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Age-related alterations in default mode network: Impact on working memory performance
Abstract
The default mode network (DMN) is a set of functionally connected brain regions which shows deactivation (task-induced deactivation, TID) during a cognitive task. Evidence shows an age-related decline in task-load-related modulation of the activity within the DMN during cognitive tasks. However, the effect of age on the functional coupling within the DMN and their relation to cognitive performance has hitherto been unexplored. Using functional magnetic resonance imaging, we investigated functional connectivity within the DMN in older and younger subjects during a working memory task with increasing task load. Older adults showed decreased connectivity and ability to suppress low frequency oscillations of the DMN. Additionally, the strength of the functional coupling of posterior cingulate (pCC) with medial prefrontal cortex (PFC) correlated positively with performance and was lower in older adults. pCC was also negatively coupled with task-related regions, namely the dorsolateral PFC and cingulate regions. Our results show that in addition to changes in canonical task-related brain regions, normal aging is also associated with alterations in the activity and connectivity of brain regions within the DMN. These changes may be a reflection of a deficit in cognitive control associated with advancing age that results in deficient resource allocation to the task at hand.
... Compared to young individuals, older adults typically show reduced deactivations of DMN structures like the mPFC and the precuneus during various cognitive tasks, including successful episodic encoding, working memory, or semantic categorization (Hayes et al., 2017;Persson et al., 2014;Sambataro et al., 2010). This finding is commonly thought to reflect the decreased ability of older adults to direct resources towards the task-away from spontaneous inwardly directed thought. ...
... This seemingly paradoxical phenomenon of reduced DMN deactivation predicting later remembering in older adults with poor behavioral memory performance constitutes a well-replicated finding. However, it is yet unclear whether this observation is best explained by a general, task-independent hyperactivity of the DMN in old age (Sambataro et al., 2010;Wang et al., 2010) or whether it reflects different encoding strategies that older adults adopt to compensate for age-related deficits in hippocampusdependent encoding (Cabeza et al., 2005). ...
... They suggested that this might indicate a shift in strategy by relying more on prior knowledge, supporting the defaultexecutive coupling hypothesis which poses that prior knowledge increasingly supports executive processes to compensate for agerelated decline (Craik & Bialystok, 2006). Indeed, especially the DMN's midline regions, especially the mPFC and precuneus, have been implicated in cognition focused on internal representations, such as selfreference (Craik et al., 1999;Macrae et al., 2004), social processing (Meyer et al., 2019), reward-related processing (Adcock et al., 2006;Wittmann et al., 2005), and emotion processing Sambataro et al., 2010). ...
The default mode network (DMN) typically exhibits deactivations during demanding tasks compared to periods of relative rest. In functional magnetic resonance imaging (fMRI) studies of episodic memory encoding, increased activity in DMN regions even predicts later forgetting in young healthy adults. This association is attenuated in older adults and, in some instances, increased DMN activity even predicts remembering rather than forgetting. It is yet unclear whether this phenomenon is due to a compensatory mechanism, such as self-referential or schema-dependent encoding, or whether it reflects overall reduced DMN activity modulation in older age. We approached this question by systematically comparing DMN activity during successful encoding and tonic, task-independent, DMN activity at rest in a sample of 106 young (18–35 years) and 111 older (60–80 years) healthy participants. Using voxel-wise multimodal analyses, we assessed the age-dependent relationship between DMN resting-state amplitude (mean percent amplitude of fluctuation, mPerAF) and DMN fMRI signals related to successful memory encoding, as well as their modulation by age-related hippocampal volume loss, while controlling for regional grey matter volume. Older adults showed lower resting-state DMN amplitudes and lower task-related deactivations. However, a negative relationship between resting-state mPerAF and subsequent memory effect within the precuneus was observed only in young, but not older adults. Hippocampal volumes showed no relationship with the DMN subsequent memory effect or mPerAF. Lastly, older adults with higher mPerAF in the DMN at rest tend to show higher memory performance, pointing towards the importance of a maintained ability to modulate DMN activity in old age.
... This dilatory response is referred to as cerebrovascular reactivity (CVR). Of note, both the BOLD response to functional tasks and CVR have been reported to decrease (5,12,13), remain unchanged (14)(15)(16), and increase with age (9,17). Potentially, depressed BOLD responses to functional tasks may be explained by decreased CVR. ...
... Although increases in the %BOLD responses to the working memory task were not blunted, differential activation patterns were observed in the old group, which included disinhibition of regions associated with the default mode network. The latter may be interpreted as an age-related alteration in neural recruitment or neurocognitive control characterized by impaired resource allocation during cognitive processing (5,12). This can coincide with decreased engagement of the prefrontal cortex (corresponding with Brodmann areas 9 and 10 in Table 3) and Values are means ± SD. ...
The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower grey matter volume (GMV), resting cerebral blood flow (CBF 0 ), and depressed responses to iso-metabolic and neuro-metabolic stimuli. Additionally, increased carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF 0 , cerebrovascular reactivity (CVR) and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age=24±3 y, range=22-28 y; N=13) and old (age=71±4 y; range=67-82 y, N=14) participants, and CBF 0 , CVR (iso-metabolic %BOLD in response to a breath-hold (BH)), brain activation patterns during a working memory task (neuro-metabolic %BOLD response to N-back trial), GMV, PWV, IMT and FMD were measured. CBF 0 and to a lesser extent CVR BH were lower in the old group (P≤0.050); however, the increase in the %BOLD response to the memory task was not blunted (P≥0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P<0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF 0 , CVR BH and GMV across age groups, but within the old group alone only the relationships between PWV-CVR BH and IMT-GMV remained significant (P≤0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus-specific, brain ageing involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular ageing.
... In our parametric design, variance attributable to both encoding success and recognition confidence was captured by the parametric subsequent memory regressor (Soch, Richter, Schutze, Kizilirmak, Assmann, Knopf, et al., 2021b). Despite the overlap of brain networks involved in novelty detection and successful episodic encoding, there are differences in detail (Maass et al., 2014), and, importantly, the memory-related brain regions contributing to the scores such as the dorsolateral and ventrolateral prefrontal cortex, the parahippocampal gyrus and medial temporal lobe are not only relevant for episodic encoding but also for cognitive processes like alertness (Liu et al., 2019) or working memory (Sambataro et al., 2010;Steffener et al., 2020;Steiger et al., 2019). ...
... In the current study, the correlation of the SAME memory score with global cognition could be primarily accounted for by the deactivation component, which may, at least in part, reflect an older individual's general ability to suppress ongoing DMN activation during attention-demanding tasks. In line with this interpretation, reduced DMN deactivation has also been associated with lower working memory performance in older adults (Sambataro et al., 2010), and a meta-analysis revealed that reduced DMN deactivation in old age can be observed across a variety of cognitive tasks (Li et al., 2015). On the other hand, several authors discuss the role of the DMN as a potential cognitive resource in older adults (Billette et al., 2022;Colangeli et al., 2016), which should be further addressed in future studies (see Supplementary Discussion in Data S1). ...
Memory-related functional magnetic resonance imaging (fMRI) activations show age-related differences across multiple brain regions that can be captured in summary statistics like single-value scores. Recently, we described two single-value scores reflecting deviations from prototypical whole-brain fMRI activity of young adults during novelty processing and successful encoding. Here, we investigate the brain-behavior associations of these scores with age-related neurocognitive changes in 153 healthy middle-aged and older adults. All scores were associated with episodic recall performance. The memory network scores, but not the novelty network scores, additionally correlated with medial temporal gray matter and other neuropsychological measures including flexibility. Our results thus suggest that novelty-network-based fMRI scores show high brain-behavior associations with episodic memory and that encoding-network-based fMRI scores additionally capture individual differences in other aging-related functions. More generally, our results suggest that single-value scores of memory-related fMRI provide a comprehensive measure of individual differences in network dysfunction that may contribute to age-related cognitive decline.
... These regions interact at rest to form three functional subdivisions of the DMN, including the medial temporal (MT) and dorsal medial prefrontal cortex (dmPFC) subsystems that converge on a separate core subsystem composed of the PCC and anterior medial prefrontal cortex (Andrews-Hanna et al., 2014;Yeo et al., 2011). Functional connectivity within and between these DMN regions has been associated with self-rumination, memory formation, and thinking about others (Bartova et al., 2015;Daselaar et al., 2004;Sambataro et al., 2010;Whitfield-Gabrieli and Ford, 2012). In addition, the ability to suppress the DMN during task performance has been associated with variability in multiple domains of cognitive performance, including working memory, general intelligence, and naturalistic viewing tendencies (Brandman et al., 2021;DeSerisy et al., 2021;Hearne et al., 2016;Sambataro et al., 2010). ...
... Functional connectivity within and between these DMN regions has been associated with self-rumination, memory formation, and thinking about others (Bartova et al., 2015;Daselaar et al., 2004;Sambataro et al., 2010;Whitfield-Gabrieli and Ford, 2012). In addition, the ability to suppress the DMN during task performance has been associated with variability in multiple domains of cognitive performance, including working memory, general intelligence, and naturalistic viewing tendencies (Brandman et al., 2021;DeSerisy et al., 2021;Hearne et al., 2016;Sambataro et al., 2010). ...
