Learned equivalence in schizophrenia: novel method for the measurement of memory functions of the hippocampus and basal ganglia

The purpose of the present study was to investigate basal ganglia (BG) and medial temporal lobe (MTL) dependent learning in patients with schizophrenia. Acquired equivalence is a phenomenon in which prior training to treat two stimuli as equivalent (if two stimuli are associated with the same response) increases generalization between them. The learning of stimulus-response pairs is related to the BG, whereas the MTL system participates in stimulus generalization. Forty-three patients with DSM-IV schizophrenia and 28 matched healthy controls participated in the study. Volunteers received the acquired equivalence associative learning task (FISHES) during which associations between faces and pet fishes are learned. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was unaffected. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, patients with schizophrenia showed deficits during MTL-dependent learning, but not during BG-dependent learning. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-striatal system.     

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.     

Associative learning in deficit and nondeficit schizophrenia

When two stimuli are associated and treated as equivalent, generalization occurs between them (acquired equivalence). The feedback-guided learning of associations is related to the basal ganglia, whereas the medial temporal lobe participates in acquired equivalence learning. In this study, we investigated feedback-guided associative learning and acquired equivalence in deficit and nondeficit schizophrenia. Results revealed that acquired equivalence learning was similarly impaired in deficit and nondeficit patients, whereas feedback-guided associative learning was impaired only in deficit patients. Associative learning and acquired equivalence were not related to frontal lobe tests. These results suggest that the enduring negative symptoms of deficit patients may be related to decreased response to cognitive feedback and deficient basal ganglia functioning.     

Probabilistic classification learning with corrective feedback is selectively impaired in early Huntington's disease--evidence for the role of the striatum in learning with feedback

In general, declarative learning is associated with the activation of the medial temporal lobes (MTL), while the basal ganglia (BG) are considered the substrate for procedural learning. More recently it has been demonstrated the distinction of these systems may not be as absolute as previously thought and that not only the explicit or implicit nature of the memory task alone is important for the distinction of MTL or BG systems. Nevertheless, patients with BG dysfunction - such as patients with Parkinson's disease (PD) or Huntington's disease (HD) - are considered to be impaired at implicit learning. However, a more recent study demonstrated that one implicit learning task, probabilistic classification learning (examples include the weather prediction (WPT) and Mr. Potato Head tasks) is only impaired in PD when it involves learning with corrective feedback (FB) but not when it involves learning in a paired associate (PA) manner, without feedback. Therefore, it has been argued that the presence of feedback rather than the implicit nature of these tasks determines whether or not the BG are recruited. As patients with HD as well as those with PD, have also been shown to be impaired on the standard FB based version of probabilistic classification learning, the question remains as to whether or not there is a similar selective deficit in FB but not PA based probabilistic classification learning in HD. 18 patients with early HD and 18 healthy controls completed FB and PA versions of the WPT task. Relative to controls, HD patients were selectively impaired at WPT learning with feedback. These findings are consistent with previous evidence from studies of probabilistic classification learning in PD. Unlike PD, selective deficits in WPT learning in HD cannot be attributed to the effects of dopaminergic medication and must be directly related to BG dysfunction; for instance even in early HD, only 50% of the neurons in the medial head of caudate remain. We conclude that the striatum is important for WPT learning with feedback. Our findings are consistent with imaging evidence showing recruitment of the caudate during FB based WPT learning, while the MTL is associated with PA based learning.     

Computational cognitive models of prefrontal-striatal-hippocampal interactions in Parkinson’s disease and schizophrenia

Disruption to different components of the prefrontal cortex, basal ganglia, and hippocampal circuits leads to various psychiatric and neurological disorders including Parkinson’s disease (PD) and schizophrenia. Medications used to treat these disorders (such as levodopa, dopamine agonists, antipsychotics, among others) affect the prefrontal-striatal-hippocampal circuits in a complex fashion. We have built models of prefrontal-striatal and striatal-hippocampal interactions which simulate cognitive dysfunction in PD and schizophrenia. In these models, we argue that the basal ganglia is key for stimulus-response learning, the hippocampus for stimulus-stimulus representational learning, and the prefrontal cortex for stimulus selection during learning about multidimensional stimuli. In our models, PD is associated with reduced dopamine levels in the basal ganglia and prefrontal cortex. In contrast, the cognitive deficits in schizophrenia are associated primarily with hippocampal dysfunction, while the occurrence of negative symptoms is associated with frontostriatal deficits in a subset of patients. In this paper, we review our past models and provide new simulation results for both PD and schizophrenia. We also describe an extended model that includes simulation of the different functional role of D1 and D2 dopamine receptors in the basal ganglia and prefrontal cortex, a dissociation we argue is essential for understanding the non-uniform effects of levodopa, dopamine agonists, and antipsychotics on cognition. Motivated by clinical and physiological data, we discuss model limitations and challenges to be addressed in future models of these brain disorders.     

