Intact implicit habit learning in Alzheimer's disease

Habit learning refers to the incremental implicit learning of associations. Patients with Alzheimer's disease (AD) exhibit deficits in explicit memory and in conceptual implicit memory tasks that rely on the cortical areas damaged in AD. The authors tested patients with AD and controls on a probabilistic classification task in which participants implicitly acquire cue-outcome associations. Both groups showed evidence of learning across 50 trials, and performance did not differ significantly between the groups. In contrast, patients with AD exhibited a profound impairment in explicit memory for the testing episode. These results are consistent with the idea that habit learning relies on subcortical structures, including the basal ganglia, and is independent of the medial temporal and cortical areas damaged in AD.     

Alcohol dementia: "cortical" or "subcortical" dementia?

Most dementias are considered to exhibit either a predominantly "cortical" (e.g. Alzheimer's disease, AD) or "subcortical" (e.g. Parkinson's disease) pattern. A double dissociation has been reported, such that cortical and subcortical dementias can be differentiated based on performance on tests of declarative and procedural learning. The goal of this study was to determine if subjects with alcohol dementia exhibit a predominantly cortical or subcortical dementia profile. The performance of 10 elderly subjects diagnosed with alcohol dementia, 29 elderly subjects with histories of alcohol dependence but who were not demented, and 11 subjects with AD was compared to 20 elderly control subjects. The results indicated that the procedural learning task did not differentiate among the groups, whereas the discriminability index from the California Learning Test (the declarative learning task) did. Thus, alcohol dementia cannot clearly be ascribed to either dementia classification.     

The neurophysiology of attention-deficit/hyperactivity disorder.

Recent reviews of the neurobiology of Attention-Deficit/Hyperactivity Disorder (AD/HD) have concluded that there is no single pathophysiological profile underlying this disorder. Certainly, dysfunctions in the frontal/subcortical pathways that control attention and motor behavior are implicated. However, no diagnostic criteria or behavioral/neuroimaging techniques allow a clear discrimination among subtypes within this disorder, especially when problems with learning are also considered. Two major Quantitative EEG (QEEG) subtypes have been found to characterize AD/HD. Here we review the major findings in the neurophysiology of AD/HD, focusing on QEEG, and briefly present our previous findings using a source localization technique called Variable Resolution Electromagnetic Tomography (VARETA). These two techniques represent a possible objective method to identify specific patterns corresponding to EEG-defined subtypes of AD/HD. We then propose a model representing the distribution of the neural generators in these two major AD/HD subtypes, localized within basal ganglia and right anterior cortical regions, and hippocampal, para-hippocampal and temporal cortical regions, respectively. A comprehensive review of neurochemical, genetic, neuroimaging, pharmacological and neuropsychological evidence in support of this model is then presented. These results indicate the value of the neurophysiological model of AD/HD and support the involvement of different neuroanatomical systems, particularly the dopaminergic pathways.     

Role of the basal ganglia in category learning: how do patients with Parkinson's disease learn?

The purpose of the present study was to gain a deeper understanding of the role of the basal ganglia in learning and memory by examining learning strategies among patients with basal ganglia dysfunction. Using a probabilistic category learning task (the "weather prediction" task) previously shown to be sensitive to basal ganglia function, the authors examined patterns of performance during learning and used mathematical models to capture different learning strategies. Results showed that patients with Parkinson's disease exhibit different patterns of strategy use. Specifically, most controls initially used a simple, but suboptimal, strategy that focused on single-cue-outcome associations; eventually, however, most controls adopted a more complex, optimal learning strategy, integrating single-cue associations to predict outcomes for multiple-cue stimuli. In contrast, the majority of individuals with Parkinson's disease continued to rely on simple single-cue learning strategies throughout the experiment.     

