Nole M. Hiebert

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

Cognitive deficits are recognized in Parkinsons 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 Parkinsons 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.

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

Cognitive dysfunction is a feature of Parkinsons 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.

Network mechanisms of intentional learning

The ability to learn new tasks rapidly is a prominent characteristic of human behaviour. This ability relies on flexible cognitive systems that adapt in order to encode temporary programs for processing non-automated tasks. Previous functional imaging studies have revealed distinct roles for the lateral frontal cortices (LFCs) and the ventral striatum in intentional learning processes. However, the human LFCs are complex; they house multiple distinct sub-regions, each of which co-activates with a different functional network. It remains unclear how these LFC networks differ in their functions and how they coordinate with each other, and the ventral striatum, to support intentional learning. Here, we apply a suite of fMRI connectivity methods to determine how LFC networks activate and interact at different stages of two novel tasks, in which arbitrary stimulus-response rules are learnt either from explicit instruction or by trial-and-error. We report that the networks activate en masse and in synchrony when novel rules are being learnt from instruction. However, these networks are not homogeneous in their functions; instead, the directed connectivities between them vary asymmetrically across the learning timecourse and they disengage from the task sequentially along a rostro-caudal axis. Furthermore, when negative feedback indicates the need to switch to alternative stimulus–response rules, there is additional input to the LFC networks from the ventral striatum. These results support the hypotheses that LFC networks interact as a hierarchical system during intentional learning and that signals from the ventral striatum have a driving influence on this system when the internal program for processing the task is updated.

Dopaminergic therapy affects learning and impulsivity in Parkinson's disease

The aim was to examine the effect of dopaminergic medication on stimulus‐response learning versus performing decisions based on learning.

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.

Dorsal striatum does not mediate feedback-based, stimulus-response learning

&NA; 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 Parkinsons 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. HighlightsThe effect of dopamine and Parkinsons disease was investigated in SR learning.We modelled the stimulus‐response and feedback phases of each trial separately.DS activity correlated with response selection and was improved by dopamine.VS activity correlated with learning and was impaired by dopamine.Suggest DS mediates decision making processes and not SR learning.

SLC6A3 Polymorphism Predisposes to Dopamine Overdose in Parkinson's Disease

In Parkinsons 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.