The default mode network (DMN) plays a crucial role in internal self-processing, rumination, and social functions. Disruptions to DMN connectivity have been linked with early adversity and the emergence of psychopathology in adolescence and early adulthood. Herein, we investigate how subclinical psychiatric symptoms can impact DMN functional connectivity during the pubertal transition. Resting-state fMRI data were collected annually from 190 typically-developing youth (9-15 years-old) at three timepoints and within-network DMN connectivity was computed. We used latent growth curve modeling to determine how self-reported depressive and posttraumatic stress symptoms predicted rates of change in DMN connectivity over the three-year period. In the baseline model without predictors, we found no systematic changes in DMN connectivity over time. However, significant modulation emerged after adding psychopathology predictors; greater depressive symptomatology was associated with significant decreases in connectivity over time, whereas posttraumatic stress symptoms were associated with significant increases in connectivity over time. Follow-up analyses revealed that these effects were driven by connectivity changes involving the dorsal medial prefrontal cortex subnetwork. In conclusion, these data suggest that subclinical depressive and posttraumatic symptoms alter the trajectory of DMN connectivity, which may indicate that this network is a nexus of clinical significance in mental health disorders.
... All these reports linked a more deactivated ACC (especially ventral) to better WM performance, possibly due to the successful inhibition of irrelevant information during tasks (Jonides et al., 1998;Vogt, 2009). It should also be noted that as previous investigations into WM ageing mainly focused on regions with task-evoked positive activity (as detailed in recent meta-analyses (Wager and Smith, 2003;Rottschy et al., 2012)), our findings of ACC with negative activity during task, along with a few recent investigations into task-negative areas (Sambataro et al., 2010;Anticevic et al., 2012a), thus implied that those negatively activated regions were as important as the positively activated regions in supporting human cognitions, especially for externally oriented cognitive functions such as working memory and executive function. Moreover, our studies failed to find any pattern of increased activity in frontal and parietal regions, and it was possible that the age-related regression analysis method based on a single group of older individuals, rather than a typical comparison between young and older individuals, was the reason that no increases were identified in activated regions. ...
... The associations between functional connectivity and WM performance have been well-characterized in previous studies. Consistent evidence from resting state neuroimaging data has identified that regions activated in the WM task, such as DLPFC, PreCG, and IPL, were highly connected (Fox et al., 2005;Power et al., 2011) and that connections among task-deactivated regions (such as the medial PFC and PCC) also made considerable contributions to WM (Hampson et al., 2006;Hampson et al., 2010;Sambataro et al., 2010). Furthermore, task fMRI studies, which modelled task-induced BOLD signals using methods such as PPI and DCM, provided further evidence on how information flow was modulated during WM tasks, depicting more details on frontoparietal interactions in different conditions (Ma et al., 2012;Heinzel et al., 2017;Jung et al., 2018). ...
Working memory (WM) impairment has been well characterized in normal ageing. Various studies have explored changes in either the regional activity or the interregional connectivity underlying the WM ageing process. We proposed that brain activity and connectivity would independently alter with ageing and affect WM performance. WM was assessed with a classical N-back task during functional magnetic resonance imaging in a community-based sample comprising 168 elderly subjects (aged 55 to 86 years old). Following the rationale of background functional connectivity, we assessed age-related alterations in brain activity and seed-based interregional connectivity independently. Analyses revealed age-related decrease in the activity of the inferior parietal lobule (IPL) and an increase in the activity of the ventral anterior cingulate cortex (ACC), and the local functional dysfunctions were accompanied by alterations in their connectivity to other cortical regions. Importantly, regional activity impairments in the IPL and ACC could mediate age-related effects on accuracy rate and reaction time, respectively, and those effects were further counterbalanced by enhancement of their background functional connectivity. We thus claimed that age-induced alterations in regional activity and interregional connectivity occurred independently and contributed to WM changes in ageing. Our findings presented the way brain activity and functional connectivity interact in the late adulthood, thus providing a new perspective for understanding WM and cognitive ageing.
... It is well known that increased age is associated with reduced deactivation of the DMN during task execution (e.g. Sambataro et al. 2010;Gordon et al. 2014;Berghuis et al. 2019), which is generally interpreted as impaired switching from taskirrelevant to task-relevant networks (Sambataro et al. 2010;Li et al. 2015). Evidence for an indirect role of the DMN in bimanual performance is provided by the observation that level of performance at retention, following training of bimanual coordination tasks, is positively associated with a decrease in DMN activation in older adults . ...
... It is well known that increased age is associated with reduced deactivation of the DMN during task execution (e.g. Sambataro et al. 2010;Gordon et al. 2014;Berghuis et al. 2019), which is generally interpreted as impaired switching from taskirrelevant to task-relevant networks (Sambataro et al. 2010;Li et al. 2015). Evidence for an indirect role of the DMN in bimanual performance is provided by the observation that level of performance at retention, following training of bimanual coordination tasks, is positively associated with a decrease in DMN activation in older adults . ...
The Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) proposes a framework for understanding task-related brain activity changes as a function of healthy aging and task complexity. Specifically, it affords the following predictions: (i) all adult age groups display more brain activation with increases in task complexity, (ii) older adults show more brain activation compared with younger adults at low task complexity levels, and (iii) disproportionately increase brain activation with increased task complexity, but (iv) show smaller (or no) increases in brain activation at the highest complexity levels. To test these hypotheses, performance on a bimanual tracking task at 4 complexity levels and associated brain activation were assessed in 3 age groups (20–40, 40–60, and 60–80 years, n = 99). All age groups showed decreased tracking accuracy and increased brain activation with increased task complexity, with larger performance decrements and activation increases in the older age groups. Older adults exhibited increased brain activation at a lower complexity level, but not the predicted failure to further increase brain activity at the highest complexity level. We conclude that older adults show more brain activation than younger adults and preserve the capacity to deploy increased neural resources as a function of task demand.
... VN interaction is important for motor control and motor learning [38] and reduced VN-SMN interactions in PD may contribute to postural instability and compromised gait. The robust involvement of the DMN in cognitive functioning has been validated by findings in the context of typical aging and neurodegenerative conditions [39]. The lack of dopamine in PD patients can damage the auditory processing system, altering brain responses to sound and affecting the emotional state of higher brain regions [40]. ...
... Furthermore, successful speech perception in noise requires inhibiting task-unrelated long-term memory supported by DMN. Older adults have been reported to exhibit deficits in cognitive control and resource reallocation to task-related regions, indicating that failure to inhibit DMN in the elderly is detrimental to task performance [59,60]. In high-performing ONM, we detected a less similar functional lateralization pattern to that of YNM, displaying more bilateral and even leftward lateralization of DMN. ...
Musical training can counteract age-related decline in speech perception in noisy environments. However, it remains unclear whether older non-musicians and musicians rely on functional compensation or functional preservation to counteract the adverse effects of aging. This study utilized resting-state functional connectivity (FC) to investigate functional lateralization, a fundamental organization feature, in older musicians (OM), older non-musicians (ONM), and young non-musicians (YNM). Results showed that OM outperformed ONM and achieved comparable performance to YNM in speech-in-noise and speech-in-speech tasks. ONM exhibited reduced lateralization than YNM in lateralization index (LI) of intrahemispheric FC (LI_intra) in the cingulo-opercular network (CON) and LI of interhemispheric heterotopic FC (LI_he) in the language network (LAN). Conversely, OM showed higher neural alignment to YNM (i.e., a more similar lateralization pattern) compared to ONM in CON, LAN, frontoparietal network (FPN), dorsal attention network (DAN), and default mode network (DMN), indicating preservation of youth-like lateralization patterns due to musical experience. Furthermore, in ONM, stronger left-lateralized and lower alignment-to-young of LI_intra in the somatomotor network (SMN) and DAN and LI_he in DMN correlated with better speech performance, indicating a functional compensation mechanism. In contrast, stronger right-lateralized LI_intra in FPN and DAN and higher alignment-to-young of LI_he in LAN correlated with better performance in OM, suggesting a functional preservation mechanism. These findings highlight the differential roles of functional preservation and compensation of lateralization in speech perception in noise among elderly individuals with and without musical expertise, offering insights into successful aging theories from the lens of functional lateralization and speech perception.
... The gap where the working memory stores the concepts for long-term retrieval is inhibited by the brain's default mode network (DMN), which reduces the inputs available for memory retrieval (Guy & Byrne, 2013, p. 1). Though plenty of debate exists around how age modulates the DMN, it does seem that neural activity decreases task induced function causing the brain to rely on internal or self-centered articles for task completion (Sambataro, 2010). This suggests that the brain of the older person may be more likely to miss socio-emotional inputs, such as mirroring neurons. ...
Abstract:
This research attempted to address a gap in the leadership development industry. As an interdisciplinary research project addressing leader-developed empathy, the research explored the acceptance of combining senior leadership training with entheogenic compounds as a catalyst for emotional development. The guiding question asked what participants valued about emotional intelligence (EQ) and their thoughts on alternate methods of achieving EQ in their leadership journey. The participants were not aware of the entheogenic questions prior to the interview. The broader literature tells a story of micro examples of exemplary leadership, yet the epidemic of mental health issues in the workplace, ghosting, burnout, etc., suggested another story. Short-term or temporary leadership training benefits have been met with a growing $160 billion US trend in the industry, which shows no discernable macro benefit to the economy or society in general. A multimethod qualitative approach was used, starting with a modified Bar-On emotional competences questionnaire and followed-up with semi-structured interview questions using a priori structured sections and values coding for analysis. Participants were recruited by convenience and were inclusive of senior leaders, who have tenure, age, and subordinate oversite to establish a possible neurological condition of power or cognitive rigidity. The findings informed future research for a leadership training program. The results found that these senior leaders are not amiable to this form of personal or professional development, require further evidence, but are not opposed to other people trying to improve.
... Moreover, cognitive style can modulate the working memory storage of biological motion when the task becomes demanding (i.e., at set size 5). These results are analogous to those of previous studies that revealed individual differences when memory load was high in working memory (Haenschel et al., 2009;Robinson & Bennink, 1978;Sambataro et al., 2010). It is possible to argue that memory performance is nearly perfect when set sizes are within working memory capacity (Vogel et al., 2001). ...