Changing brain networks for visuomotor control with increased movement automaticity

Learning a motor skill is associated with changes in patterns of brain activation with movement. Here we have further characterized these dynamics during fast (short-term) learning of a visuomotor skill using functional magnetic resonance imaging. Subjects (n = 15) were studied as they learned to visually track a moving target by varying the isometric force applied to a pressure plate held in the right hand. Learning was confirmed by demonstration of improved performance and automaticity (the relative lack of need for conscious attention during task execution). We identified two distinct, time-dependent patterns of functional changes in the brain associated with these behavioral changes. An initial, more attentionally demanding stage of learning was associated with the greatest relative activity in widely distributed, predominantly cortical regions including prefrontal, bilateral sensorimotor, and parietal cortices. The caudate nucleus and ipsilateral cerebellar hemisphere also showed significant activity. Over time, as performance improved, activity in these regions progressively decreased. There was an increase in activity in subcortical motor regions including that of the cerebellar dentate and the thalamus and putamen. Short-term motor-skill learning thus is associated with a progressive reduction of widely distributed activations in cortical regions responsible for executive functions, processing somatosensory feedback and motor planning. The results suggest that early performance gains rely strongly on prefrontal-caudate interactions with later increased activity in a subcortical circuit involving the cerebellum and basal ganglia as the task becomes more automatic. Characterization of these changes provides a potential tool for functional "dissection" of pathologies of movement and motor learning.     

Performance of everyday actions in mild Alzheimer's disease

Early neuropsychological deficits associated with mild Alzheimer's disease (AD) have been characterized as memory deficits and impaired executive function or attention. The functional impact of early impairment was investigated by evaluating performance of everyday actions in older adults with mild AD (n = 15) as compared with healthy age-matched controls (n = 16). Everyday actions were familiar activities, for example, making a cup of tea, but were varied in complexity (simple, complex) and were performed under varied attention demand (single task, dual task). Although both participant groups responded to increasing task complexity by making more errors, the AD group made more errors under dual-task conditions regardless of the complexity of the task. Furthermore, a task requiring strategic retrieval of semantic information from long-term memory and manipulation of attention online (category fluency) was able to account for a large proportion of the group-related variance in everyday task performance. Results are discussed in relation to the role of components of working memory in performance of everyday actions in mild AD.     

Repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex improves probabilistic category learning

Traditionally, it has been thought that probabilistic category learning, one of the implicit memory functions, is dependent on the basal ganglia. However, there is growing evidence indicating the involvement of the dorsolateral prefrontal cortex (DLPFC) in probabilistic category learning. In order to identify the causal role of DLPFC in probabilistic category learning, we investigated whether repetitive transcranial magnetic stimulation (rTMS) over the left DLPFC influences the learning ability in healthy subjects using the weather prediction task (WPT). Application of 10?Hz rTMS over the left DLPFC induced significant improvement in the total hit rate during the total trials of the WPT, compared with sham stimulation. Specifically, the improvement was significant in the early and late learning blocks of the WPT, but not in the intermediate block of learning. These results indicate that the left DLPFC may play an important role in probabilistic category learning, possibly by influencing not only on embodied information application in late stage of the learning but also on memory encoding for working memory demands in early stage of the learning via frontostriatal and frontohippocampal circuits, respectively. They also may lend support to the possibility that rTMS can improve implicit learning ability in patients with basal ganglia disorders.     

Coffee with jelly or unbuttered toast: commissions and omissions are dissociable aspects of everyday action impairment in Alzheimer's disease

Relative to our understanding of the memory and language deficits associated with Alzheimer's disease (AD), little is known about problems with everyday action performance (i.e., meal preparation, grooming). The resource theory proposes that everyday action problems are best explained by a unitary deficit in general cognitive resources. However, recent research suggests that omission and commission errors may reflect dissociable aspects of action impairment, with only omissions associated with resource limitations. This study examined everyday action performance in 70 participants with AD who also underwent a neuropsychological evaluation. First, correlation and principal component analyses were performed to examine the construct(s) that might explain everyday action impairment. Second, relations between everyday task component(s) and neuropsychological tests were examined by using correlation and regression analyses. Third, differences in everyday action error patterns were examined among participants of comparable overall impairment levels. Results showed omission and commission errors were uncorrelated and distinct components of everyday action performance, predicted by different neuropsychological tests, and differentially distributed even among participants with comparable overall impairment.     

