Implicit learning on a probabilistic classification task in adults and adolescents with Bulimia Nervosa

BackgroundDysfunction in frontostriatal circuits likely contributes to impaired regulatory control in Bulimia Nervosa (BN), resulting in binge-eating and purging behaviors that resemble maladaptive habits. Less is known about the implicit learning processes of these circuits, which may contribute to habit formation.MethodsWe compared 52 adolescent and adult females with BN to 55 healthy matched-controls during performance of a probabilistic classification learning task, one form of implicit learning. Groups were compared in accuracy and response times, using mixed-models with block, age, and diagnosis as predictors, corrected for multiple comparisons with confounds covaried.ResultsBN participants showed differences in performance on a probabilistic classification learning task that varied by age. Adolescents with BN initially performed as accurately as healthy adolescents, but showed poorer perseverance over time. Adults with BN initially performed less accurately than healthy adults, but improved to perform equivalently. Symptom severity was associated with poorer accuracy in both adults and adolescents with BN.ConclusionsFrontostriatal dysfunction may underlie abnormalities in regulatory control and probabilistic classification learning in BN, likely contributing to the dysregulation of implicitly learned, maladaptive binge-eating and purging behaviors. Such dysfunction in BN may progress with increasing age, first manifesting in poor regulatory control over behaviors and then expanding to implicit learning processes that may underlie habitual behaviors.     

The role of the basal ganglia and its cortical connections in sequence learning: Evidence from implicit and explicit sequence learning in Parkinson's disease

Implicit (unconscious/incidental) and explicit (conscious/intentional) learning are considered to have distinct neural substrates. It is proposed that implicit learning is mediated by the basal ganglia (BG), while explicit learning has been linked to the medial temporal lobes (MTL). To test such a dissociation we investigated implicit and explicit sequence learning in Parkinson's disease (PD), a disorder characterized by striatal dysfunction. We studied both implicit and explicit learning of a 12-item sequence of target locations in 13 PD patients and 15 age-matched controls. In the implicit sequence learning task all participants completed 10 blocks of a probabilistic serial reaction time (SRT) task in which they were exposed to the sequence without explicit knowledge of it. Participants also completed between 1 and 10 blocks of an explicit sequence learning task in which the sequence was learned deliberately by trial-and-error. Both implicit and explicit sequence learning were significantly impaired in PD patients compared to controls. The results indicate that, in addition to playing a role in implicit sequence learning, the BG and its frontal projections are also involved in explicit sequence learning.     

The feedback-related negativity is modulated by feedback probability in observational learning

The feedback-related negativity (FRN), an event-related potentials (ERPs) component reflecting activity of the anterior cingulate cortex (ACC), has been shown to be modulated by feedback expectancy following active choices in feedback-based learning tasks. A general reduction of FRN amplitude has been described in observational feedback learning, raising the question whether FRN amplitude is modulated in a similar way in this type of learning. The present study investigated whether the FRN and the P300 - a second ERP component related to feedback processing - are modulated by feedback probability in observational learning. Thirty-two subjects participated in the experiment. They observed a virtual person choosing between two symbols and receiving positive or negative feedback. Learning about stimulus-specific feedback probabilities was assessed in active test trials without feedback. In addition, the bias to learn from positive or negative feedback and - in a subsample of 17 subjects - empathy scores were obtained. General FRN and P300 modulations by feedback probability were found across all subjects. Only for the FRN in learners, an interaction between probability and valence was observed. Larger FRN amplitudes for negative relative to positive feedback only emerged for the lowest outcome probability. The results show that feedback expectancy modulates FRN amplitude also in observational learning, suggesting a similar ACC function as in active learning. On the other hand, the modulation is only seen for very low feedback expectancy, which suggests that brain regions other than those of the reward system contribute to feedback processing in an observation setting.     

Medication impairs probabilistic classification learning in Parkinson's disease

In Parkinson's disease (PD), it is possible that tonic increase of dopamine associated with levodopa medication overshadows phasic release of dopamine, which is essential for learning. Thus while the motor symptoms of PD are improved with levodopa medication, learning would be disrupted. To test this hypothesis, we investigated the effect of levodopa medication on learning on the weather prediction task (WPT), which involves probabilistic classification learning. 11 PD patients and 13 matched controls completed 200 trials of the WPT, with the patients either on or off their usual levodopa medication. Consistent with prior studies, when PD patients were assessed on medication, overall WPT performance was significantly worse than controls. However, when these patients were studied following withdrawal from medication, overall performance was equivalent to controls, and significantly better than when on medication. The significant deterioration of learning on the WPT in PD patients when on compared to off medication supports the proposal that tonic increase of dopamine with dopaminergic medication masks phasic changes in dopamine release essential for learning. These results highlight the need for careful ‘titration’ of dopaminergic medication to produce the desired improvement of the motor symptoms without the associated detrimental effects on cognition and learning.     