The biological motion refers to the continuous configuration movement of live agents in space. The perceptual processing of biological motion has the specificity of the dissociation between body form and body motion. However, there is limited evidence for whether such specificity continues when holding biological motion in working memory. We explored this question from the perspective of field dependence (FD) and field independence (FI) cognitive styles in the current study. Three categories of biological motion have been developed: intact movement, motion feature, and form feature. We examined the working memory capacity of motion features, form features, intact movements (Experiments 1–3), and the recognition of three categories of biological motion when remembering intact movements (Experiment 4). The results showed that for the motion features, FI individuals had better memory performance when remembering five items and showed greater working memory capacity and recognition compared with FD individuals, whereas the opposite pattern was observed between FI and FD individuals for the form features. The cognitive style could modulate the working memory storage of biological motion when the task becomes demanding, suggesting that body form and body motion are dissociable in working memory. Our study provided additional evidence for the specificity of biological motion processing in working memory, extending the hierarchical neural model.
... Furthermore, the default mode network (Raichle, 2015) is a set of active brain regions when the mind is at rest and engaged in self-referential thinking. Physical exercise has been shown to influence the connectivity patterns of the poster cingulate cortex within DMN (Boraxbekk et al., 2016;Sambataro et al., 2010), potentially leading to decreased rumination and increased focus on the present moment, contributing to improved mental health. Furthermore, the prefrontal cortex acts as a control structure by integrating information produced during exercise (Robertson and Marino, 2016), both centrally and peripherally. ...
... Notably, individuals with SCD exhibited largely preserved temporo-parietal memory network activations during novelty processing and successful encoding, but reduced novelty-related deactivations of DMN structures like the precuneus (Figure 1), replicating previous results based on a different first-level GLM 24 . This observation is compatible with earlier findings suggesting that age-related reduced deactivations of DMN structures are associated with lower memory performance 25 and with the notion that reduced inhibitory activity may constitute an early mechanism of neurocognitive aging 63,64 . ...
Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer's disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD).
To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants' whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype.
Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ϵ4 carriers and non-carriers in AD-rel.
Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.
... Core regions of the DMN include the medial prefrontal cortex, posterior cingulate cortex, and parts of the precuneus, as well as the hippocampus, retrosplenial cortex, and angular gyrus [91]. Changes in activation of the DMN have been associated with several psychiatric conditions, including post-traumatic stress disorder, Alzheimer's disease, autism, depression, and chronic pain [92][93][94][95][96]. DMN activation can be modulated by different interventions and physiological processes, including physical activity and exercise, sleeping, resting wakefulness, sleep deprivation [97][98][99], and age [100]. The panel regarded the DMN as an important biomarker of brain function, and given its relationship to other cognitive functions (e.g., attention), they thought it could be useful for understanding changes in operational performance. ...
Biomarkers, ranging from molecules to behavior, can be used to identify thresholds beyond which performance of mission tasks may be compromised and could potentially trigger the activation of countermeasures. Identification of homologous brain regions and/or neural circuits related to operational performance may allow for translational studies between species. Three discussion groups were directed to use operationally relevant performance tasks as a driver when identifying biomarkers and brain regions or circuits for selected constructs. Here we summarize small-group discussions in tables of circuits and biomarkers categorized by (a) sensorimotor, (b) behavioral medicine and (c) integrated approaches (e.g., physiological responses). In total, hundreds of biomarkers have been identified and are summarized herein by the respective group leads. We hope the meeting proceedings become a rich resource for NASA’s Human Research Program (HRP) and the community of researchers.
... It should further be noted that age-related activation increases in brain structures not typically involved in the task at hand have also been observed in cognitive domains other than explicit memory 62 , and even in the motor system 63 . As, in the latter study, ipsilateral motor system activity did not predict better performance (e.g., reaction times), the authors suggested that their results speak against a compensatory role of age-related task-related hyperactivations. ...
Successful explicit memory encoding is associated with inferior temporal activations and medial parietal deactivations, which are attenuated in aging. Here we used Dynamic Causal Modeling (DCM) of functional magnetic resonance imaging data to elucidate effective connectivity patterns between hippocampus, parahippocampal place area (PPA) and precuneus during encoding of novel visual scenes. In 117 young adults, DCM revealed pronounced activating input from the PPA to the hippocampus and inhibitory connectivity from the PPA to the precuneus during novelty processing, with both being enhanced during successful encoding. This pattern could be replicated in two cohorts (N = 141 and 148) of young and older adults. In both cohorts, older adults selectively exhibited attenuated inhibitory PPA-precuneus connectivity, which correlated negatively with memory performance. Our results provide insight into network dynamics underlying explicit memory encoding and suggest that age-related differences in memory-related network activity are, at least partly, attributable to altered temporo-parietal neocortical connectivity.
... Studies combining multiple task-evoked fMRI modalities in adults have consistently revealed age-related (29) and disease-related FNC patterns (30) through independent component analysis (ICA) (29)(30)(31). ICA-based methods are data-driven strategies that capture activation covariance between regions, even across multiple fMRI modalities, and are used to measure FNC (32). Importantly, if FNC patterns are invariant across resting state and task-evoked fMRI modalities, then such patterns are possibly intrinsic to an individual and do not depend exclusively on a specific neuroimaging session or cognitive task condition (25). ...
Alterations in fMRI-based brain functional network connectivity (FNC) are associated with schizophrenia (SCZ) and the genetic risk or subthreshold clinical symptoms preceding the onset of SCZ, which often occurs in early adulthood. Thus, age-sensitive FNC changes may be relevant to SCZ risk-related FNC. We used independent component analysis to estimate FNC from childhood to adulthood in 9,236 individuals. To capture individual brain features more accurately than single-session fMRI, we studied an average of three fMRI scans per individual. To identify potential familial risk-related FNC changes, we compared age-related FNC in first-degree relatives of SCZ patients mostly including unaffected siblings (SIB) with neurotypical controls (NC) at the same age stage. Then, we examined how polygenic risk scores for SCZ influenced risk-related FNC patterns. Finally, we investigated the same risk-related FNC patterns in adult SCZ patients (oSCZ) and young individuals with subclinical psychotic symptoms (PSY). Age-sensitive risk-related FNC patterns emerge during adolescence and early adulthood, but not before. Young SIB always followed older NC patterns, with decreased FNC in a cerebellar-occipitoparietal circuit and increased FNC in two prefrontal-sensorimotor circuits when compared to young NC. Two of these FNC alterations were also found in oSCZ, with one exhibiting reversed pattern. All were linked to polygenic risk for SCZ in unrelated individuals (R2 varied from 0.02 to 0.05). Young PSY showed FNC alterations in the same direction as SIB when compared to NC. These results suggest that age-related neurotypical FNC correlates with genetic risk for SCZ and is detectable with MRI in young participants.
... This is also supported by the results of the follow-up MANCOVA comparing the average pairwise correlations between auditory regions and mPFC, which resulted in a significant Group × Liking interaction. This is consistent with previous work demonstrating that functional connectivity of the default-mode network, and especially mPFC, decreases with age (Staffaroni et al., 2018;Sambataro et al., 2010), and continues to decline with age-related illnesses such as Alzheimer's disease (Staffaroni et al., 2018;Schouten et al., 2016;Hafkemeijer et al., 2015). ...
The intrinsic organization of functional brain networks is known to change with age, and is affected by perceptual input and task conditions. Here, we compare functional activity and connectivity during music listening and rest between younger (n = 24) and older (n = 24) adults, using whole-brain regression, seed-based connectivity, and ROI-ROI connectivity analyses. As expected, activity and connectivity of auditory and reward networks scaled with liking during music listening in both groups. Younger adults show higher within-network connectivity of auditory and reward regions as compared with older adults, both at rest and during music listening, but this age-related difference at rest was reduced during music listening, especially in individuals who self-report high musical reward. Furthermore, younger adults showed higher functional connectivity between auditory network and medial prefrontal cortex that was specific to music listening, whereas older adults showed a more globally diffuse pattern of connectivity, including higher connectivity between auditory regions and bilateral lingual and inferior frontal gyri. Finally, connectivity between auditory and reward regions was higher when listening to music selected by the participant. These results highlight the roles of aging and reward sensitivity on auditory and reward networks. Results may inform the design of music-based interventions for older adults and improve our understanding of functional network dynamics of the brain at rest and during a cognitively engaging task.
... Similar to our findings, several previous studies found linear age-related FCS decreases in the medial prefrontal cortex, precuneus, and insula and calcarine, and linear increases in sensorimotor areas based on the general linear model (32)(33)(34). The areas of FCS decrease are the prominent hubs of global and local functional connectivity, and the age-related decrease could underlie the performance decline in working memory and visual sustained attention, which are the most-affected cognitive functions that occur with aging (35)(36)(37). Conversely, the sensorimotor areas are the least affected by aging (32). Notably, in our study, although brain regions had overall increased or decreased change trajectories, the changes did not always follow a linear or quadratic change, which demonstrates the value of the normative model in characterizing the natural FCS change trajectories more accurately. ...
Background:
Major depressive disorder (MDD) is a highly heterogeneous disorder that typically emerges in adolescence and can occur throughout adulthood. Quantitatively uncovering the heterogeneity of individual functional connectome abnormalities in MDD and identifying reproducibly distinct neurophysiological MDD subtypes across the lifespan, which could provide promising insights for precise diagnosis and treatment prediction, are still lacking.