Whole-brain high-resolution metabolite mapping with 3D compressed-sensing SENSE low-rank 1H FID-MRSI

There is a growing interest in the neuroscience community to map the distribution of brain metabolites in vivo. Magnetic resonance spectroscopic imaging (MRSI) is often limited by either a poor spatial resolution and/or a long acquisition time, which severely restricts its applications for clinical and research purposes. Building on a recently developed technique of acquisition-reconstruction for 2D MRSI, we combined a fast Cartesian ¹H-FID-MRSI acquisition sequence, compressed-sensing acceleration, and low-rank total-generalized-variation constrained reconstruction to produce 3D high-resolution whole-brain MRSI with a significant acquisition time reduction. We first evaluated the acceleration performance using retrospective undersampling of a fully sampled dataset. Second, a 20 min accelerated MRSI acquisition was performed on three healthy volunteers, resulting in metabolite maps with 5 mm isotropic resolution. The metabolite maps exhibited the detailed neurochemical composition of all brain regions and revealed parts of the underlying brain anatomy. The latter assessment used previous reported knowledge and a atlas-based analysis to show consistency of the concentration contrasts and ratio across all brain regions. These results acquired on a clinical 3 T MRI scanner successfully combined 3D ¹H-FID-MRSI with a constrained reconstruction to produce detailed mapping of metabolite concentrations at high resolution over the whole brain, with an acquisition time suitable for clinical or research settings.     

The pattern of function-related regional cerebral blood flow investigated by single photon emission tomography with 99mTc-HMPAO in patients with presenile Alzheimer's disease and Korsakoff's psychosis

Single photon emission tomography (SPET) with the lipophilic blood flow marker 99mTc-hexamethyl propyleneamine oxime (99mTc-HMPAO) has been used to determine regional uptake of radiolabel into brain regions of patients with presenile Alzheimer's disease and Korsakoff's psychosis, and age-matched controls. Using occipital cortical uptake as reference area, the pattern of relative regional cerebral blood flow (rCBF) was determined in other cortical areas and basal ganglia. In Alzheimer's disease, reduction in rCBF occurred most strikingly in posterior temporal and parietal areas. By contrast, in Korsakoff's psychosis, posterior temporal rCBF was maintained, although there was a trend to reduced tracer uptake in other cortical areas. These impairments of flow were correlated with impairments of neuropsychological function. In Alzheimer's disease, left posterior temporal and left parietal regions in particular showed rCBF to be strongly correlated with most aspects of cognitive function. In Korsakoff's psychosis, however, impaired flow in frontal regions was correlated with impaired performance on tests of memory and orientation. The findings in Alzheimer's disease show quantitative parallels with those from studies using Positron Emission Tomography (PET), and extend our understanding of the relationship between cognition and regional brain function in dementia. The findings in Korsakoff's psychosis offer the first direct evidence linking frontal lobe dysfunction with the cognitive impairment seen in the disorder.     

Analyzing the subcortical dementia syndrome of Parkinson's disease using the RBANS.

On mental status examinations, groups of equally impaired patients with subcortical (Huntington's disease, HD; Parkinson's disease, PD) or cortical (Alzheimer's disease, AD) dementias exhibit different patterns of neuropsychological deficits. Using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS), classification accuracies of 90% or greater have been reported for individual patients with AD or HD. To test the generality of the RBANS classification algorithm, we studied patients with dementia (AD and PDD) and without dementia (PDND). Classification accuracies were AD: 87%, PDD: 78%, and PDND: 39%. Comparisons of performance on subtests of the RBANS showed that all groups performed more poorly on tests that require motor skill or rapid information processing and that memory performance by the PD groups was not improved by procedures that enhance encoding and facilitate retrieval. The RBANS is useful for discriminating patterns of cognitive impairment in PD and AD, but only if the diagnosis of dementia is established independent of the RBANS test results. Cognitive slowing is not specific to subcortical dementia and current concepts of memory dysfunction in PD may require re-examination.     

Impaired implicit sequence learning in depression: a probe for frontostriatal dysfunction?

BACKGROUND: Implicit learning through motor sequencing tasks is sensitive to basal ganglia dysfunction. Consequently, it is ideally suited for testing elements of the frontostriatal model of major depression and performance can be related to key clinical, neuropsychological, vascular and biochemical data. METHOD: Twenty-one subjects with moderate to severe unipolar depression and 21 age-, sex- and education-matched controls were recruited. Clinical, vascular and biochemical data were recorded. Subjects were administered a battery of neuropsychological tests that assessed speed of processing, working memory, learning, memory, language, perceptual organization and executive functioning. Additionally, subjects were administered a motor sequencing implicit learning task. Implicit learning is assumed when reaction times improve during the sequenced condition as compared to the pseudo-random baseline condition. RESULTS: The rate of implicit learning in persons with depression was only half that of control subjects (3.6% v. 7.3%). Lower rates of implicit learning in patients were associated with poorer performance on neuropsychological tests of visuomotor speed and mental flexibility, longer duration of depressive episode and severity of acute stress. In a small number of subjects, poorer performance was also related to past suicide attempt. CONCLUSIONS: Impaired implicit learning in persons with depression is consistent with frontostriatal dysfunction. Performance is related to some clinical characteristics and to neuropsychological functioning on tests of visuomotor speed and mental flexibility.     