Increasing dopamine levels in the brain improves feedback-based procedural learning in healthy participants: An artificial-grammar-learning experiment

Recently, an increasing number of studies have suggested a role for the basal ganglia and related dopamine inputs in procedural learning, specifically when learning occurs through trial-by-trial feedback (Shohamy, Myers, Kalanithi, & Gluck. (2008). Basal ganglia and dopamine contributions to probabilistic category learning. Neuroscience and Biobehavioral Reviews, 32, 219-236). A necessary relationship has however only been demonstrated in patient studies. In the present study, we show for the first time that increasing dopamine levels in the brain improves the gradual acquisition of complex information in healthy participants. We implemented two artificial-grammar-learning tasks, one with and one without performance feedback. Learning was improved after levodopa intake for the feedback-based learning task only, suggesting that dopamine plays a specific role in trial-by-trial feedback-based learning. This provides promising directions for future studies on dopaminergic modulation of cognitive functioning.     

Rule-based category learning in patients with Parkinson's disease

Measures of explicit rule-based category learning are commonly used in neuropsychological evaluation of individuals with Parkinson's disease (PD) and the pattern of PD performance on these measures tends to be highly varied. We review the neuropsychological literature to clarify the manner in which PD affects the component processes of rule-based category learning and work to identify and resolve discrepancies within this literature. In particular, we address the manner in which PD and its common treatments affect the processes of rule generation, maintenance, shifting and selection. We then integrate the neuropsychological research with relevant neuroimaging and computational modeling evidence to clarify the neurobiological impact of PD on each process. Current evidence indicates that neurochemical changes associated with PD primarily disrupt rule shifting, and may disturb feedback-mediated learning processes that guide rule selection. Although surgical and pharmacological therapies remediate this deficit, it appears that the same treatments may contribute to impaired rule generation, maintenance and selection processes. These data emphasize the importance of distinguishing between the impact of PD and its common treatments when considering the neuropsychological profile of the disease.     

Probabilistic classification learning with corrective feedback is associated with in vivo striatal dopamine release in the ventral striatum,while learning without feedback is not

The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the ‘weather prediction task’ (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT‐learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial ¹¹C‐raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT‐learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region‐of‐interest approach, striatal RAC‐binding potentials reduced by 13–17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non‐significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision‐making is also relevant, we conclude striatal dopamine is released during FB‐based WPT‐learning, implicating the striatum and its dopamine connections in mediating learning with FB. Hum Brain Mapp 35:5106–5115, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

The effect of Parkinson's disease and Huntington's disease on human visuomotor learning

Visuomotor adaptation is often driven by error‐based (EB) learning in which signed errors update motor commands. There are, however, visuomotor tasks where signed errors are unavailable or cannot be mapped onto appropriate motor command changes, rendering EB learning ineffective; and yet, healthy subjects can learn in these EB learning‐free conditions. While EB learning depends on cerebellar integrity, the neural bases of EB‐independent learning are poorly understood. As basal ganglia are involved in learning mechanisms that are independent of signed error feedback, here we tested whether patients with basal ganglia lesions, including those with Huntington's disease and Parkinson's disease, would show impairments in a visuomotor learning task that prevents the use of EB learning. We employed two visuomotor throwing tasks that were similar, but were profoundly different in the resulting visual feedback. This difference was implemented through the introduction of either a lateral displacement of the visual field via a wedge prism (EB learning) or a horizontal reversal of the visual field via a dove prism (non‐EB learning). Our results show that patients with basal ganglia degeneration had normal EB learning in the wedge prism task, but were profoundly impaired in the reversing prism task that does not depend on the signed error signal feedback. These results represent the first evidence that human visuomotor learning in the absence of EB feedback depends on the integrity of the basal ganglia.     

Facilitation of probabilistic classification learning by transcranial direct current stimulation of the prefrontal cortex in the human

The aim of our study was to test if the electrical stimulation of the prefrontal cortex (PFC) could modify probabilistic classification learning (PCL). Transcranial direct current stimulation (tDCS) was administered to the left prefrontal and to the primary visual cortex of 22 healthy subjects while they performed a PCL task. In this task subjects learned which of two outcomes would occur on each trial after presentation of a particular combination of cues. Ten minutes of anodal, but not cathodal, stimulation improved implicit learning only when the left PFC was stimulated. Our results show that implicit PLC can be modified by weak anodal tDCS, which probably increases neural excitability, as has been shown in the motor and visual cortices previously. Our results suggest that further studies on the facilitation of learning and memory processes by tDCS are warranted.     