How to find the way out from four rooms? The learning of "chaining" associations may shed light on the neuropsychology of the deficit syndrome of schizophrenia

Recent meta-analytic evidence suggests that clinical neuropsychological methods are not likely to uncover circumscribed cognitive impairments in the deficit syndrome of schizophrenia. To overcome this issue, we adapted a cognitive neuroscience perspective and used a new "chaining" habit learning task. Participants were requested to navigate a cartoon character through a sequence of 4 rooms by learning to choose the open door from 3 colored doors in each room. The aim of the game was to learn the full sequence of rooms until the character reached the outside. In the training phase, each stimulus leading to reward (open door in each room) was trained via feedback until the complete sequence was learned. In the probe phase, the context of rewarded stimuli was manipulated: in a given room, in addition to the correct door of that room, there also appeared a door which was open in another room. Whereas the training phase is dominantly related to basal ganglia circuits, the context-dependent probe phase requires intact medial-temporal lobe functioning. Results revealed that deficit and non-deficit patients were similarly impaired on the probe phase compared with controls. However, the training phase was only compromised in deficit patients. More severe negative symptoms were associated with more errors on the training phase. Executive functions were unrelated to performance on the "chaining" task. These results indicate that the deficit syndrome is associated with prominently impaired stimulus-response reinforcement learning, which may indicate abnormal functioning of basal ganglia circuits.     

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.     

Relation of prefrontal cortex dysfunction to working memory and symptoms in schizophrenia.

OBJECTIVE: The dorsolateral prefrontal cortex has been implicated in both working memory and the pathophysiology of schizophrenia. A relationship among dorsolateral prefrontal cortex activity, working memory dysfunction, and symptoms in schizophrenia has not been firmly established, partly because of generalized cognitive impairments in patients and task complexity. Using tasks that parametrically manipulated working memory load, the authors tested three hypotheses: 1) patients with schizophrenia differ in prefrontal activity only when behavioral performance differentiates them from healthy comparison subjects, 2) dorsolateral prefrontal cortex dysfunction is associated with poorer task performance, and 3) dorsolateral prefrontal cortex dysfunction is associated with cognitive disorganization but not negative or positive symptoms. METHOD: Seventeen conventionally medicated patients with schizophrenia and 16 healthy comparison subjects underwent functional magnetic resonance imaging while performing multiple levels of the "n-back" sequential-letter working memory task. RESULTS: Patients with schizophrenia showed a deficit in physiological activation of the right dorsolateral prefrontal cortex (Brodmann's area 46/9) in the context of normal task-dependent activity in other regions, but only under the condition that distinguished them from comparison subjects on task performance. Patients with greater dorsolateral prefrontal cortex dysfunction performed more poorly. Dorsolateral prefrontal cortex dysfunction was selectively associated with disorganization symptoms. CONCLUSIONS: These results are consistent with the hypotheses that working memory dysfunction in patients with schizophrenia is caused by a disturbance of the dorsolateral prefrontal cortex and that this disturbance is selectively associated with cognitive disorganization. Further, the pattern of behavioral performance suggests that dorsolateral prefrontal cortex dysfunction does not reflect a deficit in the maintenance of stimulus representations per se but points to deficits in more associative components of working memory.     

Dissociating hippocampal versus basal ganglia contributions to learning and transfer

Based on prior animal and computational models, we propose a double dissociation between the associative learning deficits observed in patients with medial temporal (hippocampal) damage versus patients with Parkinson's disease (basal ganglia dysfunction). Specifically, we expect that basal ganglia dysfunction may result in slowed learning, while individuals with hippocampal damage may learn at normal speed. However, when challenged with a transfer task where previously learned information is presented in novel recombinations, we expect that hippocampal damage will impair generalization but basal ganglia dysfunction will not. We tested this prediction in a group of healthy elderly with mild-to-moderate hippocampal atrophy, a group of patients with mild Parkinson's disease, and healthy controls, using an "acquired equivalence" associative learning task. As predicted, Parkinson's patients were slower on the initial learning but then transferred well, while the hippocampal atrophy group showed the opposite pattern: good initial learning with impaired transfer. To our knowledge, this is the first time that a single task has been used to demonstrate a double dissociation between the associative learning impairments caused by hippocampal versus basal ganglia damage/dysfunction. This finding has implications for understanding the distinct contributions of the medial temporal lobe and basal ganglia to learning and memory.     

