in Parkinson's disease (PD) that increases fall risk and impairs the quality of life. FOG has been associated with anxiety, with experimental support for the notion that anxiety itself provokes FOG. We investigated the effect of acute anxiety reduction via alprazolam on FOG in PD. Methods: In ten patients with PD, FOG, and normal cognition, we administered 0.25 mg alprazolam in one session and placebo in another, in counterbalanced order. At each session, on separate days, patients walked on a pressure-sensitive walkway. Using Oculus Rift virtual-reality goggles, patients walked along a plank that appeared to be (a) level with the floor, in the low-anxiety condition or (b) raised high above the ground, in the high-anxiety conditions. In this way, we assessed the impacts of anxiety and alprazolam (i.e., anxiety reduction) on FOG frequency and other gait parameters. Results: FOG events appeared only in the high-anxiety conditions. Alprazolam significantly reduced subjective and objective measures of anxiety, as well as the prevalence of FOG (p = 0.05). Furthermore, alprazolam improved swing time (p < 0.05) and gait variability in all conditions, particularly during the elevated plank trials. Interpretation. Our results suggest that (1) anxiety induces FOG, and (2) alprazolam concomitantly reduces anxiety and FOG. Alprazolam further improved gait stability (i.e., swing time and gait variability). These findings reveal that anxiety triggers FOG in PD. Treating anxiety can reduce FOG and improve gait stability, potentially offering new therapeutic avenues for this intractable and disabling symptom in PD.

Establishing the Roles of the Dorsal and Ventral Striatum in Humor Comprehension and Appreciation with fMRI.

Humor comprehension (i.e., getting a joke) and humor appreciation (i.e., enjoying a joke) are distinct, cognitively complex processes. Functional magnetic resonance imaging (fMRI) investigations have identified several key cortical regions but have overlooked subcortical structures that have theoretical importance in humor processing. The dorsal striatum (DS) contributes to working memory, ambiguity processing, and cognitive flexibility, cognitive functions that are required to accurately recognize humorous stimuli. The ventral striatum (VS) is critical in reward processing and enjoyment. We hypothesized that the DS and VS play important roles in humor comprehension and appreciation, respectively. We investigated the engagement of these regions in these distinct processes using fMRI. Twenty-six healthy young male and female human adults completed two humor-elicitation tasks during a 3 tesla fMRI scan consisting of a traditional behavior-based joke task and a naturalistic audiovisual sitcom paradigm (i.e., Seinfeld viewing task). Across both humor-elicitation methods, whole-brain analyses revealed cortical activation in the inferior frontal gyrus, the middle frontal gyrus, and the middle temporal gyrus for humor comprehension, and the temporal cortex for humor appreciation. Additionally, with region of interest analyses, we specifically examined whether DS and VS activation correlated with these processes. Across both tasks, we demonstrated that humor comprehension implicates both the DS and the VS, whereas humor appreciation only engages the VS. These results establish the role of the DS in humor comprehension, which has been previously overlooked, and emphasize the role of the VS in humor processing more generally.SIGNIFICANCE STATEMENT Humorous stimuli are processed by the brain in at least two distinct stages. First, humor comprehension involves understanding humorous intent through cognitive and problem-solving mechanisms. Second, humor appreciation involves enjoyment, mirth, and laughter in response to a joke. The roles of smaller subcortical brain regions in humor processing, such as the DS and VS, have been overlooked in previous investigations. However, these regions are involved in functions that support humor comprehension (e.g., working memory ambiguity resolution, and cognitive flexibility) and humor appreciation (e.g., reward processing, pleasure, and enjoyment). In this study, we used neuroimaging to demonstrate that the DS and VS play important roles in humor comprehension and appreciation, respectively, across two different humor-elicitation tasks.

Striatum-Mediated Deficits in Stimulus-Response Learning and Decision-Making in OCD.

