Altered Gray Matter Structural Covariance Networks in Early Stages of Alzheimer's Disease.

Clinical symptoms observed in Alzheimer's disease (AD) patients may reflect variations within specific large-scale brain networks, modeling AD as a disconnection syndrome. The present magnetic resonance imaging study aims to compare the organization of gray matter structural covariance networks between 109 cognitively unimpaired controls (CTRL) and 109 AD patients positive to beta-amyloid at the early stages of the disease, using voxel-based morphometry. The default-mode network (DMN; medial temporal lobe subsystem) was less extended in AD patients in comparison with CTRL, with a significant decrease in the structural association between the entorhinal cortex and the medial prefrontal and the dorsolateral prefrontal cortices. The DMN (midline core subsystem) was also less extended in AD patients. Trends toward increased structural association were observed in the salience and executive control networks. The observed changes suggest that early disruptions in structural association between heteromodal association cortices and the entorhinal cortex could contribute to an isolation of the hippocampal formation, potentially giving rise to the clinical hallmark of AD, progressive memory impairment. It also provides critical support to the hypothesis that the reduced connectivity within the DMN in early AD is accompanied by an enhancement of connectivity in the salience and executive control networks.

Exploration of the dynamics between brain regions associated with the default-mode network and frontostriatal pathway with regards to task familiarity.

Specific brain regions have consistently been reported to be activated during resting state period, and they were described as being part of a particular network called the default-mode network (DMN). It has been shown that the DMN would deactivate during goal-directed tasks, but the actual relationship between them is still a matter of debate. In a previous study, we reported a specific pattern of activation of the frontostriatal regions during a set-shifting task in which these regions were increasing their activity as set-shifts were performed continuously and decreasing when the same rule was executed repeatedly. The present study aimed at assessing the relationship between the frontostriatal regions and the DMN. We hypothesized that the DMN would be anticorrelated with the frontostriatal regions so the DMN would be more deactivated as set-shifts are executed for a long period, but would start increasing when the same rule is being executed for a long period. Here, 15 participants underwent functional magnetic resonance imaging while performing a card-sorting task. We observed increased activity in the frontostriatal regions as more set-shifts are being performed while the DMN gets more deactivated. Interestingly, as decreased activity was observed in the frontostriatal regions during the execution of the same rule for a long period, the DMN showed increasing activity. We argue that there is an anticorrelation between the frontostriatal regions and the DMN, but also that the DMN could show positive activation during performance of a familiar goal-directed task.

Changes in regional and temporal patterns of activity associated with aging during the performance of a lexical set-shifting task.

Some older individuals seem to use compensatory mechanisms to maintain high-level performance when submitted to cognitive tasks. However, whether and how these mechanisms affect fronto-striatal activity has never been explored. The purpose of this study was to investigate how aging affects brain patterns during the performance of a lexical analog of the Wisconsin Card Sorting Task, which has been shown to strongly depend on fronto-striatal activity. In the present study, both younger and older individuals revealed significant fronto-striatal loop activity associated with planning and execution of set-shifts, though age-related striatal activity reduction was observed. Most importantly, while the younger group showed the involvement of a "cognitive loop" during the receiving negative feedback period (which indicates that a set-shift will be required to perform the following trial) and the involvement of a "motor loop" during the matching after negative feedback period (when the set-shift must be performed), older participants showed significant activation of both loops during the matching after negative feedback period only. These findings are in agreement with the "load-shift" model postulated by Velanova et al. (Velanova K, Lustig C, Jacoby LL, Buckner RL. 2007. Evidence for frontally mediated controlled processing differences in older adults. Cereb Cortex. 17:1033-1046.) and indicate that the model is not limited to memory retrieval but also applies to executive processes relying on fronto-striatal regions.

Investigating the long-lasting residual effect of a set shift on frontostriatal activity.

Previous studies have shown the involvement of the ventrolateral prefrontal cortex (PFC) and the caudate nucleus when performing a set shift. However, the effect of set shifting on the frontostriatal activity observed during the later trials within a series of same-set classifications has yet to be determined. Here, young healthy adults underwent the functional magnetic resonance imaging while performing a card-sorting task in which the classification rule was provided prior to each trial. We observed a significant activation in the dorsolateral PFC, regardless of whether a set shift occurred or not. By contrast, the ventrolateral PFC and caudate nucleus showed an increased activity in both the shifting trials versus the control and in trials where the same rule was applied for a few trials before a set shift occurred, unlike trials where the same rule was applied for a longer period. Finally, decreased activity in the caudate nucleus correlated with an increasing trial position in trials where no set shift occurred, suggesting that the more a rule is executed, the better it is established. We argue that a new rule needs to be performed multiple times until the brain areas usually associated with the set shifting are no longer significantly required anymore.