Abnormal medial temporal activity for bound information during working memory maintenance in patients with schizophrenia

Alterations of binding in long‐term memory in schizophrenia are well established and occur as a result of aberrant activity in the medial temporal lobe (MTL). In working memory (WM), such a deficit is less clear and the pathophysiological bases remain unstudied. Seventeen patients with schizophrenia and 17 matched healthy controls performed a WM binding task while undergoing functional magnetic resonance imaging. Binding was assessed by contrasting two conditions comprising an equal amount of verbal and spatial information (i.e., three letters and three spatial locations), but differing in the absence or presence of a link between them. In healthy controls, MTL activation was observed for encoding and maintenance of bound information but not for its retrieval. Between‐group comparisons revealed that patients with schizophrenia showed MTL hypoactivation during the maintenance phase only. In addition, BOLD signals correlated with behavioral performance in controls but not in patients with schizophrenia. Our results confirm the major role that the MTL plays in the pathophysiology of schizophrenia. Short‐term and long‐term relational memory deficits in schizophrenia may share common cognitive and functional pathological bases. Our results provide additional information about the episodic buffer that represents an integrative interface between WM and long‐term memory. © 2009 Wiley‐Liss, Inc.     

Cognitive patterns in subtypes of schizophrenia.

AIM: Because of the heterogeneity of schizophrenia, this study researched different cognitive patterns in distinct subtypes of schizophrenic patients. METHODS: Thirty-five Diagnostic and Statistical Manual IV (DSM IV) schizophrenic patients and 35 healthy controls were included. Patients were categorized into deficit, disorganized and positive subtypes with the schedule for the deficit syndrome (SDS) and the positive and negative syndrome scale (PANSS). Executive/attentional functions were assessed with the modified card sorting test (MCST), a test of verbal fluency, the trail making test (TMT) and the Stroop color-word test (Stroop test). Episodic memory was explored through the California verbal learning test (CVLT). RESULTS: The positive subtype had some executive/attentional (fluency and Stroop tests) and mnesic performances in the normal range, suggesting the preservation of good cognitive skills. In contrast, the deficit and disorganized subtypes had major mnesic and executive/attentional dysfunctions compared to healthy subjects. The deficit subtype compared to the control group performed predominantly worse on the MCST and fluency, whereas the disorganized subtype had the lowest scores on the TMT and the Stroop test. CONCLUSION: This study showed distinct cognitive patterns in deficit, disorganized and positive patients in comparison with the controls, suggesting a heterogeneous cognitive dysfunction in schizophrenia.     

Visual and verbal learning in a genetic metabolic disorder

Visual and verbal learning in a genetic metabolic disorder (cystinosis) were examined in the following three studies. The goal of Study I was to provide a normative database and establish the reliability and validity of a new test of visual learning and memory (Visual Learning and Memory Test; VLMT) that was modeled after a widely used test of verbal learning and memory (California Verbal Learning Test; CVLT). One hundred seventy-two neurologically intact individuals ages 5 years through 50 years were administered the VLMT and the CVLT. Normative data were collected and the results suggested that the VLMT is a reliable and valid new measure of visual learning and memory. The aim of Study II was to examine possible dissociations between verbal and visual learning and memory performances in individuals with cystinosis as well as to assess changes in performance as individuals with the disorder age. Thirty-seven individuals with cystinosis and 37 matched controls were administered a new test of visual learning and memory (Visual Learning and Memory Test; VLMT) and the California Verbal Learning Test (CVLT). Individuals with cystinosis performed at a lower level than controls on almost all indices of visual learning and memory while no differences were found between the groups on the verbal measure. Examination of the results on the VLMT indicated that the visual learning and memory impairment in cystinosis may result from difficulty with processing visual information quickly. Study III aimed to remediate the observed visual learning and memory deficit by implementing an intervention that increased the exposure time for visual stimuli. Fifteen individuals with cystinosis were administered a version of the VLMT in which the stimuli were exposed for 3 s rather than 1 s. Fifteen matched controls were administered the 1-s version of the VLMT. The results of Study III indicated that by increasing the exposure time for each visual stimulus, individuals with cystinosis were able to perform at the same level as control subjects. This is the first study to demonstrate impaired visual learning and spared verbal learning in individuals with cystinosis. These results may provide the foundation for designing cognitive interventions, may lead to further hypotheses regarding the underlying mechanism of the observed visual learning and memory deficit, and have implications for a greater understanding of gene–behavior relationships.     

