Basal forebrain integrity and cognitive memory profile in healthy aging

Age-related dysfunctions in cholinergic and dopaminergic neuromodulation are assumed to contribute to age-associated impairment of explicit memory. Both neurotransmitters also modulate attention, working memory, and processing speed. To date, in vivo evidence linking structural age-related changes in these neuromodulatory systems to dysfunction within or across these cognitive domains remains scarce. Using a factor analytical approach in a cross-sectional study including 86 healthy older (aged 55 to 83 years) and 24 young (aged 18 to 30 years) adults, we assessed the relationship between structural integrity-as measured by magnetization transfer ratio (MTR)-of the substantia nigra/ventral tegmental area (SN/VTA), main origin of dopaminergic projections, basal forebrain (major origin of cortical cholinergic projections), frontal white matter (FWM), and hippocampus to neuro psychological and psychosocial scores. Basal forebrain MTR and FWM changes correlated with a factor combining verbal learning and memory and working memory and, as indicated by measures of diffusion, were most likely due to vascular pathology. These findings suggest that frontal white matter integrity and cholinergic neuromodulation provide clues as to why age-related cognitive decline is often correlated across cognitive domains. (C) 2009 Elsevier B.V. All rights reserved

Dopamine restores reward prediction errors in old age.

Senescence affects the ability to utilize information about the likelihood of rewards for optimal decision-making. Using functional magnetic resonance imaging in humans, we found that healthy older adults had an abnormal signature of expected value, resulting in an incomplete reward prediction error (RPE) signal in the nucleus accumbens, a brain region that receives rich input projections from substantia nigra/ventral tegmental area (SN/VTA) dopaminergic neurons. Structural connectivity between SN/VTA and striatum, measured by diffusion tensor imaging, was tightly coupled to inter-individual differences in the expression of this expected reward value signal. The dopamine precursor levodopa (L-DOPA) increased the task-based learning rate and task performance in some older adults to the level of young adults. This drug effect was linked to restoration of a canonical neural RPE. Our results identify a neurochemical signature underlying abnormal reward processing in older adults and indicate that this can be modulated by L-DOPA

Parcellation of the human substantia nigra based on anatomical connectivity to the striatum

Substantia nigra/ventral tegmental area (SN/VTA) subregions, defined by dopaminergic projections to the striatum, are differentially affected by health (e.g. normal aging) and disease (e.g. Parkinson's disease). This may have an impact on reward processing which relies on dopaminergic regions and circuits. We acquired diffusion tensor imaging (DTI) with probabilistic tractography in 30 healthy older adults to determine whether subregions of the SN/VTA could be delineated based on anatomical connectivity to the striatum. We found that a dorsomedial region of the SN/VTA preferentially connected to the ventral striatum whereas a more ventrolateral region connected to the dorsal striatum. These SN/VTA subregions could be characterised by differences in quantitative structural imaging parameters, suggesting different underlying tissue properties. We also observed that these connectivity patterns differentially mapped onto reward dependence personality trait. We show that tractography can be used to parcellate the SN/VTA into anatomically plausible and behaviourally meaningful compartments, an approach that may help future studies to provide a more fine-grained synopsis of pathological changes in the dopaminergic midbrain and their functional impact

Contextual novelty modulates the neural dynamics of reward anticipation

We investigated how rapidly the reward-predicting properties of visual cues are signaled in the human brain and the extent these reward prediction signals are contextually modifiable. In a magnetoencephalography study, we presented participants with fractal visual cues that predicted monetary rewards with different probabilities. These cues were presented in the temporal context of a preceding novel or familiar image of a natural scene. Starting at similar to 100 ms after cue onset, reward probability was signaled in the event-related fields (ERFs) over temporo-occipital sensors and in the power of theta (5-8 Hz) and beta (20-30 Hz) band oscillations over frontal sensors. While theta decreased with reward probability beta power showed the opposite effect. Thus, in humans anticipatory reward responses are generated rapidly, within 100 ms after the onset of reward-predicting cues, which is similar to the timing established in non-human primates. Contextual novelty enhanced the reward anticipation responses in both ERFs and in beta oscillations starting at similar to 100 ms after cue onset. This very early context effect is compatible with a physiological model that invokes the mediation of a hippocampal-VTA loop according to which novelty modulates neural response properties within the reward circuitry. We conclude that the neural processing of cues that predict future rewards is temporally highly efficient and contextually modifiable

