Disconnected aging: cerebral white matter integrity and age-related differences in cognition.

Cognition arises as a result of coordinated processing among distributed brain regions and disruptions to communication within these neural networks can result in cognitive dysfunction. Cortical disconnection may thus contribute to the declines in some aspects of cognitive functioning observed in healthy aging. Diffusion tensor imaging (DTI) is ideally suited for the study of cortical disconnection as it provides indices of structural integrity within interconnected neural networks. The current review summarizes results of previous DTI aging research with the aim of identifying consistent patterns of age-related differences in white matter integrity, and of relationships between measures of white matter integrity and behavioral performance as a function of adult age. We outline a number of future directions that will broaden our current understanding of these brain-behavior relationships in aging. Specifically, future research should aim to (1) investigate multiple models of age-brain-behavior relationships; (2) determine the tract-specificity versus global effect of aging on white matter integrity; (3) assess the relative contribution of normal variation in white matter integrity versus white matter lesions to age-related differences in cognition; (4) improve the definition of specific aspects of cognitive functioning related to age-related differences in white matter integrity using information processing tasks; and (5) combine multiple imaging modalities (e.g., resting-state and task-related functional magnetic resonance imaging; fMRI) with DTI to clarify the role of cerebral white matter integrity in cognitive aging

Structural and functional differences in medial prefrontal cortex underlie distractibility and suppression deficits in ageing.

Older adults experience deficits in working memory (WM) that are acutely exacerbated by the presence of distracting information. Human neurophysiological studies have revealed that these changes are accompanied by a diminished ability to suppress visual cortical activity associated with task-irrelevant information. Although this is often attributed to deficits in top-down control from a prefrontal cortical source, this has not yet been directly demonstrated. Here we evaluate the neural basis of distraction's negative impact on WM and the impairment in neural suppression in older adults by performing structural and functional MRIs while older participants engage in tasks that require remembering relevant visual stimuli in the context of overlapping irrelevant stimuli. Analysis supports both an age-related distraction effect and neural suppression deficit, and extends our understanding by revealing an alteration in functional connectivity between visual cortices and a region in the default network, the medial prefrontal cortex (mPFC). Moreover, within the older population, the magnitude of WM distractibility and neural suppression are both associated with individual differences in cortical volume and activity of the mPFC, as well as its associated white-matter tracts

Investigating White Matter Lesion Load, Intrinsic Functional Connectivity, and Cognitive Abilities in Older Adults

Changes to the while matter of the brain disrupt neural communication between spatially distributed brain regions and are associated with cognitive changes in later life. While approximately 95% of older adults experience these brain changes, not everyone who has significant white matter damage displays cognitive impairment. Few studies have investigated the association between white matter changes and cognition in the context of functional brain network integrity. This study used a data-driven, multivariate analytical model to investigate intrinsic functional connectivity patterns associated with individual variability in white matter lesion load as related to fluid and crystallized intelligence in a sample of healthy older adults (n = 84). Several primary findings were noted. First, a reliable pattern emerged associating whole-brain resting-state functional connectivity with individual variability in measures of white matter lesion load, as indexed by total white matter lesion volume and number of lesions. Secondly, white matter lesion load was associated with increased network disintegration and dedifferentiation. Specifically, lower white matter lesion load was associated with greater within- versus between-network connectivity. Higher white matter lesion load was associated with greater between-network connectivity compared to within. These associations between intrinsic functional connectivity and white matter lesion load were not reliably associated with crystallized and fluid intelligence performance. These results suggest that changes to the white matter of the brain in typically aging older adults are characterized by increased functional brain network dedifferentiation. The findings highlight the role of white matter lesion load in altering the functional network architecture of the brain

Exercise Training and Functional Connectivity Changes in Mild Cognitive Empairment and Healthy Elders

Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated

Salience and default mode network coupling predicts cognition in aging and Parkinson’s disease

