Dissociating medial temporal and basal ganglia memory systems with a latent learning task

The medial temporal (MT) lobes and basal ganglia have both been implicated as brain substrates of associative learning. Here, we show a dissociation between medial temporal and basal ganglia damage using a latent learning task, in which prior exposure to cues, uncorrelated with each other, slows subsequent learning of an association between them. Consistent with prior work, we found a robust exposure effect in healthy controls, with exposed controls learning more slowly than non-exposed controls. This effect was abolished in medial temporal amnesia: both exposed and non-exposed amnesic patients learned at the same speed. A group of patients with basal ganglia damage due to Parkinson’s disease showed a reversal of the effect: exposed subjects learned faster than non-exposed subjects. Our findings point to distinct and dissociable contributions of medial temporal lobe and basal ganglia structures to learning and memory.     

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.     

Spatial and temporal sequence learning in patients with Parkinson's disease or cerebellar lesions

The functional role of different subcortical areas in sequence learning is not clear. In the current study, Parkinson's patients, patients with cerebellar damage, and age-matched control participants performed a serial reaction time task in which a spatial sequence and a temporal sequence were presented simultaneously. The responses were based on the spatial sequence, and the temporal sequence was incidental to the task. The two sequences were of the same length, and the phase relationship between them was held constant throughout training. Sequence learning was assessed comparing performance when both sequences were present versus when the dimension of interest was randomized. In addition, sequence integration was assessed by introducing phase-shift blocks. A functional dissociation was found between the two patient groups. Whereas the Parkinson's patients learned the spatial and temporal sequences individually, they did not learn the relationship between the two sequences, suggesting the basal ganglia play a functional role in sequence integration. In contrast, the cerebellar patients did not show any evidence of sequence learning at all, suggesting the cerebellum might play a general role in forming sequential associations.     

Dissociation between medial temporal lobe and basal ganglia memory systems in schizophrenia

The purpose of this 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. Volunteers received the Rutgers acquired equivalence task (face-fish task) by [Myers, C.E., Shohamy, D., Gluck, M.A. et al., 2003. Dissociating hippocampal versus basal ganglia contributions to learning and transfer. J. Cogn. Neurosci. 15, 185-193.], the California Verbal Learning Test (CVLT), and the n-back working memory test. The Rutgers acquired equivalence task investigates BG-dependent processes (stimulus-response learning) and MTL-dependent processes (stimulus generalization) with a single test. Results revealed that patients with schizophrenia showed a selective deficit on stimulus generalization, whereas stimulus-response learning was spared. The stimulus generalization deficit correlated with the CVLT performance (total scores from trials 1-5 and long-delay recall), but not with the n-back test performance. The number of errors during stimulus-response learning correlated with the daily chlorpromazine-equivalent dose of antipsychotics. In conclusion, this is the first study to show that patients with schizophrenia exhibit deficits during MTL-dependent learning, but not during BG-dependent learning within a single task. High-dose first generation antipsychotics may disrupt BG-dependent learning by blocking dopaminergic neurotransmission in the nigro-stiratal system.     

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.     

Cognitive deficits in progressive supranuclear palsy, Parkinson's disease, and multiple system atrophy in tests sensitive to frontal lobe dysfunction.

Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The groups with palsy and Parkinson's disease were slower in the measure of initial thinking time, whereas the group with multiple system atrophy was only slower in a measure of thinking time subsequent to the first move, resembling patients with frontal lobe damage. On a test of spatial working memory, each group showed deficits relative to their matched control groups, but the three groups differed in their strategy for dealing with this task. On a test of attentional set shifting, each group was again impaired, mainly at the extradimensional shifting stage, but the group with Steele-Richardson-Olszewski syndrome exhibited the greatest deficit. The results are compared with previous findings in patients with Alzheimer's disease or frontal lobe damage. It is concluded that these basal ganglia disorders share a distinctive pattern of cognitive deficits on tests of frontal lobe dysfunction, but there are differences in the exact nature of the impairments, in comparison not only with frontal lobe damage but also with one another.     