Obsessive compulsive disorder (OCD) is a prevalent psychiatric disorder characterized by obsessions and compulsions. Studies investigating symptomatology and cognitive deficits in OCD frequently implicate the striatum. The aim of this study was to explore striatum-mediated cognitive deficits in patients with OCD as they complete a stimulus-response learning task previously shown to differentially rely on the dorsal (DS) and ventral striatum (VS). We hypothesized that patients with OCD will show both impaired decision-making and learning, coupled with reduced task-relevant activity in DS and VS, respectively, compared to healthy controls. We found that patients with OCD (n = 14) exhibited decision-making deficits and learned associations slower compared to healthy age-matched controls (n = 16). Along with these behavioral deficits, OCD patients had reduced task-relevant activity in DS and VS, compared to controls. This study reveals that responses in DS and VS are altered in OCD, and sheds light on the cognitive deficits and symptoms experienced by patients with OCD.

Dorsal striatum does not mediate feedback-based, stimulus-response learning: An event-related fMRI study in patients with Parkinson's disease tested on and off dopaminergic therapy.

Learning associations between stimuli and responses is essential to everyday life. Dorsal striatum (DS) has long been implicated in stimulus-response learning, though recent results challenge this contention. We have proposed that discrepant findings arise because stimulus-response learning methodology generally confounds learning and response selection processes. In 19 patients with Parkinson's disease (PD) and 18 age-matched controls, we found that dopaminergic therapy decreased the efficiency of stimulus-response learning, with corresponding attenuation of ventral striatum (VS) activation. In contrast, exogenous dopamine improved response selection accuracy related to enhanced DS BOLD signal. Contrasts between PD patients and controls fully support these within-subject patterns. These double dissociations in terms of behaviour and neural activity related to VS and DS in PD and in response to dopaminergic therapy, strongly refute the view that DS mediates stimulus-response learning through feedback. Our findings integrate with a growing literature favouring a role for DS in decision making rather than learning, and unite two literature that have been evolving independently.

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.

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease.

In Parkinson's disease (PD), cognitive functions mediated by brain regions innervated by ventral tegmental area (VTA) worsen with dopamine replacement therapy, whereas processes relying on regions innervated by the substantia nigra pars compacta (SNc) improve. The SLC6A3 gene encodes the dopamine transporter (DAT). The common 9R polymorphism produces higher DAT concentrations and consequently lower baseline dopamine than SLC6A3 wildtype. Whether SLC6A3 genotype modulates the effect of dopaminergic therapy on cognition in PD is not known. We investigated the effect of dopaminergic therapy and SLC6A3 genotype on encoding and recall of abstract images using the Aggie Figures Learning Test in PD patients. Encoding depends upon brain regions innervated by the VTA, whereas recall is mediated by widespread brain regions, a number innervated by the SNc. We found that dopaminergic therapy worsened encoding of abstract images in 9R carriers only. In contrast, dopaminergic therapy improved recall of abstract images in all PD patients, irrespective of SLC6A3 genotype. Our findings suggest that 9R-carrier PD patients are more predisposed to dopamine overdose and medication-induced impairment of cognitive functions mediated by VTA-innervated brain regions. Interestingly, PD patients without the 9R polymorphism did not show such an impairment. SLC6A3 genotype does not modulate the dopaminergic therapy-induced improvement of functions mediated by SNc-innervated regions in PD patients.

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.

Automatic Online Motor Control Is Intact in Parkinson's Disease With and Without Perceptual Awareness.

In the double-step paradigm, healthy human participants automatically correct reaching movements when targets are displaced. Motor deficits are prominent in Parkinson's disease (PD) patients. In the lone investigation of online motor correction in PD using the double-step task, a recent study found that PD patients performed unconscious adjustments appropriately but seemed impaired for consciously-perceived modifications. Conscious perception of target movement was achieved by linking displacement to movement onset. PD-related bradykinesia disproportionately prolonged preparatory phases for movements to original target locations for patients, potentially accounting for deficits. Eliminating this confound in a double-step task, we evaluated the effect of conscious awareness of trajectory change on online motor corrections in PD. On and off dopaminergic therapy, PD patients (n = 14) and healthy controls (n = 14) reached to peripheral visual targets that remained stationary or unexpectedly moved during an initial saccade. Saccade latencies in PD are comparable to controls'. Hence, target displacements occurred at equal times across groups. Target jump size affected conscious awareness, confirmed in an independent target displacement judgment task. Small jumps were subliminal, but large target displacements were consciously perceived. Contrary to the previous result, PD patients performed online motor corrections normally and automatically, irrespective of conscious perception. Patients evidenced equivalent movement durations for jump and stay trials, and trajectories for patients and controls were identical, irrespective of conscious perception. Dopaminergic therapy had no effect on performance. In summary, online motor control is intact in PD, unaffected by conscious perceptual awareness. The basal ganglia are not implicated in online corrective responses.