Methods:
Leveraging resting-state functional MRI data from 1,148 MDD patients and 1,079 healthy controls (ages 11-93), we conducted the largest multisite analysis to date for neurophysiological MDD subtyping. We first characterized typical lifespan trajectories of functional connectivity strength based on the normative model and quantitatively mapped the heterogeneous individual deviations among MDD patients. Then, we identified neurobiological MDD subtypes using an unsupervised clustering algorithm and evaluated intersite reproducibility. Finally, we validated the subtype differences in baseline clinical variables and longitudinal treatment predictive capacity.
Results:
Our findings indicated great intersubject heterogeneity in the spatial distribution and severity of functional connectome deviations among MDD patients, which inspired the identification of two reproducible neurophysiological subtypes. Subtype 1 showed severe deviations with positive deviations in the default mode, limbic, and subcortical areas and negative deviations in the sensorimotor and attention areas. Conversely, subtype 2 showed a moderate but converse deviation pattern. More importantly, subtype differences were observed in depressive item scores and predictive ability of baseline deviations for antidepressant treatment outcomes.
Conclusions:
These findings shed light on our understanding of different neurobiological mechanisms underlying the clinical heterogeneity of MDD and are essential for developing personalized treatments for this disorder.
... Research on functional connectivity in older adults has shown mixed results. Some studies found that older adults showed reduced functional connectivity within the DMN compared to younger adults (e.g., Greicius et al., 2003;Biswal et al., 2010;Sambataro et al., 2010;Zhang and Raichle, 2010;Ferreira and Busatto, 2013;Dennis and Thompson, 2014;Sala-Llonch et al., 2015;Ng et al., 2016;Damoiseaux, 2017). Also, some studies have reported reduced functional connectivity in the FPN in older adults compared to younger adults (e.g., Andrews-Hanna et al., 2007;Voss et al., 2010;Marstaller et al., 2015;Ng et al., 2016). ...
Recent research has shown that the Default Mode Network (DMN) typically exhibits increased activation during processing of social and personal information but shows deactivation during working memory (WM) tasks. Previously, we reported the Frontal Parietal Network (FPN) and DMN showed coactivation during task preparation whereas the DMN exhibited deactivation during task execution in working memory tasks. Aging research has shown that older adults exhibited decreased functional connectivity in the DMN relative to younger adults. Here, we investigated whether age-related cognitive decline is related to a reduced relationship between the FPN and DMN using a working memory task during the execution period. First, we replicated our previous finding that the FPN and DMN showed coactivation during the preparation period, whereas the DMN showed deactivation during the execution period. The older adults showed reduced DMN activity during task preparation and reduced deactivation during task execution; however, they exhibited a higher magnitude of activation in the FPN than the young individuals during task execution. Functional connectivity analyses showed that the elderly group, compared to the young group, showed weaker correlations within the FPN and the DMN, weaker positive correlations between the FPN and DMN during task preparation, and weaker negative correlations between the FPN and DMN during execution. The results suggest that cognitive decline in the older adults might be related to reduced connectivity within the DMN as well as between the FPN and DMN.
... Previous studies also found that functional connectivity in DMN and attentional networks predicted adherence to an exercise intervention and a mental training programs 38,39 . Meanwhile, both DMN and DAN play an important role in supporting executive function 40,41 , which were found to contribute to voluntary physical activity engagement 42 . One potential psychological mechanism behind this relationship is that executive function facilitates initiating and adhering to health behaviors through "temporal self-regulation" 36 , with three important determinants for physical activity engagement: physical activity prepotency, intention, and executive function 43 . ...
Prior research has demonstrated the importance of a healthy lifestyle to protect brain health and diminish dementia risk in later life. While a multidomain lifestyle provides an ecological perspective to voluntary engagement, its association with brain health is still under-investigated. Therefore, understanding the neural mechanisms underlying multidomain lifestyle engagement, particularly in older adults at risk for Alzheimer's disease (AD), gives valuable insights into providing lifestyle advice and intervention for those in need. The current study included 139 healthy older adults with familial risk for AD from the Prevent-AD longitudinal aging cohort. Self-reported exercise engagement, cognitive activity engagement, healthy diet adherence, and social activity engagement were included to examine potential phenotypes of an individual's lifestyle adherence. Two adherence profiles were discovered using data-driven clustering methodology [i.e., Adherence to healthy lifestyle (AL) group and Non-adherence to healthy lifestyle group]. Resting-state functional connectivity matrices and grey matter brain features obtained from magnetic resonance imaging were used to classify the two groups using a support vector machine (SVM). The SVM classifier was 75% accurate in separating groups. The features that show consistently high importance to the classification model were functional connectivity mainly between nodes located in different prior-defined functional networks. Most nodes were located in the default mode network, dorsal attention network, and visual network. Our results provide preliminary evidence of neurobiological characteristics underlying multidomain healthy lifestyle choices.
... Studies combining multiple task-evoked fMRI modalities in adults have consistently revealed age-related (29) and disease-related FNC patterns (30) through independent component analysis (ICA) (29)(30)(31). ICA-based methods are data-driven strategies that capture activation covariance between regions, even across multiple fMRI modalities, and are used to measure FNC (32). Importantly, if FNC patterns are invariant across resting state and task-evoked fMRI modalities, then such patterns are possibly intrinsic to an individual and do not depend exclusively on a specific neuroimaging session or cognitive task condition (25). ...
... DMN is a set of widely distributed brain regions, showing reductions in activity during attention-demanding tasks but increased activity during tasks linked to memory (29)(30)(31). The enhanced activity in the older adults' DMN is thought to reflect disinhibition and has been shown to be detrimental to task performance (32,33). Notably, musicians show stronger structural and resting-state functional connectivity in DMN regions than nonmusicians (34)(35)(36). ...
Musicianship can mitigate age-related declines in audiovisual speech-in-noise perception. We tested whether this benefit originates from functional preservation or functional compensation by comparing fMRI responses of older musicians, older nonmusicians, and young nonmusicians identifying noise-masked audiovisual syllables. Older musicians outperformed older nonmusicians and showed comparable performance to young nonmusi-cians. Notably, older musicians retained similar neural specificity of speech representations in sensorimotor areas to young nonmusicians, while older nonmusicians showed degraded neural representations. In the same region, older musicians showed higher neural alignment to young nonmusicians than older nonmusicians, which was associated with their training intensity. In older nonmusicians, the degree of neural alignment predicted better performance. In addition, older musicians showed greater activation in frontal-parietal, speech motor, and visual motion regions and greater deactivation in the angular gyrus than older nonmusicians, which predicted higher neural alignment in sensorimotor areas. Together, these findings suggest that musician-ship-related benefit in audiovisual speech-in-noise processing is rooted in preserving youth-like representations in sensorimotor regions.
... Older adults showed less increase in load-modulated connectivity strength as task demands increased, as has been reported in activation studies (Cappell et al., 2010;Heinzel et al., 2017;Kaup et al., 2014;Kennedy et al., 2017). Reduced connectivity with age in the default mode network is a consistent finding in the literature across both task-based and resting state studies (Andrews-Hanna et al., 2007;Bethlehem et al., 2020;Damoiseaux et al., 2008;Geerligs et al., 2012Geerligs et al., , 2015Grady et al., 2010;Sambataro et al., 2010;Samu et al., 2017;Tsvetanov et al., 2016), one that we replicate here. Our study additionally shows a novel finding of decreased load-modulated connectivity with increasing age within the somatomotor, dorsal attention, ventral attention, and frontoparietal networks, and between the visual network and other networks and between the dorsal attention and frontoparietal networks. ...
Working memory is critical to higher-order executive processes and declines throughout the adult lifespan. However, our understanding of the neural mechanisms underlying this decline is limited. Recent work suggests that functional connectivity between frontal control and posterior visual regions may be critical, but examinations of age differences therein have been limited to a small set of brain regions and extreme group designs (i.e., comparing young and older adults). In this study, we build on previous research by using a lifespan cohort and a whole-brain approach to investigate working memory load-modulated functional connectivity in relation to age and performance. The article reports on analysis of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data. Participants from a population-based lifespan cohort (N=101, age 23-86) performed a visual short-term memory task during functional magnetic resonance imaging. Visual short-term memory was measured with a delayed recall task for visual motion with three different loads. Whole-brain load-modulated functional connectivity was estimated using psychophysiological interactions in a hundred regions of interest, sorted into seven networks (Schaefer et al., 2018, Yeo et al., 2011). Results showed that load-modulated functional connectivity was strongest within the dorsal attention and visual networks during encoding and maintenance. With increasing age, load-modulated functional connectivity strength decreased throughout the cortex. Whole-brain analyses for the relation between connectivity and behavior were non-significant. Our results give additional support to the sensory recruitment model of working memory. We also demonstrate the widespread negative impact of age on the modulation of functional connectivity by working memory load. Older adults might already be close to ceiling in terms of their neural resources at the lowest load and therefore less able to further increase connectivity with increasing task demands.
... impairment. Sambataro (44) pointed out that in the DMN, the strength of the functional connection between the PCC and medial prefrontal cortex is positively correlated with working memory performance. The results of the relevant analysis show that the connection strength of the posterior buckle in the DMN network is related to RT only when the working memory is in trouble, and the weaker the connection strength, the worse the working memory performance. ...
Background: Most temporal lobe epilepsy patients accompany with working memory impairment, but the specific brain network mechanism is still unclear. In this study, we used independent component analysis (ICA) to segregate resting-state magnetic resonance imaging (MRI) and evaluated the brain network mechanism of working memory impairment in patients with temporal lobe epilepsy (TLE).
Methods: Resting-state functional magnetic resonance imaging (fMRI) data were collected from 38 patients with TLE and 20 healthy controls. TLE patients were divided into a disordered working memory group (TLE-DWM) and a non-disordered working memory group (TLE-NWM) according to their performance in a delayed matching-to-sample (DMS) working memory task. We used ICA to extract the default mode network (DMN), left central executive network (LCEN), right central executive network (RCEN), and salience network (SN), and to compare the functional connection changes between the four groups. Pearson correlation analysis was used to calculate the correlation between connection strength and working memory performance.