Neural basis for impaired time reproduction in Parkinson's disease: an fMRI study.

Studies involving brain-lesioned subjects have used the paced finger tapping (PFT) task to investigate the neural systems that govern motor timing. Patients with Parkinson's disease (PD), for example, demonstrate abnormal performance on the PFT, characterized by decreased accuracy and variability changes, suggesting that the basal ganglia may play a critical role in motor timing. Consistent with this hypothesis, an fMRI study of healthy participants demonstrated that the medial frontostriatal circuit (dorsal putamen, ventrolateral thalamus, SMA) correlated with explicit time-dependent components of the PFT task. In the current fMRI study, PD patients and healthy age-matched controls were imaged while performing the PFT. PD patients underwent 2 imaging sessions, 1 on and the other off dopamine supplementation. Relative to controls, PD patients were less accurate and showed greater variability on the PFT task relative to controls. No PFT performance differences were observed between the on and off medication states despite significantly greater motor symptoms on the Unified Parkinson's Disease Rating Scale (UPDRS) in the off medication state. Functional imaging results demonstrated decreased activation within the sensorimotor cortex (SMC), cerebellum, and medial premotor system in the PD patients compared to controls. With dopamine replacement, an increase in the spatial extent of activation was observed within the SMC, SMA, and putamen in the PD patients. These results indicate that impaired timing reproduction in PD patients is associated with reduced brain activation within motor and medial premotor circuits. Despite a lack of improvement in PFT performance, PD patient's brain activation patterns were partially "normalized" with dopamine supplementation. These findings could not be attributed to greater head movement artifacts or basal ganglia atrophy within the PD group.     

The performance on learning tasks of patients in the early stages of Parkinson's disease

It is known that in animals learning is disrupted by caudate lesions; but there has been no agreement about whether pathology in the basal ganglia causes a similar impairment in man. Nineteen patients in the early stages of Parkinson's disease were tested on two associative learning tasks and on the Wisconsin Card Sorting Task; and their performance was compared with that of patients with frontal or temporal lobe lesions. On the two associative learning tasks there was no overall difference between the Parkinsonian group and the controls. However, a minority of the Parkinsonian patients performed very poorly on these tasks; and it was noted that these tended to be the older patients.     

The striatum and probabilistic implicit sequence learning

The distinction between implicit (unconscious) and explicit (conscious) learning is controversial. Some argue that explicit learning is dependent on the medial temporal lobes, whereas implicit learning is mediated by the basal ganglia and others propose that all learning is explicit. The purpose of the present study was to investigate the involvement of the basal ganglia in implicit learning by examining learning of a probabilistic sequence of targets, in patients with Parkinson's disease (PD) and controls. Following learning, we assessed participants' awareness of the sequence structure by asking them to generate or withhold sequence consistent responses (process dissociation procedure) and to perform a recognition test in which measures of priming and recognition were obtained concurrently. Although the PD group demonstrated evidence of probabilistic sequence learning in this study, learning was significantly attenuated compared to controls. Residual learning in the PD group was genuinely implicit in nature because (a) PD patients were not able to control the expression of their acquired knowledge, and (b) their knowledge supported subsequent priming of sequence-consistent responses but recognition ratings were at chance. In contrast, following learning controls were capable of above chance recognition indicating that their sequential knowledge was acquired in a more explicit way. The results support the view that (i) the basal ganglia contribute to probabilistic implicit sequence learning (ii) that such learning can occur implicitly without explicit knowledge in PD patients.     

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.     

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.     