Rule-based categorization deficits in focal basal ganglia lesion and Parkinson's disease patients

Patients with basal ganglia (BG) pathology are consistently found to be impaired on rule-based category learning tasks in which learning is thought to depend upon the use of an explicit, hypothesis-guided strategy. The factors that influence this impairment remain unclear. Moreover, it remains unknown if the impairments observed in patients with degenerative disorders such as Parkinson's disease (PD) are also observed in those with focal BG lesions. In the present study, we tested patients with either focal BG lesions or PD on two categorization tasks that varied in terms of their demands on selective attention and working memory. Individuals with focal BG lesions were impaired on the task in which working memory demand was high and performed similarly to healthy controls on the task in which selective-attention demand was high. In contrast, individuals with PD were impaired on both tasks, and accuracy rates did not differ between on and off medication states for a subset of patients who were also tested after abstaining from dopaminergic medication. Quantitative, model-based analyses attributed the performance deficit for both groups in the task with high working memory demand to the utilization of suboptimal strategies, whereas the PD-specific impairment on the task with high selective-attention demand was driven by the inconsistent use of an optimal strategy. These data suggest that the demands on selective attention and working memory affect the presence of impairment in patients with focal BG lesions and the nature of the impairment in patients with PD.     

When artificial grammar acquisition in Parkinson's disease is impaired: the case of learning via trial-by-trial feedback

Although there is strong evidence that human category learning is mediated by qualitatively distinct systems, the neural substrates of procedural category learning remain largely unclear. The present research sought to investigate the role of the basal ganglia in the acquisition of categorical knowledge via an examination of the ability of people with Parkinson's disease (PD) to learn an artificial grammar (AG) system in a format akin to habit learning tasks such as probabilistic classification learning. Eighteen nondemented patients with PD were compared with 22 matched controls on a task modified so that participants' grammar learning depended on making use of feedback provided on each trial. Results showed that patients with PD exhibited abnormal AG learning, with the deficit more pronounced early in the task. Impaired categorisation performance in patients was not related to declarative knowledge obtained during the test and was independent of frontal functioning. The findings presented here indicate that prior inconsistencies across category learning tasks in PD performance may be explained, at least in part, by whether the task necessitates the formation of associations between stimulus cues and categorical responses, and support the hypothesis that the basal ganglia play a specific role in procedural learning in complex feedback-based categorisation tasks.     

Decoding emotional prosody in Parkinson's disease and its potential neuropsychological basis

Parkinson's disease patients may have difficulty decoding prosodic emotion cues. These data suggest that the basal ganglia are involved, but may reflect dorsolateral prefrontal cortex dysfunction. An auditory emotional n-back task and cognitive n-back task were administered to 33 patients and 33 older adult controls, as were an auditory emotional Stroop task and cognitive Stroop task. No deficit was observed on the emotion decoding tasks; this did not alter with increased frontal lobe load. However, on the cognitive tasks, patients performed worse than older adult controls, suggesting that cognitive deficits may be more prominent. The impact of frontal lobe dysfunction on prosodic emotion cue decoding may only become apparent once frontal lobe pathology rises above a threshold.     

Procedural learning in schizophrenia can reflect the pharmacologic properties of the antipsychotic treatments.

BACKGROUND: Conventional and atypical antipsychotics have different affinities for D2 receptors, and these receptors are principally located in the striatum. Given that this cerebral structure was previously found to play a major role in procedural learning, the antipsychotic treatment in schizophrenia may be determinant for the procedural learning profile of these patients. OBJECTIVE: The current study was aimed at verifying whether procedural learning differs in patients with schizophrenia treated with conventional antipsychotics and patients treated with atypical antipsychotics. METHOD: Forty-five patients with schizophrenia were divided into 3 different groups according to their pharmacologic treatment: (1) haloperidol, a classical neuroleptic with high D2 receptor affinity; (2) clozapine, an atypical neuroleptic with practically no D2 receptor affinity; and (3) risperidone, an atypical neuroleptic that nevertheless shows high D2 receptor affinity. Patients were compared to 35 control subjects on a visuomotor procedural learning task (mirror drawing). RESULTS: All patients were able to learn the task. However, those treated with haloperidol showed some degree of learning impairment, while those treated with clozapine or risperidone did not show this impairment. In addition, performance per se, regardless of the learning, was found to be affected in the haloperidol and risperidone, but not in the clozapine groups. CONCLUSION: Procedural learning in schizophrenia may be differentially affected, depending on the pharmacologic profiles of the antipsychotics used for the treatment of this illness.     