Results: intra-network, inter-network, DMS working test, pearson correlation.
We found that the connectivity of the right inferior parietal lobe and precuneus lobe in the control and TLE-NWM groups was higher than that in the TLE-DWM group. The connectivity of the posterior cingulate gyrus in the control and TLE-NWM groups was higher than that in the TLE-DWM group. The connection of the putamen in the control and TLE-NWM groups was greater than that in the TLE-DWM group. The Z values of the TLE-DWM, TLE-NWM, and control groups in the posterior cingulate gyrus of the LCEN network were negatively correlated with response time (RT).
Conclusion: This study demonstrated that the functional connectivity of right inferior lobe, left precuneus lobe, left posterior cingulate gyrus, left putamen, and DMN-LECN network was decreased in TLE-DWM individuals, indicating that these network alternations correlated with the working memory impairment. In addition, we also found the connectivity of the posterior cingulate gyrus in LECN was negatively correlated with RT, which suggested that posterior cingulate gyrus was associated with the performance of working memory.
... ; https://doi.org/10. 1101 Age-related increases activations of brain activity not typically involved in a task have also been observed in cognitive domains other than explicit memory (Sambataro et al., 2010), and even in the motor system (Knights et al., 2021). As, in the latter study, ipsilateral motor system activity did not predict better performance (e.g., reaction times), the authors suggested that their results speak against a compensatory role of age-related task-related hyperactivations. ...
... There is evidence that the decline of performance in the WM tasks is related to changes in communication between different regions of the brain. Aging not only affects functional connectivity within specific functional networks but also alters the communication between different functional networks [33][34][35]. In this study, the elderly group has a lower clustering coefficient and local efficiency, which indicates that with the increase of age, the network connectivity decreases, and the functional brain network becomes less differentiated or specific. ...
Working memory (WM) is a memory system with a limited capacity that can process and store information temporarily in the performing of cognitive tasks. Despite WM is known to be influenced by age, the difficulty of tasks and trained or not from behavior studies, little is known about their relationships from the aspect of the brain functional network. Our goal was to explore the factor of aging-related changes of WM with brain functional networks.
Methods:
In this study, 25 healthy elderly and 23 healthy young volunteers were recruited for electroencephalogram (EEG) recording during the visual WM task with four difficulty levels (1-4 backs). In each back, we repeat the experiment with four sessions, and we add training sections between session one and session two as well as between session two and session three. However, we remove any training section between session three and session four in order to evaluate the impact of forgetting on WM in different age groups. After the experiment, we utilized graph theoretical analysis to characterize the brain functional network in three frequency bands (alpha, beta, and theta).
Results:
From the well-designed experiment, we found that physiological aging influences brain network connectivity and makes the functional brain network less differentiated. Moreover, there is an inverse relationship between alpha activity and WM load for the elderly group, which is absent in the young group. At the same time, theta band activity will be correlated with behavioral performance for the elderly group with WM training between sessions, which is also absent in the young group. To further study the influence of difficulty of tasks and training on the WM, we distinguish the tasks with quantified topological characteristics, and the classification results manifest that the training is more effective for the young group. Finally, through the establishment of a brain map before and after training, we find that the right parietal lobe plays an important role in the training of WM for the elderly group whereas the beta band plays an important role in WM for both the elderly group and the young group.
Conclusion:
Taken together, our findings clarify the underlying mechanism of WM under different frequency bands in terms of physiological aging, the influence of training, and task difficulty.
Significance: the working memory capacities can be uncovered in terms of the combination of three-way ANOVA and EEG-based graph theoretical analysis.
... ; https://doi.org/10. 1101 Age-related increases activations of brain activity not typically involved in a task have also been observed in cognitive domains other than explicit memory (Sambataro et al., 2010), and even in the motor system (Knights et al., 2021). As, in the latter study, ipsilateral motor system activity did not predict better performance (e.g., reaction times), the authors suggested that their results speak against a compensatory role of age-related task-related hyperactivations. ...
Successful explicit memory encoding is associated with inferior temporal activations and medial parietal deactivations, which are attenuated in aging. Here we used Dynamic Causal Modeling (DCM) of functional magnetic resonance imaging data to elucidate the information flow between hippocampus, parahippocampal place area (PPA) and precuneus during encoding of novel visual scenes. In 117 young adults, DCM revealed pronounced activating input from the PPA to the hippocampus and inhibitory connectivity from the PPA to the precuneus during novelty processing, with both being further up-regulated during successful encoding. This pattern could be replicated in two cohorts (N = 141 and 148) of young and older adults. In both cohorts, older adults selectively exhibited attenuated (negative) PPA-precuneus connectivity, which correlated negatively with memory performance. Our results provide insight into network dynamics underlying explicit memory encoding and suggest that age-related differences in memory-related network activity manifest in altered temporo-parietal neocortical rather than hippocampal connectivity.
... The PCC is thought to play a critical role in regulating the focus of attention both internally and externally [29], and at least one study showed that neural response strength in the PCC scales with cognitive load in healthy individuals [30]. Further, those who fail to adequately reduce activity in the PCC while undergoing cognitively-demanding tasks often exhibit cognitive inefficiencies [31][32][33][34][35], and studies have shown that healthy older individuals express stronger PCC activity while undergoing an externally directed task relative to younger individuals [36][37][38]. ...
Background:
Despite effective antiretroviral therapy, cognitive impairment and other aging-related comorbidities are more prevalent in people with HIV (PWH) than in the general population. Previous research examining DNA methylation has shown PWH exhibit accelerated biological aging. However, it is unclear how accelerated biological aging may affect neural oscillatory activity in virally suppressed PWH, and more broadly how such aberrant neural activity may impact neuropsychological performance.
Methods:
In the present study, participants (n = 134) between the ages of 23 - 72 years underwent a neuropsychological assessment, a blood draw to determine biological age via DNA methylation, and a visuospatial processing task during magnetoencephalography (MEG). Our analyses focused on the relationship between biological age and oscillatory theta (4-8 Hz) and alpha (10 - 16 Hz) activity among PWH (n=65) and seronegative controls (n = 69).
Results:
PWH had significantly elevated biological age when controlling for chronological age relative to controls. Biological age was differentially associated with theta oscillations in the left posterior cingulate cortex (PCC) and with alpha oscillations in the right medial prefrontal cortex (mPFC) among PWH and seronegative controls. Stronger alpha oscillations in the mPFC were associated with lower CD4 nadir and lower current CD4 counts, suggesting such responses were compensatory. Participants who were on combination antiretroviral therapy for longer had weaker theta oscillations in the PCC.
Conclusions:
These findings support the concept of interactions between biological aging and HIV status on the neural oscillatory dynamics serving visuospatial processing. Future work should elucidate the long-term trajectory and impact of accelerated aging on neural oscillatory dynamics in PWH.
... Together with patterns of increased FC, negative correlations between the right frontal pole and regions encompassing the DMN, such as the superior occipital cortex and posterior cingulate gyrus, were observed in subjective cognitive complainers. Previous studies demonstrated that reduced functional coupling between frontal and posterior cingulate regions is predictive of poor performance during attentional and working memory tasks, both in healthy and pathological aging ( Sala-Llonch et al., 2012, Damoiseaux et al., 2008, Greicius et al., 2004, Sambataro et al., 2010. In line with these results, we observed that COVID-19 survivors report-ing subjective cognitive impairments exhibit reduced FC between the frontal pole and the DMN during rest, possibly reflecting altered attentional and memory processes which are independent from performance at cognitive tasks. ...
Cognitive impairment represents a leading residual symptom of COVID-19 infection, which lasts for months after the virus clearance. Up-to-date scientific reports documented a wide spectrum of brain changes in COVID-19 survivors following the illness's resolution, mainly related to neurological and neuropsychiatric consequences. Preliminary insights suggest abnormal brain metabolism, microstructure, and functionality as neural under-layer of post-acute cognitive dysfunction. While previous works focused on brain correlates of impaired cognition as objectively assessed, herein we investigated long-term neural correlates of subjective cognitive decline in a sample of 58 COVID-19 survivors with a multimodal imaging approach. Diffusion Tensor Imaging (DTI) analyses revealed widespread white matter disruption in the sub-group of cognitive complainers compared to the non-complainer one, as indexed by increased axial, radial, and mean diffusivity in several commissural, projection and associative fibres. Likewise, the Multivoxel Pattern Connectivity analysis (MVPA) revealed highly discriminant patterns of functional connectivity in resting-state among the two groups in the right frontal pole and in the middle temporal gyrus, suggestive of inefficient dynamic modulation of frontal brain activity and possible metacognitive dysfunction at rest. Beyond COVID-19 actual pathophysiological brain processes, our findings point toward brain connectome disruption conceivably translating into clinical post-COVID cognitive symptomatology. Our results could pave the way for a potential brain signature of cognitive complaints experienced by COVID-19 survivors, possibly leading to identify early therapeutic targets and thus mitigating its detrimental long-term impact on quality of life in the post-COVID-19 stages.
... That is, individuals with higher cognitive reserve displayed a greater positive link between brain maintenance and our measure of efficiency, at least cross-sectionally. In addition to its role in episodic memory, the precuneus is considered a functional core of the default mode network, an area sensitive to task-load-related modulation of activation (Sambataro et al., 2010). The fact that increases in cognitive reserve and brain maintenance were linked to greater PS in this region potentially supports a mechanism for neural efficiency and general preservation of neural processing, meriting further investigation via functional network analysis and better-defined mechanistic models. ...
