The Disconnected Brain and Executive Function Decline in Aging

Abstract Higher order speeded cognitive abilities depend on efficient coordination of activity across the brain, rendering them vulnerable to age reductions in structural and functional brain connectivity. The concept of "disconnected aging" has been invoked, suggesting that degeneration of connections between distant brain regions cause cognitive reductions. However, it has not been shown that changes in cognitive functions over time can be explained by simultaneous changes in brain connectivity. We followed 119 young and middle-aged (23-52 years) and older (63-86 years) adults for 3.3 years with repeated assessments of structural and functional brain connectivity and executive functions. We found unique age-related longitudinal reductions in executive function over and above changes in more basic cognitive processes. Intriguingly, 82.5% of the age-related decline in executive function could be explained by changes in connectivity over time. While both structural and functional connectivity changes were related to longitudinal reductions in executive function, only structural connectivity change could explain the age-specific decline. This suggests that the major part of the age-related reductions in executive function can be attributed to micro-and macrostructural alterations in brain connectivity. Although correlational in nature, we believe the present results constitute evidence for a "disconnected brain" view on cognitive aging

Evidence for widespread alterations in cortical microstructure after 32 h of sleep deprivation

Cortical microstructure is influenced by circadian rhythm and sleep deprivation, yet the precise underpinnings of these effects remain unclear. The ratio between T1-weighted and T2-weighted magnetic resonance images (T1w/T2w ratio) has been linked to myelin levels and dendrite density and may offer novel insight into the intracortical microstructure of the sleep deprived brain. Here, we examined intracortical T1w/T2w ratio in 41 healthy young adults (26 women) before and after 32 h of either sleep deprivation (n = 18) or a normal sleep-wake cycle (n = 23). Linear models revealed significant group differences in T1w/T2w ratio change after 32 h in four clusters, including bilateral effects in the insular, cingulate, and superior temporal cortices, comprising regions involved in attentional, auditory and pain processing. Across clusters, the sleep deprived group showed an increased T1w/T2w ratio, while the normal sleep-wake group exhibited a reduced ratio. These changes were not explained by in-scanner head movement, and 95% of the effects across clusters remained significant after adjusting for cortical thickness and hydration. Compared with a normal sleep-wake cycle, 32 h of sleep deprivation yields intracortical T1w/T2w ratio increases. While the intracortical changes detected by this study could reflect alterations in myelin or dendritic density, or both, histological analyses are needed to clarify the precise underlying cortical processes.publishedVersio

Brain Microstructure Across the Lifespan: Cognitive Links, Network Architecture, and Clinical Implications

Assessment of brain microstructure by way of magnetic resonance imaging-derived signal intensity putatively reflecting myelin i) increased detection accuracy of Alzheimer’s disease, ii) revealed age-related differences in myelin grade and myelin network organization across the lifespan, and iii) was related to cognitive functioning as measured by an attention task. The findings implicate myelin as an underlying neurobiological factor to brain alterations in normal development and aging, with cognitive links, as well as suggesting a clinical application in dementia. The human brain undergoes large structural changes through life with contemporaneous alterations in most cognitive functions. Diseases such as Alzheimer’s dementia are characterized by deviations from these normal age-related change patterns. The advent of modern neuroimaging has yielded important new knowledge concerning brain development and aging, its aberrant path in disease, and its relation to cognition. Based on magnetic resonance imaging (MRI) for instance, structural measures such as volume and cortical thickness can be derived. A plethora of studies demonstrate that these measures show age-related differences, correlate with memory, attention and other cognitive functions, and demonstrate significant atrophy in specific regions in Alzheimer’s dementia. Still, both volume and thickness lack specificity regarding the underlying neurobiological mechanisms. Interestingly, studies demonstrate that, by using signal intensity derived from T1- and T2-weighted MRI scans, more information about underlying neurobiological processes can be obtained. For instance, a recent report shows how increased sensitivity to myelin could be obtained by dividing the T1w signal by a co-registered T2w image, enabling the opportunity to putatively assess myelin in vivo. The present thesis aims to assess myelin structure across the lifespan using signal intensity, and test for cognitive links to intracortical myelin maturation and senescence. In addition, we probe the ability to increase detection of Alzheimer’s dementia to potentially show clinical relevance

Amnesi og herpes simplex encefalitt : en studie med diffusion tensor imaging og hjernemorfometri