OBJECTIVES: Cognitive impairment is common in Parkinson’s disease (PD). Three neurocognitive networks support efficient cognition: the salience network, the default mode network, and the central executive network. The salience network is thought to switch between activating and deactivating the default mode and central executive networks. Anti-correlated interactions between the salience and default mode networks in particular are necessary for efficient cognition. Our previous work demonstrated altered functional coupling between the neurocognitive networks in non-demented individuals with PD compared to age-matched control participants. Here, we aim to identify associations between cognition and functional coupling between these neurocognitive networks in the same group of participants. METHODS: We investigated the extent to which intrinsic functional coupling among these neurocognitive networks is related to cognitive performance across three neuropsychological domains: executive functioning, psychomotor speed, and verbal memory. Twenty-four non-demented individuals with mild to moderate PD and 20 control participants were scanned at rest and evaluated on three neuropsychological domains. RESULTS: PD participants were impaired on tests from all three domains compared to control participants. Our imaging results demonstrated that successful cognition across healthy aging and Parkinson’s disease participants was related to anti-correlated coupling between the salience and default mode networks. Individuals with poorer performance scores across groups demonstrated more positive salience network/default-mode network coupling. CONCLUSIONS: Successful cognition relies on healthy coupling between the salience and default mode networks, which may become dysfunctional in PD. These results can help inform non-pharmacological interventions (repetitive transcranial magnetic stimulation) targeting these specific networks before they become vulnerable in early stages of Parkinson’s disease.Published versio

Neuroplasticity of language networks in aphasia: advances, updates, and future challenges

Researchers have sought to understand how language is processed in the brain, how brain damage affects language abilities, and what can be expected during the recovery period since the early 19th century. In this review, we first discuss mechanisms of damage and plasticity in the post-stroke brain, both in the acute and the chronic phase of recovery. We then review factors that are associated with recovery. First, we review organism intrinsic variables such as age, lesion volume and location and structural integrity that influence language recovery. Next, we review organism extrinsic factors such as treatment that influence language recovery. Here, we discuss recent advances in our understanding of language recovery and highlight recent work that emphasizes a network perspective of language recovery. Finally, we propose our interpretation of the principles of neuroplasticity, originally proposed by Kleim and Jones (1) in the context of extant literature in aphasia recovery and rehabilitation. Ultimately, we encourage researchers to propose sophisticated intervention studies that bring us closer to the goal of providing precision treatment for patients with aphasia and a better understanding of the neural mechanisms that underlie successful neuroplasticity.P50 DC012283 - NIDCD NIH HHSPublished versio

Limbic Tract Integrity Contributes to Pattern Separation Performance Across the Lifespan.

Accurate memory for discrete events is thought to rely on pattern separation to orthogonalize the representations of similar events. Previously, we reported that a behavioral index of pattern separation was correlated with activity in the hippocampus (dentate gyrus, CA3) and with integrity of the perforant path, which provides input to the hippocampus. If the hippocampus operates as part of a broader neural network, however, pattern separation would likely also relate to integrity of limbic tracts (fornix, cingulum bundle, and uncinate fasciculus) that connect the hippocampus to distributed brain regions. In this study, healthy adults (20-89 years) underwent diffusion tensor imaging and completed the Behavioral Pattern Separation Task-Object Version (BPS-O) and Rey Auditory Verbal Learning Test (RAVLT). After controlling for global effects of brain aging, exploratory skeleton-wise and targeted tractography analyses revealed that fornix integrity (fractional anisotropy, mean diffusivity, and radial diffusivity; but not mode) was significantly related to pattern separation (measured using BPS-O and RAVLT tasks), but not to recognition memory. These data suggest that hippocampal disconnection, via individual- and age-related differences in limbic tract integrity, contributes to pattern separation performance. Extending our earlier work, these results also support the notion that pattern separation relies on broad neural networks interconnecting the hippocampus

Neural correlates of cognitive intervention in persons at risk of developing Alzheimer's disease.

Cognitive training is an emergent approach that has begun to receive increased attention in recent years as a non-pharmacological, cost-effective intervention for Alzheimer's disease (AD). There has been increasing behavioral evidence regarding training-related improvement in cognitive performance in early stages of AD. Although these studies provide important insight about the efficacy of cognitive training, neuroimaging studies are crucial to pinpoint changes in brain structure and function associated with training and to examine their overlap with pathology in AD. In this study, we reviewed the existing neuroimaging studies on cognitive training in persons at risk of developing AD to provide an overview of the overlap between neural networks rehabilitated by the current training methods and those affected in AD. The data suggest a consistent training-related increase in brain activity in medial temporal, prefrontal, and posterior default mode networks, as well as increase in gray matter structure in frontoparietal and entorhinal regions. This pattern differs from the observed pattern in healthy older adults that shows a combination of increased and decreased activity in response to training. Detailed investigation of the data suggests that training in persons at risk of developing AD mainly improves compensatory mechanisms and partly restores the affected functions. While current neuroimaging studies are quite helpful in identifying the mechanisms underlying cognitive training, the data calls for future multi-modal neuroimaging studies with focus on multi-domain cognitive training, network level connectivity, and individual differences in response to training