The aging process is characterized by change across several measures that index cognitive status and brain integrity. In the present study, 54 cognitively-healthy younger and older adults, were analyzed, longitudinally, on a verbal working memory task to investigate the effect of brain maintenance (i.e., cortical thickness) and cognitive reserve (i.e., NART IQ as proxy) factors on a derived measure of neural efficiency. Participants were scanned using fMRI while presented with the Letter Sternberg task, a verbal working memory task consisting of encoding, maintenance and retrieval phases, where cognitive load is manipulated by varying the number of presented items (i.e., between one and six letters). Via correlation analysis, we looked at region-level and whole-brain relationships between load levels within each phase and then computed a global task measure, what we term phase specificity, to analyze how similar neural responses were across load levels within each phase compared to between each phase. We found that longitudinal change in phase specificity was positively related to longitudinal change in cortical thickness, at both the whole-brain and regional level. Additionally, baseline NART IQ was positively related to longitudinal change in phase specificity over time. Furthermore, we found a longitudinal effect of sex on change in phase specificity, such that females displayed higher phase specificity over time. Cross-sectional findings aligned with longitudinal findings, with the notable exception of behavioral performance being positively linked to phase specificity cross-sectionally at baseline. Taken together, our findings suggest that phase specificity positively relates to brain maintenance and reserve factors and should be better investigated as a measure of neural efficiency.
Single-value scores reflecting the deviation from (FADE score) or similarity with (SAME score) prototypical novelty-related and memory-related functional magnetic resonance imaging (fMRI) activation patterns in young adults have been proposed as imaging biomarkers of healthy neurocognitive aging. Here, we tested the utility of these scores as potential diagnostic and prognostic markers in Alzheimer’s disease (AD) and risk states like mild cognitive impairment (MCI) or subjective cognitive decline (SCD).
To this end, we analyzed subsequent memory fMRI data from individuals with SCD, MCI, and AD dementia as well as healthy controls (HC) and first-degree relatives of AD dementia patients (AD-rel) who participated in the multi-center DELCODE study (N = 468). Based on the individual participants’ whole-brain fMRI novelty and subsequent memory responses, we calculated the FADE and SAME scores and assessed their association with AD risk stage, neuropsychological test scores, CSF amyloid positivity, and ApoE genotype.
Memory-based FADE and SAME scores showed a considerably larger deviation from a reference sample of young adults in the MCI and AD dementia groups compared to HC, SCD and AD-rel. In addition, novelty-based scores significantly differed between the MCI and AD dementia groups. Across the entire sample, single-value scores correlated with neuropsychological test performance. The novelty-based SAME score further differed between Aβ-positive and Aβ-negative individuals in SCD and AD-rel, and between ApoE ε4 carriers and non-carriers in AD-rel.
Hence, FADE and SAME scores are associated with both cognitive performance and individual risk factors for AD. Their potential utility as diagnostic and prognostic biomarkers warrants further exploration, particularly in individuals with SCD and healthy relatives of AD dementia patients.
Introduction
Associative memory is arguably the most basic memory function and therein constitutes the foundation of all episodic and semantic memory processes. At the same time, the decline of associative memory represents a core feature of age-related cognitive decline in both, healthy and pathological (i.e., dementia-related) aging. The neural mechanisms underlying age-related impairments in associative memory are still not fully understood, especially regarding incidental (i.e., non-intentional) learning.
Methods
We investigated the impact of age on the incidental learning and memory retrieval of face-name combinations in a total sample of 46 young ( N = 23; mean age = 23.39 years) and elderly ( N = 22, mean age = 69.05 years) participants. More specifically, particular interest was placed in age-related changes in encoding/retrieval (E/R) flips, which denote a neural antagonism of opposed activation patterns in the same brain region during memory encoding and retrieval, which were assessed using fMRI.
Results
According to our hypothesis, the results showed a significant age-related decline in the retrieval performance in the old group. Additionally, at the neural level, we discovered an abolished E/R flip in the right anterior insula and a joint but reduced E/R flip activation magnitude in the posterior middle cingulate cortex in older subjects.
Discussion
In conclusion, the present findings suggest that the impaired neural modulation of the E/R flip in the right aIC might be a sensitive marker in the early detection of neural aging.
Preservation of executive function, like inhibition, closely links to the quality of life in senior adults. Although neuroimaging literature has shown enhanced inhibitory function followed by aerobic exercise, current evidence implies inconsistent neuroplasticity patterns along different time durations of exercise. Hence, we conducted a 12-week exercise intervention on 12 young and 14 senior volunteers and repeatedly measured the inhibitory functionality of distinct aspects (facilitation and interference effects) using the numerical Stroop task and functional Magnetic Resonance Imaging. Results showcased improved accuracy and reduced reaction times (RT) after 12-week exercise, attributed to frontoparietal and default mode network effects. In young adults, the first phase (0 to six weeks) exercise increased the activation of the right superior medial frontal gyrus, associated with reduced RT in interference, but in the second intervention phase (six to twelve weeks), the decreased activation of the left superior medial frontal gyrus positively correlated with reduced RT in facilitation. In senior adults, the first six-week intervention led to reduced activations of the inferior frontal gyrus, inferior parietal gyrus, and default mode network regions, associated with the reduced RT in interference. Still, in the second intervention phase, only the visual area exhibited increased activity, associated with reduced RT in interference. Except for the distinctive brain plasticity between the two phases of exercise intervention, the between-group comparison also presented that the old group gained more cognitive benefits within the first six weeks of exercise intervention; however, the cognitive improvements in the young group occurred after six weeks of intervention. Limited by the sample size, these preliminary findings corroborated the benefits of aerobic exercise on the inhibitory functions, implying an age × exercise interaction on the brain plasticity for both facilitation and interference.
Functional brain networks have preserved architectures in rest and task; nevertheless, previous work consistently demonstrated task-related brain functional reorganization. Efficient rest-to-task functional network reconfiguration is associated with better cognition in young adults. However, aging and cognitive load effects, as well as contributions of intra- and inter-network reconfiguration, remain unclear. We assessed age-related and load-dependent effects on global and network-specific functional reconfiguration between rest and a spatial working memory (SWM) task in young and older adults, then investigated associations between functional reconfiguration and SWM across loads and age groups. Overall, global and network-level functional reconfiguration between rest and task increased with age and load. Importantly, more efficient functional reconfiguration associated with better performance across age groups. However, older adults relied more on inter-network reconfiguration of higher cognitive and task-relevant networks. These reflect the consistent importance of efficient network updating despite recruitment of additional functional networks to offset reduction in neural resources and a change in brain functional topology in older adults. Our findings generalize the association between efficient functional reconfiguration and cognition to aging and demonstrate distinct brain functional reconfiguration patterns associated with SWM in aging, highlighting the importance of combining rest and task measures to study aging cognition.
Working memory (WM) impairment has been well characterized in normal aging. Various studies have explored changes in either the regional activity or the interregional connectivity underlying the aging process of WM. We proposed that brain activity and connectivity would independently alter with aging and affect WM performance. WM was assessed with a classical N‐back task during functional magnetic resonance imaging in a community‐based sample comprising 168 elderly subjects (aged 55–86 years old). Following the rationale of background functional connectivity, we assessed age‐related alterations in brain activity and seed‐based interregional connectivity independently. Analyses revealed age‐related decrease in positive activity of the inferior parietal lobule (IPL) and an increase in the negative activity of the ventral anterior cingulate cortex (ACC), and the local functional dysfunctions were accompanied by alterations in their connectivity to other cortical regions. Importantly, regional activity impairments in the IPL and ACC could mediate age‐related effects on accuracy rate and reaction time, respectively, and those effects were further counterbalanced by enhancement of their background functional connectivity. We thus claimed that age‐induced alterations in regional activity and interregional connectivity occurred independently and contributed to WM changes in aging. Our findings presented the way brain activity and functional connectivity interact in the late adulthood, thus providing a new perspective for understanding WM and cognitive aging.
Introduction:
Efficient learning is critical to adapting to different environments. There are well-known learning principles in cognitive rehabilitation, including errorless (EL) and trial-and-error (T&E) learning; however, little is known about their underlying neural mechanisms. In the current study, to understand the age-related changes in learning benefits and neural mechanisms applying EL and T&E learning methods in healthy middle-aged adults, we conducted a graph theoretical analysis using functional magnetic resonance imaging data and analyzed the relationship between learning benefits and age, as well as functional network connectivity and age, with both learning principles.
Method:
A total of 43 participants performed a color-name association task through EL and T&E learning methods. We focused on the functional connectivity patterns of the default mode network (DMN) since previous studies demonstrated this network to be more distinctive and important for the T&E learning method than EL. Within-network functional connectivity was used as the graph metric.
Results:
Age showed significant moderate negative correlations with T&E scores and within-DMN functional connectivity in the test state following T&E learning. Conversely, age was not significantly correlated with EL scores or within-DMN functional connectivity in either the EL learning or test states.
Conclusions:
Our findings demonstrate the age-related learning decline associated with decreased DMN integration with aging, when applying the T&E method but not the EL method, even in healthy middle-aged adults. Relationships between the underlying neural network and age are different depending on the learning method. This suggests the need to take into consideration the remaining learning ability through the T&E learning method compared to normal aging and to utilize residual DMN functioning, in addition to the comparison between score differences between EL and T&E methods, when tailoring an individual learning approach.