The effect of dopamine therapy on ventral and dorsal striatum-mediated cognition in Parkinson's disease: support from functional MRI.

The central aim of our study was to elucidate functions mediated by the ventral and dorsal striatum, respectively, to better understand the cognitive effects of dopamine replacement in Parkinson's disease. We proposed that the ventral striatum underlies general learning of stimulus associations, whereas the dorsal striatum promotes integration of various influences on selecting. In Parkinson's disease, dopamine depletion is substantially less notable in the ventral relative to the dorsal striatum, and therefore greater improvements are expected for dorsal striatum-mediated functions with dopamine replacement. Using a simple selection task, we found that dopamine replacement impaired encoding and facilitation of consistent stimulus-stimulus relations across trials. This finding was in line with our contention that ventral striatum mediates learning stimulus associations, even when explicit feedback or reward is not provided. In contrast, dopamine replacement enhanced interference related to assimilating conflicting influences on selection across trials, consistent with our hypothesis that the dorsal striatum supports deciding in ambiguous contexts. We further confirmed these separable roles for the ventral and dorsal striatum in our selection task with healthy young volunteers using functional magnetic resonance imaging. In summary, we present a within-subject, double dissociation of the effects of dopamine replacement in patients with Parkinson's disease for ventral striatum-mediated facilitation and dorsal striatum-mediated interference, confirmed in a separate functional magnetic resonance imaging experiment. Defining the distinct functions of the ventral and dorsal striatum will have direct clinical implications. Titration of therapy in Parkinson's disease is generally geared towards optimizing dorsal striatum-mediated motor symptoms, possibly at the expense of ventral striatum operations, a consequence that is only beginning to be recognized. Enhanced awareness of these different processes will translate into medication strategies that take into account those symptoms that dopamine replacement might hinder, as well as improve. Here, we show impairments in learning new stimulus associations compared with improvements in integrating varied influences related to selection. Ultimately, this knowledge will lead clinicians to survey a broader range of symptoms in determining optimal therapy based on individual patient priorities.

Dissociating the role of the caudate nucleus and dorsolateral prefrontal cortex in the monitoring of events within human working memory.

There is evidence that the dorsolateral prefrontal cortex is involved in the monitoring of information held in memory whether it is self-ordered or externally triggered. However, the functional contribution of the caudate nucleus in the monitoring of events has not yet been studied. We have previously proposed that the striatum is involved when a novel self-initiated action needs to be generated. The present study aimed to test the hypothesis that the caudate nucleus is significantly more required when the monitoring is self-ordered as opposed to externally triggered. Self-ordered monitoring refers to keeping track of which items have been selected so far in order to perform the current selection. Externally triggered monitoring refers to keeping track of which items have been selected by an outside source. Thirteen healthy young adults were scanned using functional magnetic resonance imaging while performing a monitoring task with three conditions: self-ordered, externally triggered and recognition. As predicted, a significant increase of activity was found in the dorsolateral prefrontal cortex bilaterally when the self-ordered and externally triggered conditions were compared with the recognition condition. Most importantly, significantly increased activity was found in the right caudate nucleus when comparing the self-ordered with the recognition condition or with the externally triggered condition, but not when comparing the externally triggered with the recognition condition. We suggest that the caudate nucleus is involved in the planning of a self-initiated novel action, especially when no clear indication is given for the response choice, and that this may be the case across different domains of cognition.

Increase of posterior connectivity in aging within the Ventral Attention Network: A functional connectivity analysis using independent component analysis.

Multiple studies have found neurofunctional changes in normal aging in a context of selective attention. Furthermore, many articles report intrahemispheric alteration in functional networks. However, little is known about age-related changes within the Ventral Attention Network (VAN), which underlies selective attention. The aim of this study is to examine age-related changes within the VAN, focusing on connectivity between its regions. Here we report our findings on the analysis of 27 participants' (13 younger and 14 older healthy adults) BOLD signals as well as their performance on a letter-matching task. We identified the VAN independently for both groups using spatial independent component analysis. Three main findings emerged: First, younger adults were faster and more accurate on the task. Second, older adults had greater connectivity among posterior regions (right temporoparietal junction, right superior parietal lobule, right middle temporal gyrus and left cerebellum crus I) than younger adults but lower connectivity among anterior regions (right anterior insula, right medial superior frontal gyrus and right middle frontal gyrus). Older adults also had more connectivity between anterior and posterior regions than younger adults. Finally, correlations between connectivity and response time on the task showed a trend toward connectivity in posterior regions for the older group and in anterior regions for the younger group. Thus, this study shows that intrahemispheric neurofunctional changes in aging also affect the VAN. The results suggest that, in contexts of selective attention, posterior regions increased in importance for older adults, while anterior regions had reduced centrality.

Age-Related Shift in Neuro-Activation during a Word-Matching Task.