Intact artificial grammar learning in patients with cerebellar degeneration and advanced Parkinson's disease

In an artificial grammar learning task, subjects were asked to memorise short lists of letter strings formed according to complex rules for letter order. After an interval they were unexpectedly asked to discriminate new grammatical strings from strings which used the same letters but violated the sequential constraints of the grammar. Artificial grammar learning can be mastered successfully by amnesic patients and is considered to be an implicit learning task independent of declarative learning and memory mechanisms. In this study, 10 patients with cerebellar degeneration (CD), 21 Parkinson's disease (PD) and 15 control subjects were tested on artificial grammar learning. Additionally PD patients with advanced disease were examined under adequate medication and dopaminergic withdrawal. All patient groups showed intact artificial grammar learning. Neither cerebellar damage nor basal ganglia dysfunction nor dopaminergic medication impairs or affects artificial grammar learning. Although the patients showed significant executive dysfunction, implicit learning remains intact. The conclusion is that cerebellar and basal ganglia circuits play no essential part in this kind of implicit learning. The results suggest that artificial grammar learning is a cortically mediated function comparable to the mechanism of visual priming.     

Electrical high frequency stimulation in the dorsal striatum: Effects on response learning and on GABA levels in rats

Electrical high frequency stimulation (HFS) has been used to treat various neurological and psychiatric diseases. The striatal area contributes to response learning and procedural memory. Therefore, we investigated the effect of striatal HFS application on procedural/declarative-like memory in rats. All rats were trained in a flooded Double-H maze for three days (4 trials/day) to swim to an escape platform hidden at a constant location. The starting place was the same for all trials. After each training session, HFS of the left dorsal striatum was performed over 4 h in alternating 20 min periods (during rest time, 10 a.m. to 3 p.m.). Nineteen hours after the last HFS and right after a probe trial assessing the rats’ strategy (procedural vs. declarative-like memory-based choice), animals were sacrificed and the dorsal striatum was quickly removed. Neurotransmitter levels were measured by HPLC. Stimulated rats did not differ from sham-operated and control rats in acquisition performance, but exhibited altered behavior during the probe trial (procedural memory responses being less frequent than in controls). In stimulated rats, GABA levels were significantly increased in the dorsal striatum on both sides. We suggest that HFS of the dorsal striatum does not alter learning behavior in rats but influences the strategy by which the rats solve the task. Given that the HFS-induced increase of GABA levels was found 19 h after stimulation, it can be assumed that HFS has consequences lasting for several hours and which are functionally significant at a behavioral level, at least under our stimulation (frequency, timing, location, side and strength of stimulation) and testing conditions.     

Procedural learning is impaired in dyslexia: Evidence from a meta-analysis of serial reaction time studies

A number of studies have investigated procedural learning in dyslexia using serial reaction time (SRT) tasks. Overall, the results have been mixed, with evidence of both impaired and intact learning reported. We undertook a systematic search of studies that examined procedural learning using SRT tasks, and synthesized the data using meta-analysis. A total of 14 studies were identified, representing data from 314 individuals with dyslexia and 317 typically developing control participants. The results indicate that, on average, individuals with dyslexia have worse procedural learning abilities than controls, as indexed by sequence learning on the SRT task. The average weighted standardized mean difference (the effect size) was found to be 0.449 (CI₉₅: .204, .693), and was significant (p < .001). However, moderate levels of heterogeneity were found between study-level effect sizes. Meta-regression analyses indicated that studies with older participants that used SRT tasks with second order conditional sequences, or with older participants that used sequences that were presented a large number of times, were associated with smaller effect sizes. These associations are discussed with respect to compensatory and delayed memory systems in dyslexia.     

Learning sequence movements in a homogenous sample of patients with Parkinson's disease

We investigated the acquisition of sequence movements in Parkinson's disease (PD) by means of the serial reaction time (SRT) task. To this end, we used a sample of PD patients that fell within the same stage of the disease. Sixteen PD patients and 16 age-, sex- and education-matched control subjects performed the SRT task with a first-order conditional (FOC) sequence and with a second-order conditional (SOC) sequence. The results showed that the group of PD patients could be divided into two distinct subgroups: a fast PD patient subgroup (n=11) and a slow PD patient subgroup (n=5). FOC and SOC sequence learning in faster PD patients proved to be highly comparable to the group of controls. In contrast, learning of FOC and SOC sequences was severely impaired in slower PD patients. Since slow PD patients also scored lower on measures of cognitive functioning than faster PD patients, we assume that the deficits in SRT learning of the former reflect some more general cognitive impairment. This indicates that SRT performance can provide additional information about the cognitive abilities of PD patients, and accordingly may contribute to disease screening.     