Aging is associated with functional activation changes in domain-specific regions and large-scale brain networks. This preregistered Functional magnetic resonance imaging (fMRI) study investigated these effects within the domain of semantic cognition. Participants completed 1 nonsemantic and 2 semantic tasks. We found no age differences in semantic activation in core semantic regions. However, the right inferior frontal gyrus showed difficulty-related increases in both age groups. This suggests that age-related upregulation of this area may be a compensatory response to increased processing demands. At a network level, older people showed more engagement in the default mode network and less in the executive multiple-demand network, aligning with older people's greater knowledge reserves and executive declines. In contrast, activation was age-invariant in semantic control regions. Finally, older adults showed reduced demand-related modulation of multiple-demand network activation in the nonsemantic task but not the semantic tasks. These findings provide a new perspective on the neural basis of semantic cognition in aging, suggesting that preserved function in specialized semantic networks may help to maintain semantic cognition in later life.
Switching is a difficult cognitive process characterised by costs in task performance; specifically, slowed responses and reduced accuracy. It is associated with the recruitment of a large coalition of task-positive regions including those referred to as the multiple demand cortex (MDC). The neural correlates of switching not only include the MDC, but occasionally the default mode network (DMN), a characteristically task-negative network. To unpick the role of the DMN during switching we collected fMRI data from 24 participants playing a switching paradigm that perturbed predictability (i.e., cognitive load) across three switch dimensions-sequential, perceptual, and spatial predictability. We computed the activity maps unique to switch vs. stay trials and all switch dimensions, then evaluated functional connectivity under these switch conditions by computing the pairwise mutual information functional connectivity (miFC) between regional timeseries. Switch trials exhibited an expected cost in reaction time while sequential predictability produced a significant benefit to task accuracy. Our results showed that switch trials recruited a broader activity map than stay trials, including regions of the DMN, the MDC, and task-positive networks such as visual, somatomotor, dorsal, salience/ventral attention networks. More sequentially predictable trials recruited increased activity in the somatomotor and salience/ventral attention networks. Notably, changes in sequential and perceptual predictability, but not spatial predictability, had significant effects on miFC. Increases in perceptual predictability related to decreased miFC between control, visual, somatomotor, and DMN regions, whereas increases in sequential predictability increased miFC between regions in the same networks, as well as regions within ventral attention/ salience, dorsal attention, limbic, and temporal parietal networks. These results provide novel clues as to how DMN may contribute to executive task performance. Specifically, the improved task performance, unique activity, and increased miFC associated with increased sequential predictability suggest that the DMN may coordinate more strongly with the MDC to generate a temporal schema of upcoming task events, which may attenuate switching costs.
Facilitating communication between generations has become increasingly important. However, individuals often demonstrate a preference for their own age group, which can impact social interactions, and such bias in young adults even extends to inhibitory control. To assess whether older adults also experience this phenomenon, a group of younger and older adults completed a Go/NoGo task incorporating young and old faces, while undergoing functional magnetic resonance imaging. Within the networks subserving successful and unsuccessful response inhibition, patterns of activity demonstrated distinct neural age bias effects in each age group. During successful inhibition, the older adult group demonstrated significantly increased activity to other-age faces, whereas unsuccessful inhibition in the younger group produced significantly enhanced activity to other-age faces. Consequently, the findings of the study confirm that neural responses to successful and unsuccessful inhibition can be contingent on the stimulus-specific attribute of age in both younger and older adults. These findings have important implications in regard to minimizing the emergence of negative consequences, such as ageism, as a result of related implicit biases.
There is growing emphasis on the importance of maintaining brain health to prevent disorders such as Alzheimer's disease, and one aspect of this challenge is measuring biomarkers of brain aging using magnetic resonance imaging (MRI). Previous studies have proposed the gray matter brain healthcare quotient (GM-BHQ) as a measure of brain aging and health, which is calculated using gray matter volume obtained from structural images of the brain. However, an index to evaluate brain health considering the functional aspect of the brain is needed, but has not yet been established. This is because resting-state functional connectivity MRI provides multivariate time-series data, which is difficult to reduce to a single feature or scalar like gray matter volume. Therefore, we used a large functional MRI (fMRI) dataset consisting of a wide age range and used the following three approaches: (1) We learned the relationship between resting-state fMRI data and the GM-BHQ, constructed a regression model between them to obtain the predictive value of a model based on functional information as a functional connectivity brain healthcare quotient (FC-BHQ), and tested its utility. (2) We verified the applicability of brain graph neural networks to regression tasks. (3) Finally, we identified brain regions that showed covariations in function and structure with aging by analyzing the model parameters and interpreting the prediction results. The constructed model achieved moderate performance correlation (r > 0.6) between the predictions and correct answers, and the clustering performed inside the model extracted brain regions and networks that reported significant changes with aging. Sparse modeling of the output clusters revealed brain regions strongly associated with the GM-BHQ, such as the amygdala, which is responsible for emotional processing, as well as the Rolandic operculum and superior temporal gyrus, which is characteristic of changes in connectivity with typical dedifferentiation associated with aging.
In the human brain, functionally and anatomically defined systems exist for encoding, consolidating, and retrieving memories of experiences (episodic memory); accumulating and accessing factual information in a body of knowledge (semantic memory); and actively processing and manipulating information (working memory). These three memory systems can be distinguished behaviorally and neurobiologically from other nondeclarative memory systems such as procedural learning and priming [1–4]. Brain-behavior studies using a variety of approaches from lesion-based research to functional MRI (fMRI) demonstrate distinct though highly interrelated neural circuitry for episodic, semantic, and working memory [3, 5]. Each of these memory systems, despite their close interaction, is affected somewhat differently by aging and dementia.KeywordsEpisodic memorySemantic memoryWorking memoryAlzheimer’s diseaseAgingMild cognitive impairmentSubjective cognitive declinefMRIFunctional connectivityBiomarkers
This chapter discusses the use of functional connectivity in fMRI neuroimaging studies. After a brief history of the field, standard data preprocessing steps are discussed. Analysis approaches, including seed-based connectivity studies, as well as whole-brain, data-driven approaches, are detailed, with attention given to the identification of nodes. Network analysis tools and their application to functional connectivity data are discussed. The chapter closes with sections dedicated to relating function to behavior, with particular focus given to cross-validated, predictive models and the potential utility of relating functional connectivity to behavior. Throughout the chapter, we highlight key papers that have contributed to the rich history of this evolving field.KeywordsFunctional connectivitySeed regionsSeed-to-seedSeed-to-whole brainIndependent components analysis
Further examples of network analysis using the directed graphs introduced in Chap. 4 are given. These networks are graphs showing the degree of relationship between variables. Given the complexity of relationships between concepts, network models are multivariate and often highly dimensional, so there is often a need to reduce the number of variables using techniques such as exploratory factor analysis and LASSO, which uses a tuning parameter specifying the threshold for the degree of removal of variables. New aspects of networks introduced in this chapter include Markov random fields, which are used to estimate the networks, the betweenness index to show the location of “hubs” in the network, clustering of nodes, and assessment of model fit and robustness using unbiased methods such as bootstrapping. One application using the connectome measuring the degree of connectivity between neurons and regions in an individual’s brain is introduced together with the size of such systems (microscopic, macroscopic) and types of connectivity. Independent component analysis can look at changes in brain networks over time. A worked example fitting and using the aspects of networks discussed earlier in the chapter to interpret the results is presented using R functions at the end of the chapter.KeywordsNetwork analysisNodesEdgesLASSOBetweennessBootstrapCentrality indexNeural networkBrain connectome
Decreased fidelity of mnemonic representations plays a critical role in age-related episodic memory deficits, yet the brain mechanisms underlying such reductions remain unclear. Using functional and structural neuroimaging, we examined how changes in two key nodes of the posterior-medial network, the hippocampus and the angular gyrus (AG), might underpin loss of memory precision in older age. Healthy young and older adults completed a memory task that involved reconstructing object features on a continuous scale. Investigation of blood-oxygen-level-dependent (BOLD) activity during retrieval revealed an age-related reduction in activity reflecting successful recovery of object features in the hippocampus, whereas trial-wise modulation of BOLD signal by graded memory precision was diminished in the AG. Gray matter volume of the AG further predicted individual differences in memory precision in older age, beyond likelihood of successful retrieval. These findings provide converging evidence for a role of functional and structural integrity of the AG in constraining the fidelity of episodic remembering in older age, yielding new insights into parietal contributions to age-related episodic memory decline.
Musical training can offset age-related decline of speech perception in noisy environments. However, whether functional compensation or functional preservation the older musicians adopt to counteract the adverse effects of aging is unclear yet, so do older non-musicians. Here, we employed the fundamental brain organization feature named functional lateralization, and calculated network-based lateralization indices (LIs) of resting-state functional connectivity (FC) in 23 older musicians (OM), 23 older non-musicians (ONM), and 24 young non-musicians (YNM). OM outperformed ONM and almost equalized YNM in speech-in-noise/speech tasks. In parallel, ONM exhibited reduced lateralization than YNM in LI of intrahemispheric FC (LI_intra) in cingulo-opercular network (CON) and interhemispheric heterotopic FC (LI_he) in language network (LAN). Moreover, OM showed higher neural alignment to YNM (i.e., similar lateralization pattern) than ONM in LI_intra in CON, LAN, frontoparietal network (FPN) and default mode network (DMN) and LI_he in DMN. These findings suggest that musical training contributes to the preservation of youth-like lateralization in older adults. Furthermore, stronger left-lateralized and lower alignment-to-young of LI_intra in somatomotor network (SMN) and dorsal attention network (DAN) and LI_he in DMN correlated with better speech performance in ONM. In contrast, stronger right-lateralized LI_intra in FPN and DAN and higher alignment-to-young of LI_he in LAN correlated with better performance in OM. Thus, functional preservation and compensation of lateralization may play different roles in speech perception in noise for the elderly with and without musical expertise, respectively. Our findings provide insight into successful aging theories from the unique perspective of functional lateralization and speech perception.