Pallidal activity is involved in visuomotor association learning in monkeys

In order to examine whether the basal ganglia are involved in arbitrary visuomotor association, we recorded neuronal activity in the internal segment of the globus pallidus (GPi) of monkeys during a conditional visuomotor learning task. Two monkeys were presented a cueing visual stimulus, and following a delay period required to push, pull or turn a manipulator according to the cue. GPi neurons showed changes in activity during the delay period when the animals performed the task on the basis of a familiar stimulus-response association. Those changes in delay activity were enhanced as the monkeys were learning a new visuomotor association. The enhancement of the changes was selective to a following response. These results suggest that the basal ganglia are involved in arbitrary visuomotor association, especially during the learning of new associations.     

Impaired context reversal learning, but not cue reversal learning, in patients with amnestic mild cognitive impairment

It has been proposed that reversal learning is impaired following damage to the orbitofrontal and ventromedial frontal cortex (OFC/VMFC) and to the medial temporal lobe (MTL), including the hippocampal formation. However, the exact characteristics of the MTL-associated reversal learning deficit are not known. To investigate this issue, we assessed 30 newly diagnosed patients with amnestic mild cognitive impairment (aMCI) and 30 matched healthy controls. All patients fulfilled the aMCI criteria of the Mayo Clinic Alzheimer's Disease Research Center and underwent head magnetic resonance imaging that confirmed MTL atrophy. Reversal learning was assessed using a novel reinforcement learning task. Participants first acquired and then reversed stimulus-outcome associations based on negative and positive feedback (losing and gaining points). Stimuli consisted of a cue (geometric shapes) and a spatial context (background color or pattern). Neuropsychological assessment included tasks related to the MTL (paired associates learning), dorsolateral prefrontal cortex (DLPFC) (extradimensional shift, One-touch Stockings of Cambridge), and OFC/VMFC (Holiday Apartment Task). Results revealed that, relative to controls, patients with aMCI exhibited a marked reversal learning deficit, which was highly selective for the reversal of context. The acquisition of stimulus-outcome associations and cue reversal learning were spared. Performance on the context reversal learning task significantly correlated with the right hippocampal volume. In addition, patients with aMCI had deficits on tests related to DLPFC but not to OFC/VMFC. However, DLPFC dysfunctions were not associated with context reversal learning. These results suggest that MTL deficits in aMCI selectively affect context reversal learning when OFC/VMFC functions are spared. This deficit is not influenced by the valence of the outcome (positive or negative feedback) and by executive dysfunctions.     

Visuo-motor and cognitive procedural learning in children with basal ganglia pathology

We investigated procedural learning in 18 children with basal ganglia (BG) lesions or dysfunctions of various aetiologies, using a visuo-motor learning test, the Serial Reaction Time (SRT) task, and a cognitive learning test, the Probabilistic Classification Learning (PCL) task. We compared patients with early (<1 year old, n = 9), later onset (>6 years old, n = 7) or progressive disorder (idiopathic dystonia, n = 2). All patients showed deficits in both visuo-motor and cognitive domains, except those with idiopathic dystonia, who displayed preserved classification learning skills. Impairments seem to be independent from the age of onset of pathology. As far as we know, this study is the first to investigate motor and cognitive procedural learning in children with BG damage. Procedural impairments were documented whatever the aetiology of the BG damage/dysfunction and time of pathology onset, thus supporting the claim of very early skill learning development and lack of plasticity in case of damage.     

Motor and non-motor sequence learning in patients with basal ganglia lesions: the case of serial reaction time (SRT)

In order to address the question of whether the basal ganglia are involved exclusively in regulation of motor sequence learning, or if they are involved in non-motor sequence learning as well, two versions of the serial reaction time (SRT) task were administered: First is the standard version of the SRT task in which the sequence is executed motorically, and the second is a non-motor version of the task which requires response only to a particular position of the sequence. Sixteen patients with damage restricted to the region of the basal ganglia and 16 matched control subjects participated in this study. In addition to the motor and non-motor SRT tasks, two declarative memory tests (Visual Paired Associates and Rey Auditory-Verbal Learning Test) were administered to the participants. Results indicate that the two groups did not differ either on learning rate of the two declarative tasks, or on the declarative component of the SRT tasks (i.e., 'generate'). However, the control group was significantly superior to the basal ganglia (BG) group in learning a specific sequence in the motor and non-motor SRT tasks. Results suggest that the basal ganglia are involved in the regulation of non- motor as well as motor sequence learning.