The impact of bilateral subthalamic stimulation on non-motor symptoms of Parkinson's disease

Objective

To evaluate the impact of bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) on the prevalence of non-motor symptoms reported by Parkinson's disease (PD) patients one year following surgery and to examine whether there was an association between number of non-motor symptoms reported and quality of life (QoL).

Methods

Twenty-four patients who received bilateral STN DBS and had follow-up evaluations one year after surgery were included in this study. Patients’ motor function was evaluated with the Unified Parkinson’s Disease Rating Scale, non-motor symptoms were assessed with the Non-Motor Symptom questionnaire (NMSQuest) and quality of life was assessed with the PDQ-39.

Results

There was a mean of 12 non-motor symptoms reported prior to surgery which was significantly reduced to a mean of 7 symptoms one year after surgery. Autonomic symptoms were the most frequently reported and demonstrated the greatest reductions following surgery. Twenty-seven of the 30 items represented in the NMSQuest were reported less frequently one year after surgery compared to before surgery. The reduction in non-motor symptoms was significantly correlated with total QoL scores and the subscales of mobility, activities of daily living, cognition and bodily discomfort.

Conclusions

Non-motor symptoms are common in patients with advanced PD. The number of non-motor symptoms was significantly decreased one year following bilateral STN DBS which was associated with a significant improvement in QoL. Further studies focused on specific non-motor symptoms are warranted in order to fully understand the impact and mechanisms of STN DBS on these symptoms.     

The role of the basal ganglia in implicit contextual learning: A study of Parkinson's disease

Implicit contextual learning refers to the ability to memorize contextual information from our environment. This contextual information can then be used to guide our attention to a specific location. Although the medial temporal lobe is important for this type of learning, the basal ganglia might also be involved considering its role in many implicit learning processes. In order to understand the role of the basal ganglia in this top-down process, a group of non-demented early-stage Parkinson's patients were tested with a contextual cueing task. In this visual search task, subjects have to quickly locate a target among a number of distractors. To test implicit contextual learning, some of the configurations are repeated during the experiment, resulting in faster responses. A significant interaction effect was found between Group and Configuration, indicating that the control subjects responded faster when the spatial context was repeated, whereas Parkinson's patients failed to do so. These results, showing that the contextual cueing effect was significantly different for the patients than for the controls, suggest an important role for the basal ganglia in implicit contextual learning, thus extending previous findings of medial temporal lobe involvement. The basal ganglia are therefore not only involved in implicit motor learning, but may also have a role in purely visual implicit learning.     

Neuroprotective effect of rasagiline in a rodent model of Parkinson's disease

Sprague-Dawley rats received a unilateral injection of 6-hydroxydopamine (6-OHDA) into the striatum and were treated daily for 6 weeks with increasing doses of monoamine oxidase type B inhibitor rasagiline [R(+)-N-propargyl-1-aminoindane] or saline (controls). Both doses of rasagiline markedly increased the survival of dopaminergic neurons in the lesioned substantia nigra, compared to controls (+97% and +119%, respectively). Treatment with the lower dose of rasagiline also abolished the motor stereotypies associated with nigrostriatal lesion. Our study supports the neuroprotective potential of chronic rasagiline administration in an experimental model of Parkinson's disease (PD).     

The effect of Parkinson's disease on interference control during action selection

Basal ganglia structures comprise a portion of the neural circuitry that is hypothesized to coordinate the selection and suppression of competing responses. Parkinson's disease (PD) may produce a dysfunction in these structures that alters this capacity, making it difficult for patients with PD to suppress interference arising from the automatic activation of salient or overlearned responses. Empirical observations thus far have confirmed this assumption in some studies, but not in others, due presumably to considerable inter-individual variability among PD patients. In an attempt to help resolve this controversy, we measured the performance of 50 PD patients and 25 healthy controls on an arrow version of the Eriksen flanker task in which participants were required to select a response based on the direction of a target arrow that was flanked by arrows pointing in the same (congruent) or opposite (incongruent) direction. Consistent with previous findings, reaction time (RT) increased with incongruent flankers compared to congruent or neutral flankers, and this cost of incongruence was greater among PD patients. Two novel findings are reported. First, distributional analyses, guided by dual-process models of conflict effects and the activation-suppression hypothesis, revealed that PD patients are less efficient at suppressing the activation of conflicting responses, even when matched to healthy controls on RT in a neutral condition. Second, this reduced efficiency was apparent in half of the PD patients, whereas the remaining patients were as efficient as healthy controls. These findings suggest that although poor suppression of conflicting responses is an important feature of PD, it is not evident in all medicated patients.     