Dorsal striatum mediates deliberate decision making, not late-stage, stimulus-response learning.

We investigated a controversy regarding the role of the dorsal striatum (DS) in deliberate decision-making versus late-stage, stimulus-response learning to the point of automatization. Participants learned to associate abstract images with right or left button presses explicitly before strengthening these associations through stimulus-response trials with (i.e., Session 1) and without (i.e., Session 2) feedback. In Session 1, trials were divided into response-selection and feedback events to separately assess decision versus learning processes. Session 3 evaluated stimulus-response automaticity using a location Stroop task. DS activity correlated with response-selection and not feedback events in Phase 1 (i.e., Blocks 1-3), Session 1. Longer response times (RTs), lower accuracy, and greater intertrial variability characterized Phase 1, suggesting deliberation. DS activity extinguished in Phase 2 (i.e., Blocks 4-12), Session 1, once RTs, response variability, and accuracy stabilized, though stimulus-response automatization continued. This was signaled by persisting improvements in RT and accuracy into Session 2. Distraction between Sessions 1 and 2 briefly reintroduced response uncertainty, and correspondingly, significant DS activity reappeared in Block 1 of Session 2 only. Once stimulus-response associations were again refamiliarized and deliberation unnecessary, DS activation disappeared for Blocks 2-8, Session 2. Interference from previously learned right or left button responses with incongruent location judgments in a location Stroop task provided evidence that automaticity of stimulus-specific button-press responses had developed by the end of Session 2. These results suggest that DS mediates decision making and not late-stage learning, reconciling two, independently evolving and well-supported literatures that implicate DS in different cognitive functions. Hum Brain Mapp 38:6133-6156, 2017. © 2017 Wiley Periodicals, Inc.

Dopaminergic Therapy Increases Go Timeouts in the Go/No-Go Task in Patients with Parkinson's Disease.

Parkinson's disease (PD) is characterized by resting tremor, rigidity and bradykinesia. Dopaminergic medications such as L-dopa treat these motor symptoms, but can have complex effects on cognition. Impulse control is an essential cognitive function. Impulsivity is multifaceted in nature. Motor impulsivity involves the inability to withhold pre-potent, automatic, erroneous responses. In contrast, cognitive impulsivity refers to improper risk-reward assessment guiding behavior. Informed by our previous research, we anticipated that dopaminergic therapy would decrease motor impulsivity though it is well known to enhance cognitive impulsivity. We employed the Go/No-go paradigm to assess motor impulsivity in PD. Patients with PD were tested using a Go/No-go task on and off their normal dopaminergic medication. Participants completed cognitive, mood, and physiological measures. PD patients on medication had a significantly higher proportion of Go trial Timeouts (i.e., trials in which Go responses were not completed prior to a deadline of 750 ms) compared to off medication (p = 0.01). No significant ON-OFF differences were found for Go trial or No-go trial response times (RTs), or for number of No-go errors. We interpret that dopaminergic therapy induces a more conservative response set, reflected in Go trial Timeouts in PD patients. In this way, dopaminergic therapy decreased motor impulsivity in PD patients. This is in contrast to the widely recognized effects of dopaminergic therapy on cognitive impulsivity leading in some patients to impulse control disorders. Understanding the nuanced effects of dopaminergic treatment in PD on cognitive functions such as impulse control will clarify therapeutic decisions.

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.

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.

Dorsal striatum mediates cognitive control, not cognitive effort per se, in decision-making: An event-related fMRI study.