Growing evidence from the neuroscience of aging suggests that executive function plays a pivotal role in maintaining semantic processing performance. However, the presumed age-related activation changes that sustain executive semantic processing remain poorly understood. The aim of this study was to explore the executive aspects of semantic processing during a word-matching task with regard to age-related neuro-functional reorganization, as well as to identify factors that influence executive control profiles. Twenty younger and 20 older participants underwent fMRI scanning. The experimental task was based on word-matching, wherein visual feedback was used to instruct participants to either maintain or switch a semantic-matching rule. Response time and correct responses were assessed for each group. A battery of cognitive tests was administrated to all participants and the older group was divided into two subgroups based on their cognitive control profiles. Even though the percentage of correct responses was equivalent in the task performance between both groups and within the older groups, neuro-functional activation differed in frontoparietal regions with regards to age and cognitive control profiles. A correlation between behavioral measures (correct responses and response times) and brain signal changes was found in the left inferior parietal region in older participants. Results indicate that the shift in age-related activation from frontal to parietal regions can be viewed as another form of neuro-functional reorganization. The greater reliance on inferior parietal regions in the older compared to the younger group suggests that the executive control system is still efficient and sustains semantic processing in the healthy aging brain. Additionally, cognitive control profiles underlie executive ability differences in healthy aging appear to be associated with specific neuro-functional reorganization throughout frontal and parietal regions. These findings demonstrate that changes in neural support for executive semantic processing during a word-matching task are not only influenced by age, but also by cognitive control profile.

Age-Related Brain Activation Changes during Rule Repetition in Word-Matching.

Objective: The purpose of this study was to explore the age-related brain activation changes during a word-matching semantic-category-based task, which required either repeating or changing a semantic rule to be applied. In order to do so, a word-semantic rule-based task was adapted from the Wisconsin Sorting Card Test, involving the repeated feedback-driven selection of given pairs of words based on semantic category-based criteria. Method: Forty healthy adults (20 younger and 20 older) performed a word-matching task while undergoing a fMRI scan in which they were required to pair a target word with another word from a group of three words. The required pairing is based on three word-pair semantic rules which correspond to different levels of semantic control demands: functional relatedness, moderately typical-relatedness (which were considered as low control demands), and atypical-relatedness (high control demands). The sorting period consisted of a continuous execution of the same sorting rule and an inferred trial-by-trial feedback was given. Results: Behavioral performance revealed increases in response times and decreases of correct responses according to the level of semantic control demands (functional vs. typical vs. atypical) for both age groups (younger and older) reflecting graded differences in the repetition of the application of a given semantic rule. Neuroimaging findings of significant brain activation showed two main results: (1) Greater task-related activation changes for the repetition of the application of atypical rules relative to typical and functional rules, and (2) Changes (older > younger) in the inferior prefrontal regions for functional rules and more extensive and bilateral activations for typical and atypical rules. Regarding the inter-semantic rules comparison, only task-related activation differences were observed for functional > typical (e.g., inferior parietal and temporal regions bilaterally) and atypical > typical (e.g., prefrontal, inferior parietal, posterior temporal, and subcortical regions). Conclusion: These results suggest that healthy cognitive aging relies on the adaptive changes of inferior prefrontal resources involved in the repetitive execution of semantic rules, thus reflecting graded differences in support of task demands.

The effect of aging on the brain network for exception word reading.

Cognitive and computational models of reading aloud agree on the existence of two procedures for reading. Pseudowords (e.g., atendier) are correctly read through subword processes only while exception words (e.g., pint) are only correctly read via whole-words processes. Regular words can be correctly read by means of either way. Previous behavioral studies showed that older adults relied more on whole-word processing for reading. The aim of the present fMRI study was to verify whether this larger whole-word reliance for reading in older adults was reflected by changes in the pattern of brain activation. Both young and elderly participants read aloud pseudowords, exception and regular words in the scanner. Behavioral results reproduced those of previous studies showing that older adults made significantly less errors when reading exception words. Neuroimaging results showed significant activation of the left anterior temporal lobe (ATL), a key region implicated in whole-word reading for exception word reading in both young and elderly participants. Critically, ATL activation was also found for regular word reading in the elderly. No differences were observed in the pattern of activation between regular and pseudowords in the young. In conclusion, these results extend evidence on the critical role of the left ATL for exception word reading to elderly participants. Additionally, our study shows for the first time from a developmental point of view that the behavioral changes found in reading during normal aging also have a brain counterpart in the reading network changes that sustain exception and regular word reading in the elderly.

Differential Involvement of the Anterior Temporal Lobes in Famous People Semantics.