The many facets of motor learning and their relevance for Parkinson's disease

The final goal of motor learning, a complex process that includes both implicit and explicit (or declarative) components, is the optimization and automatization of motor skills. Motor learning involves different neural networks and neurotransmitters systems depending on the type of task and on the stage of learning. After the first phase of acquisition, a motor skill goes through consolidation (i.e., becoming resistant to interference) and retention, processes in which sleep and long-term potentiation seem to play important roles. The studies of motor learning in Parkinson's disease have yielded controversial results that likely stem from the use of different experimental paradigms. When a task’s characteristics, instructions, context, learning phase and type of measures are taken into consideration, it is apparent that, in general, only learning that relies on attentional resources and cognitive strategies is affected by PD, in agreement with the finding of a fronto-striatal deficit in this disease. Levodopa administration does not seem to reverse the learning deficits in PD, while deep brain stimulation of either globus pallidus or subthalamic nucleus appears to be beneficial. Finally and most importantly, patients with PD often show a decrease in retention of newly learned skill, a problem that is present even in the early stages of the disease. A thorough dissection and understanding of the processes involved in motor learning is warranted to provide solid bases for effective medical, surgical and rehabilitative approaches in PD.     

Cognitive sequence learning in Parkinson's disease and amnestic mild cognitive impairment: Dissociation between sequential and non-sequential learning of associations

Evidence suggests that dopaminergic mechanisms in the basal ganglia (BG) are important in the learning of sequential associations. To test the specificity of this hypothesis, we assessed never-medicated patients with Parkinson's disease (PD) and amnestic mild cognitive impairment (aMCI) using a chaining task. In the training phase of the chaining task, each link in a sequence of stimuli leading to reward is trained step-by-step using feedback after each decision, until the complete sequence is learned. In the probe phase of the chaining task, the context of stimulus-response associations must be used (the position of the associations in the sequence). Results revealed that patients with PD showed impaired learning during the training phase of the chaining task, but their performance was spared in the probe phase. In contrast, patients with aMCI with prominent medial temporal lobe (MTL) dysfunctions showed intact learning during the training phase of the chaining task, but their performance was impaired in the probe phase of the chaining task. These results indicate that when dopaminergic mechanisms in the BG are dysfunctional, series of stimulus-response associations are less efficiently acquired, but their sequential manner is maintained. In contrast, MTL dysfunctions may result in a non-sequential learning of associations, which may indicate a loss of contextual information.     

Dynamical model of salience gated working memory, action selection and reinforcement based on basal ganglia and dopamine feedback

A simple working memory model based on recurrent network activation is proposed and its application to selection and reinforcement of an action is demonstrated as a solution to the temporal credit assignment problem. Reactivation of recent salient cue states is generated and maintained as a type of salience gated recurrently active working memory, while lower salience distractors are ignored. Cue reactivation during the action selection period allows the cue to select an action while its reactivation at the reward period allows the reinforcement of the action selected by the reactivated state, which is necessarily the action which led to the reward being found. A down-gating of the external input during the reactivation and maintenance prevents interference. A double winner-take-all system which selects only one cue and only one action allows the targeting of the cue–action allocation to be modified. This targeting works both to reinforce a correct cue–action allocation and to punish the allocation when cue–action allocations change. Here we suggest a firing rate neural network implementation of this system based on the basal ganglia anatomy with input from a cortical association layer where reactivations are generated by signals from the thalamus. Striatum medium spiny neurons represent actions. Auto-catalytic feedback from a dopamine reward signal modulates three-way Hebbian long term potentiation and depression at the cortical–striatal synapses which represent the cue–action associations. The model is illustrated by the numerical simulations of a simple example — that of associating a cue signal to a correct action to obtain reward after a delay period, typical of primate cue reward tasks. Through learning, the model shows a transition from an exploratory phase where actions are generated randomly, to a stable directed phase where the animal always chooses the correct action for each experienced state. When cue–action allocations change, we show that this is noticed by the model, the incorrect cue–action allocations are punished and the correct ones discovered.