Bakgrunn: Anterograd amnesi karakteriseres av svikt i evnen til å danne nye minner, og kan forårsakes av bilaterale lesjoner i de mediale temporallappene (MTL). Herpes simplex encefalitt (HSE) kan føre til lesjoner i MTL som er synlige ved konvensjonell hjerneavbildning, og anterograd amnesi. Nye analysemetoder av strukturell hjerneavbildning kan avdekke mer subtile skader og gi viktig informasjon om det anatomiske grunnlaget for amnesi. I denne studien ble hvit- og gråsubstans kontralateral for unilateral MTL-lesjon forårsaket av HSE, undersøkt ved hjelp av diffusion tensor imaging (DTI) og hjernemorfometri. Metoder: Fem tidligere HSE-pasienter (1 kvinne, gjennomsnittsalder = 33 år, SD = 5 år) og 51 friske kontroller (30 kvinner, gjennomsnittsalder = 33 år, SD = 5 år) gjennomgikk DTI, strukturell magnetisk resonanstomografi (MR) og nevropsykologisk testing. Forskjeller mellom gruppene i fraksjonell anisotropi (FA), kortikal tykkelse og subkortikalt volum, samt i prestasjon på tester relatert til ulike kognitive funksjoner, ble analysert. Strukturelle mål fra regioner som viste endringer hos de tidligere HSE-pasientene, ble korrelert med skårer fra en verbal hukommelsesoppgave i kontrollgruppen. Resultater: Hos de tidligere HSE-pasientene ble redusert FA observert i kontralateral hemisfære, i fiberbaner relatert til MTL og hukommelse, sammenlignet med kontrollgruppen. Betydelig svikt i både verbal og visuospatial hukommelse ble også avdekket. FA i fiberbaner som viste gruppeforskjeller, korrelerte positivt med skårer på deltester av verbal hukommelse i kontrollgruppen. Ingen gruppeforskjell ble observert i kortikal tykkelse, mens subkortikalt volum viste inkonsistente forskjeller. Konklusjon: DTI-mål indikerte redusert mikrostrukturell integritet i antatt uaffekterte områder relatert til MTL og hukommelse, i en gruppe med tidligere HSE-pasienter. Korrelasjonsanalyser kan tyde på nevrokognitve effekter av forskjeller i diffusjonsmønster i de samme områdene, og det er mulig at endrede mikrostrukturelle forhold kan ha bidratt til amnesien hos de tidligere HSE-pasientene

Intracortical Posterior Cingulate Myelin Content Relates to Error Processing – Results From T1- and T2-weighted MRI Myelin Mapping and Electrophysiology in Healthy Adults

Myelin content of the cerebral cortex likely impacts cognitive functioning, but this notion has scarcely been investigated in vivo in humans. Here we tested for a relationship between intracortical myelin and a direct measure of neural activity in the form of the electrophysiological response error-related negativity (ERN). Using magnetic resonance imaging, myelin mapping was performed in 81 healthy adults aged 40–60 years by means of a T1- and T2-weighted (T1w/T2w) signal intensity ratio approach. Error trials on a version of the Eriksen flanker task triggered the ERN, a negative deflection of the event-related potential reflecting performance monitoring. Compelling evidence from neuroimaging, lesion, and source localization studies indicates that the ERN stems from the cingulate cortex. Vertex-wise analyses across the cingulate demonstrated that increased amplitude of the ERN was related to higher levels of intracortical myelin in the left posterior cingulate cortex. The association was independent of general ability level and subjacent white matter myelin. The results fit the notion that degree of myelin within the posterior cingulate cortex as measured by T1w/T2w signal intensity plays a role in error processing and cognitive control through the relationship with neural activity as measured by ERN amplitude, potentially by facilitating local neural synchronization. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cerebral Cortex following peer review. The version of record is available online at: http://dx.doi.org/10.1093/cercor/bhv06

Longitudinal Working Memory Development Is Related to Structural Maturation of Frontal and Parietal Cortices

Parallels between patterns of brain maturation and cognitive development have been observed repeatedly, but studies directly testing the relationships between improvements in specific cognitive functions and structural changes in the brain are lacking. Working memory development extends throughout childhood and adolescence and likely plays a central role for cognitive development in multiple domains and in several neurodevelopmental disorders. Neuroimaging, lesion, and electrophysiological studies indicate that working memory emerges from coordinated interactions of a distributed neural network in which fronto-parietal cortical regions are critical. In the current study, verbal working memory function, as indexed by performance on the Keep Track task, and volumes of brain regions were assessed at two time points in 79 healthy children and adolescents in the age range of 8–22 years. Longitudinal change in cortical and subcortical volumes was quantified by the use of Quantitative Anatomical Regional Change. Improvement in working memory was related to cortical volume reduction in bilateral prefrontal and posterior parietal regions and in regions around the central sulci. Importantly, these relationships were not explained by differences in gender, age, or intelligence level or change in intellectual abilities. Furthermore, the relationships did not interact with age and were not significantly different in children, young adolescents, and old adolescents. The results provide the first direct evidence that structural maturation of a fronto-parietal cortical network supports working memory development