Relationship between hippocampal structure and memory function in elderly humans

With progressing age, the ability to recollect personal events declines, whereas familiarity-based memory remains relatively intact. It has been hypothesized that age-related hippocampal atrophy may contribute to this pattern because of its critical role for recollection in younger humans and after acute injury. Here, we show that hippocampal volume loss in healthy older persons correlates with gray matter loss (estimated with voxel-based morphometry) of the entire limbic system and shows no correlation with an electrophysiological (event-related potential [ERP]) index of recollection. Instead, it covaries with more substantial and less specific electrophysiological changes of stimulus processing. Age-related changes in another complementary structural measure, hippocampal diffusion, on the other hand, seemed to be more regionally selective and showed the expected correlation with the ERP index of recollection. Thus, hippocampal atrophy in older persons accompanies limbic atrophy, and its functional impact on memory is more fundamental than merely affecting recollection

Heart Rate Variability During Physical Exercise Is Associated With Improved Cognitive Performance in Alzheimer's Dementia Patients-A Longitudinal Feasibility Study

Heart rate variability (HRV) rapidly gains attention as an important marker of cardiovascular autonomic modulation. Moreover, there is evidence for a link between the autonomic deficit measurable by reduced HRV and the hypoactivity of the cholinergic system, which is prominently affected in Alzheimer's disease (AD). Despite the positive influence of physical exercise on cognition and its promising association with HRV, previous studies did not explore the effect of long-term physical exercise in older adults with AD. Taking advantage of a longitudinal study we analyzed the effect of a 20-week dual task training regime (3 × 15-min per week) on the vagal mediated HRV index RMSSD (root mean square of successive RR interval differences) during physical exercise and the short-term memory performance in a AD cohort (N = 14). Each training contained physical exercise on a bicycle ergometer while memorizing 30 successively presented pictures as well as the associated post-exercise picture recognition memory test. Linear-mixed modeling revealed that HRV-RMSSD significantly increased over the intervention time. Moreover, the reaction time in the picture recognition task decreased while the accuracy remained stable. Furthermore, a significantly negative relationship between increased fitness measured by HRV-RMSSD and decreased reaction time was observed. This feasibility study points to the positive effects of a dual task regime on physical and cognitive fitness in a sample with impaired cognitive performance. Beyond this, the results show that the responsiveness of parasympathetic system as measured with HRV can be improved in patients with dementia

Reconciling the object and spatial processing views of the perirhinal cortex through task-relevant unitization

The perirhinal cortex is situated on the border between sensory association cortex and the hippocampal formation. It serves an important function as a transition area between the sensory neocortex and the medial temporal lobe. While the perirhinal cortex has traditionally been associated with object coding and the "what" pathway of the temporal lobe, current evidence suggests a broader function of the perirhinal cortex in solving feature ambiguity and processing complex stimuli. Besides fulfilling functions in object coding, recent neurophysiological findings in freely moving rodents indicate that the perirhinal cortex also contributes to spatial and contextual processing beyond individual sensory modalities. Here, we address how these two opposing views on perirhinal cortex-the object-centered and spatial-contextual processing hypotheses-may be reconciled. The perirhinal cortex is consistently recruited when different features can be merged perceptually or conceptually into a single entity. Features that are unitized in these entities include object information from multiple sensory domains, reward associations, semantic features and spatial/contextual associations. We propose that the same perirhinal network circuits can be flexibly deployed for multiple cognitive functions, such that the perirhinal cortex performs similar unitization operations on different types of information, depending on behavioral demands and ranging from the object-related domain to spatial, contextual and semantic information

Motor phenotype and magnetic resonance measures of basal ganglia iron levels in Parkinson's disease

BACKGROUND: In Parkinson's disease the degree of motor impairment can be classified with respect to tremor dominant and akinetic rigid features. While tremor dominance and akinetic rigidity might represent two ends of a continuum rather than discrete entities, it would be important to have non-invasive markers of any biological differences between them in vivo, to assess disease trajectories and response to treatment, as well as providing insights into the underlying mechanisms contributing to heterogeneity within the Parkinson's disease population. METHODS: Here, we used magnetic resonance imaging to examine whether Parkinson's disease patients exhibit structural changes within the basal ganglia that might relate to motor phenotype. Specifically, we examined volumes of basal ganglia regions, as well as transverse relaxation rate (a putative marker of iron load) and magnetization transfer saturation (considered to index structural integrity) within these regions in 40 individuals. RESULTS: We found decreased volume and reduced magnetization transfer within the substantia nigra in Parkinson's disease patients compared to healthy controls. Importantly, there was a positive correlation between tremulous motor phenotype and transverse relaxation rate (reflecting iron load) within the putamen, caudate and thalamus. CONCLUSIONS: Our findings suggest that akinetic rigid and tremor dominant symptoms of Parkinson's disease might be differentiated on the basis of the transverse relaxation rate within specific basal ganglia structures. Moreover, they suggest that iron load within the basal ganglia makes an important contribution to motor phenotype, a key prognostic indicator of disease progression in Parkinson's disease