Resting state glucose utilization and the CERAD cognitive battery in patients with Alzheimer's disease

The present study examined the cortical functional representation of neuropsychological domains in Alzheimer's disease (AD) using positron emission tomography (PET) and the neuropsychological assessment battery of the Consortium to Establish a Registry of Alzheimer's Disease (CERAD). Thirty patients with clinical probable AD and 10 elderly healthy controls underwent (18)FDG brain PET imaging during a resting state. Correlations between metabolic values and cognitive measures were determined using a region of interest analysis with NEUROSTAT (University of Michigan, USA) and a voxel-based analysis with SPM96 (Wellcome Department, London, UK). Specific correlations were seen between measures of episodic memory, verbal fluency and naming and left hemispheric temporal and prefrontal metabolism. Drawing was correlated with metabolism in left prefrontal and left inferior parietal regions. The presented data support the use of metabolic-cognitive correlations to demonstrate the neuronal substrates of cognitive impairment in AD. Subtests of the CERAD battery give a good representation of left, but not of right hemisphere function in AD.     

Distribution of cerebral atrophy assessed by magnetic resonance imaging reflects patterns of neuropsychological deficits in Alzheimer's dementia

Neuropsychological deficits were investigated with respect to regional distribution of cerebral atrophy as assessed by volumetric magnetic resonance imaging (MRI) in 50 patients with Alzheimer's dementia (AD; NINCDS-ADRDA criteria) and 20 healthy volunteers. When compared between groups, test performance of all investigated neuropsychological domains including declarative memory, language, praxia, psychomotor speed, as well as attention and concentration was significantly impaired. These deficits were differentially correlated with regional atrophic changes. In particular, volumes of the right amygdala-hippocampus complex correlated with declarative memory performance, whereas volumes of the left temporo-parietal regions correlated with performance in naming and praxia. Furthermore, left frontal lobe atrophy was associated with verbal fluency. Our data confirm the central role that medial temporal atrophy plays for declarative memory deficits in AD and indicate that additional changes in the parietal, temporal and frontal lobes are responsible for further neuropsychological deficits characteristic of this disorder.     

Subcortical reorganization in amyotrophic lateral sclerosis

The cerebral cortex reorganizes in response to central or peripheral lesions. Although basal ganglia and cerebellum are key components of the network dedicated to movement control, their role in motor reorganization remains elusive. We therefore tested if slowly progressive neurodegenerative motor disease alters the subcortical functional anatomy of the basal ganglia-thalamo-cerebellar circuitry. Ten patients with amyotrophic lateral sclerosis (ALS) and ten healthy controls underwent functional magnetic resonance imaging (fMRI), while executing a simple finger flexion task. Cued by an acoustic trigger, they squeezed a handgrip force transducer with their right hand at 10% of their maximum voluntary contraction force. Movement frequency, amplitude, and force were controlled. Statistical parametric mapping of task-related BOLD-response revealed increased activation in ALS patients as compared to healthy controls. The main activation increases were found in the supplementary motor area, basal ganglia, brainstem, and cerebellum. These findings suggest that degeneration of cortical and spinal motor neurons in ALS leads to a recruitment of subcortical motor structures. These subcortical activation patterns strongly resemble functional activation in motor learning and might therefore represent adaptations of cortico-subcortical motor loops as a—albeit finally ineffective—mechanism to compensate for the ongoing loss of motor neurons in ALS.Konrad C. and Jansen A. contributed equally to their work     

Separate neural substrates for skill learning and performance in the ventral and dorsal striatum

It is widely accepted that the striatum of the basal ganglia is a primary substrate for the learning and performance of skills. We provide evidence that two regions of the rat striatum, ventral and dorsal, play distinct roles in instrumental conditioning (skill learning), with the ventral striatum being critical for learning and the dorsal striatum being important for performance but, notably, not for learning. This implies an actor (dorsal) versus director (ventral) division of labor, which is a new variant of the widely discussed actor-critic architecture. Our results also imply that the successful performance of a skill can ultimately result in its establishment as a habit outside the basal ganglia.     