Mechanisms underlying encoding of short-lived versus durable episodic memories

We continuously encounter and process novel events in the surrounding world, but only some episodes will leave detailed memory traces that can be recollected after weeks and months. Here, our aim was to monitor brain activity during encoding of events that eventually transforms into long-term stable memories. Previous functional magnetic resonance imaging (fMRI) studies have shown that the degree of activation of different brain regions during encoding is predictive of later recollection success. However, most of these studies tested participants' memories the same day as encoding occurred, whereas several lines of research suggest that extended post-encoding processing is of crucial importance for long-term consolidation. Using fMRI, we tested whether the same encoding mechanisms are predictive of recollection success after hours as after a retention interval of several weeks. Seventy-eight participants were scanned during an associative encoding task and given a source memory test the same day or after ∼6 weeks. We found a strong link between regional activity levels during encoding and recollection success over short time intervals. However, results further showed that durable source memories, i.e., events recollected after several weeks, were not simply the events associated with the highest activity levels at encoding. Rather, strong levels of connectivity between the right hippocampus and perceptual areas, as well as with parts of the self-referential default-mode network, seemed instrumental in establishing durable source memories. Thus, we argue that an initial intensity-based encoding is necessary for short-term encoding of events, whereas additional processes involving hippocampal–cortical communication aid transformation into stable long-term memories

The Roots of Alzheimer’s Disease: Are High-Expanding Cortical Areas Preferentially Targeted?

Alzheimer's disease (AD) is regarded a human-specific condition, and it has been suggested that brain regions highly expanded in humans compared with other primates are selectively targeted. We calculated shared and unique variance in the distribution of AD atrophy accounted for by cortical expansion between macaque and human, affiliation to the default mode network (DMN), ontogenetic development and normal aging. Cortical expansion was moderately related to atrophy, but a critical discrepancy was seen in the medial temporo-parietal episodic memory network. Identification of “hotspots” and “coldspots” of expansion across several primate species did not yield compelling evidence for the hypothesis that highly expanded regions are specifically targeted. Controlling for distribution of atrophy in aging substantially attenuated the expansion–AD relationship. A path model showed that all variables explained unique variance in AD atrophy but were generally mediated through aging. This supports a systems-vulnerability model, where critical networks are subject to various negative impacts, aging in particular, rather than being selectively targeted in AD. An alternative approach is suggested, focused on the interplay of the phylogenetically old and preserved medial temporal lobe areas with more highly expanded association cortices governed by different principles of plasticity and stability. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cerebral Cortex following peer review. The version of record is available online at: http://dx.doi.org/10.1093/cercor/bhu05

The Disconnected Brain and Executive Function Decline in Aging

Higher order speeded cognitive abilities depend on efficient coordination of activity across the brain, rendering them vulnerable to age reductions in structural and functional brain connectivity. The concept of “disconnected aging” has been invoked, suggesting that degeneration of connections between distant brain regions cause cognitive reductions. However, it has not been shown that changes in cognitive functions over time can be explained by simultaneous changes in brain connectivity. We followed 119 young and middle-aged (23–52 years) and older (63–86 years) adults for 3.3 years with repeated assessments of structural and functional brain connectivity and executive functions. We found unique age-related longitudinal reductions in executive function over and above changes in more basic cognitive processes. Intriguingly, 82.5% of the age-related decline in executive function could be explained by changes in connectivity over time. While both structural and functional connectivity changes were related to longitudinal reductions in executive function, only structural connectivity change could explain the age-specific decline. This suggests that the major part of the age-related reductions in executive function can be attributed to micro- and macrostructural alterations in brain connectivity. Although correlational in nature, we believe the present results constitute evidence for a “disconnected brain” view on cognitive aging. This is a pre-copyedited, author-produced PDF of an article accepted for publication in Cerebral Cortex following peer review. The version of record is available online at: http://dx.doi.org/10.1093/cercor/bhw082

Regional hippocampal volumes and development predict learning and memory

The hippocampus is an anatomically and functionally heterogeneous structure, but longitudinal studies of its regional development are scarce and it is not known whether protracted maturation of the hippocampus in adolescence is related to memory development. First, we investigated hippocampal subfield development using 170 longitudinally acquired brain magnetic resonance imaging scans from 85 participants aged 8-21 years. Hippocampal subfield volumes were estimated by the use of automated segmentation of 7 subfields, including the cornu ammonis (CA) sectors and the dentate gyrus (DG), while longitudinal subfield volumetric change was quantified using a nonlinear registration procedure. Second, associations between subfield volumes and change and verbal learning/memory across multiple retention intervals (5 min, 30 min and 1 week) were tested. It was hypothesized that short and intermediate memory would be more closely related to CA2-3/CA4-DG and extended, remote memory to CA1. Change rates were significantly different across hippocampal subfields, but nearly all subfields showed significant volume decreases over time throughout adolescence. Several subfield volumes were larger in the right hemisphere and in males, while for change rates there were no hemisphere or sex differences. Partly in support of the hypotheses, greater volume of CA1 and CA2-3 was related to recall and retention after an extended delay, while longitudinal reduction of CA2-3 and CA4-DG was related to learning. This suggests continued regional development of the hippocampus across adolescence and that volume and volume change in specific subfields differentially predict verbal learning and memory over different retention intervals, but future high-resolution studies are called for