The ability to recognize a famous person occurs through semantic memory. Previous neuroimaging studies have shown that the anterior temporal lobes (ATLs) are involved in the recognition of famous people. However, it is still a matter of debate whether the semantic processing of names or pictures of famous people has an impact on the activation of ATLs. The aim of this study was to explore the pattern of activation associated with a semantic processing of famous people based on face and written name stimuli. Fifteen healthy young individuals participated in our fMRI study, in which they were asked to perform a semantic categorization judgment task, based on profession, of visually presented pictures, and names of famous people. Neuroimaging findings showed a common pattern of activation for faces and names mainly involving the inferior frontal regions, the posterior temporal lobe, the visual cortex, and the ATLs. We found that the comparison names vs. pictures lead to significant activation in the anterior superior temporal gyrus. On the other hand, faces vs. names seemed associated with increased activation in the medial ATL. Moreover, our results demonstrated that the functional connectivity network anchored to the medial ATL, compared to the anterior STG, is more connected to the bilateral occipital lobe and fusiform gyrus that are regions implicated in the visual system and visual processing of faces. This study provides critical evidence of the differential involvement of ATL regions in semantics of famous people.

Neuroimaging studies of the striatum in cognition Part I: healthy individuals.

The striatum has traditionally mainly been associated with playing a key role in the modulation of motor functions. Indeed, lesion studies in animals and studies of some neurological conditions in humans have brought further evidence to this idea. However, better methods of investigation have raised concerns about this notion, and it was proposed that the striatum could also be involved in different types of functions including cognitive ones. Although the notion was originally a matter of debate, it is now well-accepted that the caudate nucleus contributes to cognition, while the putamen could be involved in motor functions, and to some extent in cognitive functions as well. With the arrival of modern neuroimaging techniques in the early 1990, knowledge supporting the cognitive aspect of the striatum has greatly increased, and a substantial number of scientific papers were published studying the role of the striatum in healthy individuals. For the first time, it was possible to assess the contribution of specific areas of the brain during the execution of a cognitive task. Neuroanatomical studies have described functional loops involving the striatum and the prefrontal cortex suggesting a specific interaction between these two structures. This review examines the data up to date and provides strong evidence for a specific contribution of the fronto-striatal regions in different cognitive processes, such as set-shifting, self-initiated responses, rule learning, action-contingency, and planning. Finally, a new two-level functional model involving the prefrontal cortex and the dorsal striatum is proposed suggesting an essential role of the dorsal striatum in selecting between competing potential responses or actions, and in resolving a high level of ambiguity.

Neuroimaging studies of striatum in cognition part II: Parkinson's disease.

In recent years a gradual shift in the definition of Parkinson's disease (PD) has been established, from a classical akinetic-rigid movement disorder to a multi-system neurodegenerative disease. While the pathophysiology of PD is complex and goes much beyond the nigro-striatal degeneration, the striatum has been shown to be responsible for many cognitive functions. Patients with PD develop impairments in multiple cognitive domains and the PD model is probably the most extensively studied regarding striatum dysfunction and its influence on cognition. Up to 40% of PD patients present cognitive impairment even in the early stages of disease development. Thus, understanding the key patterns of striatum and connecting regions' influence on cognition will help develop more specific approaches to alleviate cognitive impairment and slow down its decline. This review focuses on the contribution of neuroimaging studies in understanding how striatum impairment affects cognition in PD.

Examining dorsal striatum in cognitive effort using Parkinson's disease and fMRI.

OBJECTIVE: Understanding cognition mediated by the striatum can clarify cognitive deficits in Parkinson's disease (PD). Previously, we claimed that dorsal striatum (DS) mediates cognitive flexibility. To refute the possibility that variation in cognitive effort confounded our observations, we reexamined our data to dissociate cognitive flexibility from effort. PD provides a model for exploring DS-mediated functions. In PD, dopamine-producing cells supplying DS are significantly degenerated. DS-mediated functions are impaired off and improved on dopamine replacement medication. Functional magnetic resonance imaging (fMRI) can confirm striatum-mediated functions. METHODS: Twenty-two PD patients, off-on dopaminergic medication, and 22 healthy age-matched controls performed a number selection task. Numerical distance between number pairs varied systematically. Selecting between two numbers that are closer versus distant in magnitude is more effortful: the symbolic distance effect. However, selecting between closer versus distant number pairs is equivalent in the need to alter attention or response strategies (i.e., cognitive flexibility). In Experiment 2, 28 healthy participants performed the same task with simultaneous measurement of brain activity with fMRI. RESULTS: The symbolic distance effect was equivalent for PD versus control participants and across medication sessions. Furthermore, symbolic distance did not correlate with DS activation using fMRI. In this dataset, we showed previously that integrating conflicting influences on decision making is (1) impaired in PD and improved by dopaminergic therapy and (2) associated with preferential DS activation using fMRI. INTERPRETATION: These findings support the notion that DS mediates cognitive flexibility specifically, not merely cognitive effort, accounting for some cognitive deficits in PD and informing treatment.