Age-related deficits in context discrimination learning in Ts65Dn mice that model Down syndrome and Alzheimer's disease

All individuals with Down syndrome (DS) eventually develop the neuropathology of Alzheimer's disease (AD), which is characterized by a premature loss of basal forebrain cholinergic neurons. Similarly, between 4 and 6 months of age, Ts65Dn mice, which model DS, lose cholinergic markers in their medial septal neurons. It is not known whether Ts65Dn mice have age-related learning deficits as well. Control and Ts65Dn mice were tested at several ages in context discrimination. Controls at all ages showed no deficits in learning this task. Ts65Dn mice younger than 3 months demonstrated impaired learning, suggesting a possible developmental delay in Ts65Dn mice. Four-month-old Ts65Dn mice showed no deficits, whereas Ts65Dn mice older than 5 months were impaired in learning the task. Therefore, Ts65Dn mice have an age-related learning impairment that coincides with their age-related neuroanatomical abnormalities and, consequently, may be a useful model of AD.     

Cortical cholinergic impairment and behavioral deficits produced by kainic acid lesions of rat magnocellular basal forebrain

The magnocellular basal forebrain (MNBF) provides extensive cholinergic innervation to frontoparietal cortex. In the rat, the MNBF is homologous to the human nucleus basalis of Meynert, a structure implicated in the cholinergic hypothesis of cognitive impairment in Alzheimer's disease (AD). Kainic acid (KA) was used to make lesions in the MNBF of rats which were compared with unoperated controls, sham-operated controls, and control rats injected with KA in the cortical area directly above the MNBF. The MNBF lesions depleted choline acetyltransferase in cortex but not in striatum or hippocampus. Cortical dopamine levels were unchanged; serotonin levels were unchanged in hippocampus and parietal cortex but decreased in frontal cortex. The metabolite levels of these neurotransmitters were unchanged in all brain regions examined. Compared with controls, rats with MNBF lesions were impaired in 24-hr retention, but not acquisition, of a passive avoidance task with escapable footshock. There were no differences between groups in mean number of daily avoidances on a bar-press active avoidance task, although the data suggested a slower rate of learning in MNBF rats. In a serial spatial discrimination reversal test with a snout-poke response, the MNBF rats performed significantly worse than controls, although all groups learned the task. This rodent model is useful for studying the role of the cholinergic system in memory and possibly for developing treatment strategies to alleviate the cognitive dysfunction of AD.     

阿尔茨海默病与血管性痴呆基底细胞微管蛋白变化研究

目的：研究阿尔茨海默病与血管性痴呆皮肤基底细胞内微管蛋白的数量变化特点以及这些特点作为早期诊断Alzheimer病生物学指标的意义。方法：使用免疫组化LSAB法对Alzheimer病和血管性痴呆患者皮肤基底细胞α-微管蛋白进行检测,用图象分析仪进行定性与吸光度的定量分析。结果：Alzheimer病组的积分吸光度（IA）为261.43±25.21、平均吸光度（AA）为1.89±0.14,分别非常显著地高于血管性痴呆组的IA（120.55±19.71）和AA（0.85±0.14）,P<0.01。结论：提示基底细胞微管蛋白的定性与定量分析,有可能为老年性痴呆的早期诊断提供一种非神经系统的生物学诊断指标。     

Matrix metalloproteinase 3 haplotypes and dementia and Alzheimer's disease. The Rotterdam Study

Evidence by post-mortem and animal studies suggests that matrix metalloproteinases (MMPs) may play an important role in the pathophysiology of Alzheimer's disease (AD) through degradation of amyloid beta. We investigated in 5999 elderly whether MMP3-haplotypes are associated with cognitive performance over time, dementia and AD. We also explored the association of MMP-3 haplotypes with changes in hippocampal volume and severity of periventricular and subcortical white matter lesions (WML). There was no association between any individual polymorphism or MMP-3 haplotypes and performance in MMSE over time, dementia or AD, and there was no association between MMP-3 genotypes or haplotypes with hippocampal volume or severity of periventricular or subcortical WML. These associations did not differ between strata of APOE4 genotype. Our observations do not suggest that variation in the MMP3 gene is causally involved in dementia or AD.