Functional role of the striatum in stimulus-response learning: Evidence from functional MRI and patients with Parkinson\u27s disease

Cognitive impairment is recognized in Parkinson’s disease (PD). Understanding striatum-mediated cognitive functions will help elucidate some of these abnormalities. Learning is often impaired by dopaminergic medication. However, dorsal striatum (DS) has been implicated in learning; an unexpected result given that dopaminergic therapy, the gold standard treatment for PD, remediates DS functioning. In two separate experiments, stimulus-response association learning and decision-making were examined in healthy individuals using functional magnetic resonance imaging (fMRI), and in PD patients using behavioural methods. In Experiment 1, healthy individuals completed a stimulus-response learning task, and brain regions associated with learning versus decision-making were investigated using fMRI. In Experiment 2, patients with PD completed a similar task on and off their dopaminergic medication. Results from both experiments suggest that DS mediates decision-making and not learning. This greater understanding of striatum-mediated cognition will ultimately prompt clinicians to devise medication strategies that consider both motor and cognitive symptoms of PD

Role Of The Dorsal Striatum In Learning and Decision Making

The striatum, the input region of the basal ganglia, has been shown to mediate many cognitive functions. The striatum itself can be functionally segregated into dorsal (DS) and ventral striatum (VS). For more than 60 years, DS has been reported to mediate stimulus-response learning, though evidence has been accruing pointing to a role in decision making. These literatures have been growing independently and an aim of this thesis was to bridge these two bodies of knowledge. We directly investigated the role of DS in stimulus-response learning versus decision making using functional magnetic resonance imaging (fMRI) in patients with Parkinson’s disease (Chapter 2) and obsessive compulsive disorder (Chapter 3). In Chapter 4, the role of DS in stimulus-response habit learning was tested in healthy individuals using fMRI. In three separate experiments (Chapters 2-4), all of the results strongly support the notion that DS mediates decision making and not learning. DS is implicated in many disorders ranging from Parkinson’s disease, obsessive compulsive disorder and addiction, and clarifying the role of DS in cognitive function is paramount for understanding substrates of disease and developing treatments

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 affects learning and impulsivity in Parkinson\u27s 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\u27s 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

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

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

Cognitive deficits are recognized in Parkinson\u27s 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\u27s 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

Dopaminergic medication impairs feedback-based stimulus-response learning but not response selection in Parkinson\u27s disease.

Cognitive dysfunction is a feature of Parkinson\u27s 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

Dorsal striatum does not mediate feedback-based, stimulus-response learning: An event-related fMRI study in patients with Parkinson\u27s disease tested on and off dopaminergic therapy

© 2018 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\u27s 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

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

© Copyright © 2020 Hiebert, Lawrence, Ganjavi, Watling, Owen, Seergobin and MacDonald. 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

Biomarkers of Parkinson\u27s disease: Striatal sub-regional structural morphometry and diffusion MRI

© 2018 The Authors Parkinson\u27s 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 \u3c 0.05 and r = 0.985, p \u3c 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 striatum–the region first and most dopamine depleted in PD–distinguished 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