OBJECTIVE: Whether the dorsal striatum (DS) mediates cognitive control or cognitive effort per se in decision-making is unclear given that these effects are highly correlated. As the cognitive control requirements of a neuropsychological task intensify, cognitive effort increases proportionately. We implemented a task that disentangled cognitive control and cognitive effort to specify the particular function DS mediates in decision-making. METHODS: Sixteen healthy young adults completed a number Stroop task with simultaneous blood-oxygenation-level-dependent response (BOLD) measurement using functional magnetic resonance imaging. Participants selected the physically larger number of a pair of single-digit integers. Discriminating smaller versus larger physical size differences between a number pair requires greater cognitive effort, but does not require greater cognitive control. We also investigated the effect of conflict between the physical and numerical dimensions of targets (e.g., 2 6). Selections in this incongruent case are more cognitively effortful and require greater cognitive control to suppress responding to the irrelevant dimension. Enhancing cognitive effort or cognitive control demands increases errors and response times. Despite similar behavioural profiles, our aim was to determine whether DS mediates cognitive control or simply indexes cognitive effort, using the same data set. RESULTS: As expected, behavioural interference effects occurred for both enhanced cognitive control and/or cognitive effort conditions. Despite similar degrees of behavioural interference, DS BOLD signal only correlated with interference arising due to increased cognitive control demands in the incongruent case. DS was not preferentially activated for discriminations of smaller relative to larger physical size differences between number pairs, even when using liberal statistical criteria. However, our incongruent and physical size effects conjointly activated regions related to effortful processing (e.g., anterior cingulate cortex). INTERPRETATION: We interpret these findings as support for the increasingly accepted notion that DS mediates cognitive control specifically and does not simply index cognitive effort per se.

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.

Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI.

OBJECTIVE: Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions. METHODS: Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI. RESULTS: The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI. INTERPRETATION: These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.

Dopaminergic medication impairs feedback-based stimulus-response learning but not response selection in Parkinson's disease.

Cognitive dysfunction is a feature of Parkinson's Disease (PD). Some cognitive functions are impaired by dopaminergic medications prescribed to address the movement symptoms that typify PD. Learning appears to be the cognitive function most frequently worsened by dopaminergic therapy. However, this result could reflect either impairments in learning (i.e., acquisition of associations among stimuli, responses, and outcomes) or deficits in performance based on learning (e.g., selecting responses). We sought to clarify the specific effects of dopaminergic medication on (a) stimulus-response association learning from outcome feedback and (b) response selection based on learning, in PD. We tested 28 PD patients on and/or off dopaminergic medication along with 32 healthy, age- and education-matched controls. In Session 1, participants learned to associate abstract images with specific key-press responses through trial and error via outcome feedback. In Session 2, participants provided specific responses to abstract images learned in Session 1, without feedback, precluding new feedback-based learning. By separating Sessions 1 and 2 by 24 h, we could distinguish the effect of dopaminergic medication on (a) feedback-based learning and response selection processes in Session 1 as well as on (b) response selection processes when feedback-based learning could not occur in Session 2. Accuracy achieved at the end of Session 1 were comparable across groups. PD patients on medication learned stimulus-response associations more poorly than PD patients off medication and controls. Medication did not influence decision performance in Session 2. We confirm that dopaminergic therapy impairs feedback-based learning in PD, discounting an alternative explanation that warranted consideration.

Striatum in stimulus-response learning via feedback and in decision making.

Cognitive deficits are recognized in Parkinson's disease. Understanding cognitive functions mediated by the striatum can clarify some of these impairments and inform treatment strategies. The dorsal striatum, a region impaired in Parkinson's disease, has been implicated in stimulus-response learning. However, most investigations combine acquisition of associations between stimuli, responses, or outcomes (i.e., learning) and expression of learning through response selection and decision enactment, confounding these separate processes. Using neuroimaging, we provide evidence that dorsal striatum does not mediate stimulus-response learning from feedback but rather underlies decision making once associations between stimuli and responses are learned. In the experiment, 11 males and 5 females (mean age 22) learned to associate abstract images to specific button-press responses through feedback in Session 1. In Session 2, they were asked to provide responses learned in Session 1. Feedback was omitted, precluding further feedback-based learning in this session. Using functional magnetic resonance imaging, dorsal striatum activation in healthy young participants was observed at the time of response selection and not during feedback, when greatest learning presumably occurs. Moreover, dorsal striatum activity increased across the duration of Session 1, peaking after most associations were well learned, and was significant during Session 2 where no feedback was provided, and therefore no feedback-based learning occurred. Preferential ventral striatum activity occurred during feedback and was maximal early in Session 1. Taken together, the results suggest that the ventral striatum underlies learning associations between stimuli and responses via feedback whereas the dorsal striatum mediates enacting decisions.