Perceptual learning, awareness, and the hippocampus

Declarative memory depends on the hippocampus and related medial temporal lobe and diencephalic structures. Declarative memory has usually been found to be available to conscious recollection. A recent study (Chun and Phelps, Nat Neurosci 1999;2:844-847) found that damage to the medial temporal lobe (including the hippocampus) impaired performance on a perceptual learning task, yet the learning was accomplished in the absence of memory for the stimuli. This finding raised the possibility that some hippocampus-dependent tasks may be inaccessible to awareness and may be performed without evoking conscious memory processes. Using the same task, we show that when damage is confined largely to the hippocampal formation, perceptual learning is intact. Thus, the available data suggest that damage limited to the hippocampal formation does not impair nonconscious (nondeclarative) memory. Further, the data do not contradict the idea that hippocampus dependent memory is accessible to conscious recollection. Finally, perceptual learning was impaired in patients, with extensive damage to the medial temporal lobe and with additional variable damage to lateral temporal cortex.     

Comparison of the basal ganglia and cerebellum in shifting attention

The basal ganglia and cerebellum have traditionally been associated with motor performance. Recently, there has been considerable interest regarding the contributions of these subcortical structures to aspects of cognition. In particular, both the basal ganglia and cerebellum have been hypothesized to be involved in the control of attentional set. To date, no neuropsychological studies have directly compared the effects of basal ganglia and cerebellar dysfunction on the same attention shifting tasks. To this end, we employed an alternating attention task that has been used to demonstrate putative attentional control deficits in children with cerebellar pathology, either related to autism or neurological insult. When adult patients with either Parkinson's disease or cerebellar lesions were tested on this task, a similar pattern of deficits was observed for both groups. However, when the motor demands were reduced, cerebellar patients showed a significant improvement on the alternating attention task, whereas the Parkinson patients continued to exhibit an impairment. This dissociation suggests that attentional deficits reported previously as being due to cerebellar dysfunction may be, at least in part, secondary to problems related to coordinating successive responses. In contrast, attention-shifting deficits associated with basal ganglia impairment cannot be explained by recourse to the motor demands of the task.     

Relation between medial temporal atrophy and functional brain activity during memory processing in Alzheimer's disease: a combined MRI and SPECT study

OBJECTIVE: To investigate the relation between atrophy of the hippocampal region and brain functional patterns during episodic memory processing in Alzheimer's disease. PATIENTS AND METHODS: Whole brain structural magnetic resonance imaging (MRI) data and single photon emission computed tomography (SPECT) measures of regional cerebral blood flow (rCBF) were obtained during a verbal recognition memory task in nine subjects with mild Alzheimer's disease and 10 elderly healthy controls. Using the statistical parametric mapping approach, voxel based comparisons were made on the MRI data to identify clusters of significantly reduced grey matter concentrations in the hippocampal region in the Alzheimer patients relative to the controls. The mean grey matter density in the voxel cluster of greatest hippocampal atrophy was extracted for each Alzheimer subject. This measure was used to investigate, on a voxel by voxel basis, the presence of significant correlations between the degree of hippocampal atrophy and the rCBF SPECT measures obtained during the memory task. RESULTS: Direct correlations were detected between the hippocampal grey matter density and rCBF values in voxel clusters located bilaterally in the temporal neocortex, in the left medial temporal region, and in the left posterior cingulate cortex during the memory task in the Alzheimer's disease group (p < 0.001). Conversely, measures of hippocampal atrophy were negatively correlated with rCBF values in voxel clusters located in the frontal lobes, involving the right and left inferior frontal gyri and the insula (p < 0.001). CONCLUSIONS: Hippocampal atrophic changes in Alzheimer's disease are associated with reduced functional activity in limbic and associative temporal regions during episodic memory processing, but with increased activity in frontal areas, possibly on a compensatory basis.     

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.     

Impaired associative memory in temporal lobe epilepsy subjects after lesions of hippocampus, parahippocampal gyrus, and amygdala

There has been growing interest in the differential role of medial temporal lobe structures in learning and memory. The goal of the present study was to clarify how lesions of hippocampus, parahippocampal gyrus, and amygdala interfere with associative learning and memory. Thirty subjects with pharmacoresistant medial temporal lobe epilepsy (TLE) and temporal lobe removal were compared with 30 matched healthy control subjects. A set of neuropsychological test measures and an associative learning task requiring the learning and recall of objects and faces were administered. The lesions of hippocampus, parahippocampal gyrus, amygdala, and fusiform gyrus of TLE subjects were determined by three-dimensional magnetic resonance imaging (3-D MRI) volumetric assessment. The results indicate that TLE subjects with combined large hippocampal lesions, large parahippocampal gyrus (i.e., perirhinal/entorhinal) lesions, and large amygdala lesions learned and recalled the associative task significantly worse than control subjects or subjects with small lesions of the hippocampus, parahippocampal gyrus, and amygdala. Regression analysis revealed that larger lesions of the parahippocampal gyrus (i.e., perirhinal/entorhinal cortices) were significantly related to increasing deficits on the task, and that hippocampal and amygdala lesion size did not significantly improve the prediction. Our results suggest that perirhinal and entorhinal cortices may contribute predominantly to the associative learning and recall of objects and faces.     

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.     

Contribution of the anterior thalamic nuclei to conditional learning in rats

The anterior thalamic region is intimately linked anatomically and functionally with the hippocampus, which is critical for various forms of spatial learning. Rats with lesions to the anterior thalamic nuclei and a control group were trained on a visual-spatial conditional associative learning task in which they had to learn to go to one of two locations depending on the particular visual cue presented on each trial; the rats approached the cues from different directions. The animals were subsequently tested on a spatial working memory task, the eight-arm radial maze. Performance on both these tasks had previously been shown to be impaired by hippocampal lesions. Rats with anterior thalamic damage were able to acquire the conditional associative task at a rate comparable to that of the control animals, but were impaired on the radial maze task. The finding of a dissociation between the effects of lesions of the anterior thalamic nuclei on two different classes of behavior known to be associated with hippocampal function suggest that while different neural stations within the extended hippocampal circuit may all play a role in spatial learning, the role of each of these regions in such learning may be more selective than previously considered.     

L-dopa impairs learning, but spares generalization, in Parkinson's disease

In this study we examined the effect of dopaminergic modulation on learning and memory. Parkinson's patients were tested 'on' versus 'off' dopaminergic medication, using a two-phase learning and transfer task. We found that dopaminergic medication was associated with impaired learning of an incrementally acquired concurrent discrimination task, while patients withdrawn from dopaminergic medication performed as well as controls. In addition, we found a dissociation of the effect of medication within a single two-phase task: patients tested 'on' medication were not impaired at the ability to generalize based on learned information. The deficit among medicated patients appeared to be related specifically to the concurrent, incremental, feedback-based nature of the task: such a deficit was not found in a version of the task in which demands for concurrent error-processing learning were reduced. Taken together with a growing body of evidence emphasizing a role for midbrain dopamine in error-correcting, feedback-based learning processes, the present results suggest a framework for understanding previously conflicting results regarding the effect of medication on learning and memory in Parkinson's disease.     

Memory failure has different mechanisms in subcortical stroke and Alzheimer's disease

Patients with extensive subcortical cerebrovascular disease may have impaired memory, often despite the absence of medial temporal or diencephalic strokes. In this group, episodic memory failure may arise from frontal lobe dysfunction based on disruption of frontosubcortical loops caused by lacunae. We tested this idea by studying cognitively impaired subcortical stroke (CIS) patients and Alzheimer's disease (AD) patients with [18F]-fluorodeoxyglucose positron emission tomography using a continuous verbal memory task during the period of tracer uptake. Patients were matched on severity of cognitive impairment and overall memory task performance. As hypothesized, we found a double dissociation in the relations between metabolism and memory in these groups, such that memory in CIS (but not in AD) correlates with prefrontal lobe metabolism, whereas in AD (but not in CIS), memory correlates with left hippocampal and temporal lobe metabolism. Analysis of memory subscores showed that CIS patients made more errors on short-delay trials, which is consistent with working memory failure. It seems that different pathogenic mechanisms underlie episodic memory failure in subcortical cerebrovascular disease and AD.