Significance statement
As a positive lifestyle which contributes to neural resource enrichment, musical training experience may mitigate age-related decline in speech perception in noise through both functional compensation and preservation. What is unknown is whether older musicians rely more on one of these mechanisms, and how is it different from older non-musicians. From a unique perspective of functional lateralization, we found that high-performing older musicians showed stronger preservation of youth-like lateralization with a more right-lateralized pattern whereas high-performing older non-musicians were associated with stronger scaffolding of compensatory networks with a more left-lateralized pattern. Our findings suggest that older musicians and non-musicians exhibit different coping strategies in terms of functional lateralization against aging, which would largely enrich aging theories and inspire training intervention.
Although higher-order cognitive and lower-order sensorimotor abilities are generally regarded as distinct and studied separately, there is evidence that they not only covary but also that this covariation increases across the lifespan. This pattern has been leveraged in clinical settings where a simple assessment of sensory or motor ability (e.g. hearing, gait speed) can forecast age-related cognitive decline and risk for dementia. However, the brain mechanisms underlying cognitive, sensory, and motor covariation are largely unknown. Here, we examined whether such covariation in midlife reflects variability in common versus distinct neocortical networks using individualized maps of functional topography derived from BOLD fMRI data collected in 769 45-year-old members of a population-representative cohort. Analyses revealed that variability in basic motor but not hearing ability reflected individual differences in the functional topography of neocortical networks typically supporting cognitive ability. These patterns suggest that covariation in motor and cognitive abilities in midlife reflects convergence of function in higher-order neocortical networks and that gait speed may not be simply a measure of physical function but rather an integrative index of nervous system health.
The intrinsic organization of functional brain networks are known to change with age, and are affected by perceptual input and task conditions. Here, we compare functional activity and connectivity of auditory and reward systems during music listening and rest between young (N=24) and older (N=24) adults, using whole brain regression, seed-based connectivity, and ROI-ROI connectivity analyses. We found that although auditory and reward regions follow expected patterns of activation in response to music listening across both groups, younger adults show higher within-network connectivity of auditory and reward regions as compared to older adults during both rest and music listening. We also show that this age-related difference was reduced during music listening, especially in individuals showing high self-reported musical reward. Furthermore, young adults showed higher connectivity between auditory network and medial prefrontal cortex (mPFC) that was specific to music listening and varied as a function of self-reported musical liking. Meanwhile, older adults showed a more globally diffuse pattern of connectivity, including higher connectivity to bilateral lingual and inferior frontal gyri. Finally, connectivity between auditory and reward regions was higher during well-liked musical stimuli across all participants, and especially higher when listening to music selected by the participant. These results highlight the roles of aging and reward sensitivity on auditory and reward networks. Results may inform the design of music-based interventions in aging populations, and improve our understanding of functional network dynamics as a whole.
Abstract A neuropsychological model of memory is proposed that incorporates Fodor's (1983) idea of modules and central systems. The model has four essential components: (1) a non-frontal neocortical component that consists of perceptual (and perhaps interpretative semantic) modules that mediate performance on item-specific, implicit tests of memory, (2) a modular medial temporal/hippocampal component that mediates encoding, storage, and retrieval on explicit, episodic tests of memory that are associative/cue dependent, (3) a central system, frontal-lobe component that mediates performance on explicit tests that are strategic and on procedural tests that are rule-bound, and (4) a basal ganglia component that mediates performance on sensorimotor, procedural tests of memory. The usefulness of the modular/central system construct is explored and evidence from studies of normal, amnesic, agnosic, and demented people is provided to support the model.
Functional magnetic resonance imaging (fMRI) is a technique to map the brain, anatomically as well as physiologically, which does not require any invasive analysis. In order to obtain brain activation maps, the subject under study must perform a task or be exposed to an external stimulus. At the same time a large amount of images are acquired using ultra-fast sequences through magnetic resonance. Afterwards, these images are processed and analyzed with statistical algorithms. This study was made in collaboration with the consolidated Neuropsychology Research Group of the University of Barcelona, focusing on applications of fMRI for the study of brain function in images obtained with various subjects. This group performed a study which analyzed fMRI data, acquired with various subjects, using the General Linear Model (GLM). The aim of our work was to analyze the same fMRI data using Independent Component Analysis (ICA) and compare the results with those obtained through GLM. Results showed that ICA was able to find more active networks than GLM. The activations were found in frontal, parietal, occipital and temporal areas.
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This chapter discusses the theoretical and empirical literature that addresses aging and discourse comprehension. A series of five studies guided by a particular working memory viewpoint regarding the formation of inferences during discourse processing is described in the chapter. Compensatory strategies may be used with different degrees of likelihood across the life span largely as a function of efficiency with which inhibitory mechanisms function because these largely determine the facility with which memory can be searched. The consequences for discourse comprehension in particular may be profound because the establishment of a coherent representation of a message hinges on the timely retrieval of information necessary to establish coreference among certain critical ideas. Discourse comprehension is an ideal domain for assessing limited capacity frameworks because most models of discourse processing assume that multiple components, demanding substantially different levels of cognitive resources, are involved. For example, access to a lexical representation from either a visual array or an auditory message is virtually capacity free.
Long-term auditory-verbal memory comprises, at a neuropsychological level, a number of distinct cognitive processes. In the present study we determined the brain systems engaged during encoding (experiment 1) and retrieval (experiment 2) of episodic auditory-verbal material. In the separate experiments, PET measurements of regional cerebral blood flow (rCBF), an index of neural activity, were performed in normal volunteers during either the encoding or the retrieval of paired word associates. In experiment 1, a dual task interference paradigm was used to isolate areas involved in episodic encoding from those which would be concurrently activated by other cognitive processes associated with the presentation of paired associates, notably priming. In experiment 2, we used the cued retrieval of paired associates from episodic or from semantic memory in order to isolate the neural correlates of episodic memories. Encoding of episodic memory was associated with activation of the left prefrontal cortex and the retrosplenial area of the cingulate cortex, while retrieval from episodic memory was associated with activation of the precuneus bilaterally and of the right prefrontal cortex. These results are compatible with the patterns of activation reported in a previous PET memory experiment in which encoding and retrieval were studied concurrently. They also indicate that separate brain systems are engaged during the encoding and retrieval phases of episodic auditory-verbal memory. Retrieval from episodic memory engages a different, but overlapping, system to that engaged by retrieval from semantic memory, a finding that lends functional anatomical support to this neuropsychological distinction.
The effect of age on human striatal dopamine (DA) transporters was investigated with SPECT using the ligand [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT).
Iodine-123-beta-CIT binding in the striatum was examined in 28 healthy human subjects (14 men, 14 women) who ranged in age from 18 to 83 yr. Following injection with [123I]beta-CIT (mean +/- s.d. = 9.9 +/- 1.2 mCi), subjects were scanned with the brain-dedicated CERASPECT camera. A reconstructed transaxial slice 13.3-mm thick at the level of maximal striatal activity was used to determine tracer uptake in striatal and occipital regions of interest. The stability of regional uptake on Day 2 (approximately 18-24 hr postinjection) permitted estimation of the specific-to-nondisplaceable equilibrium partition coefficient: V3", calculated as (striatal--occipital)/occipital uptake at equilibrium.
Values of V3" ranged from 3.6 to 11.4 for this sample (6.7 +/- 1.9). V3" showed a significant inverse correlation with age (r = -0.73, n = 28, p < 0.0001). Linear regression analysis revealed that V3" declined by 51% over the age range studied or approximately 8% per decade.
These findings confirm postmortem reports of dopamine transporter loss with aging. In vivo methodologies may permit the age-related degeneration of dopamine nerve terminals to be studied in relation to the cognitive and motor deficits that occur in normal aging.
Event-related potentials and behavioral measures were obtained from young and elderly subjects while they performed two different auditory delayed match-to-sample tasks. In each experiment, subjects had to indicate whether an initial and a subsequent test sound were identical in two different conditions: one filled with distracting tone pips and one with no distractors. Electrophysiologically, elderly subjects had reduced attention-related activity over frontal regions. In addition, the distracting stimuli elicited an enhanced primary auditory evoked response in the elderly. The percentage of perseverative errors on the Wisconsin card sorting test, a putative measure of frontal lobe function, was positively correlated with the amplitude of the primary auditory evoked response in elderly subjects. Behaviorally, elderly subjects were impaired by distractors at long but not short delays. Taken together, these results suggest that increased distractibility and impaired sustained attention with aging may be due to altered prefrontal cortex function. These data support the loss of prefrontal suppression over the primary auditory regions with aging.
The electrogenesis of synaptically activated dendritic Ca2+-mediated potentials, which may contribute to synaptic signal integration in pyramidal cells, was examined in rat layers V-VI prefrontal cortical (PFC) neurons in vitro. Intrasomatically recorded suprathreshold synaptic responses evoked by stimulation of the distal dendrites were attenuated by focal Cd2+ application to the proximal apical dendritic stem (100-200 micron from soma), but not to the apical dendritic tuft (>500 micron from soma). With use of intracellular QX-314 and Cs+ to block Na+ and K+ currents, intrasomatic recordings revealed that the Cd2+-induced attenuation of synaptic responses was attributable to the blockade of a dendritic Ca2+-mediated "hump" potential and high-threshold Ca2+ spike activated by NMDA EPSPs. The hump potential was not blocked by bath application of Ni2+ (100 microM) but was blocked by focal application of Cd2+ to the proximal but not distal apical dendrites, suggesting that it was generated by Ca2+ channels located in the proximal dendrites. Direct patch-clamp recordings made from the distal apical tuft of layers V-VI PFC neurons revealed that layers I-II synaptic stimulation or intradendritic depolarizing current pulses evoked tetrodotoxin- and QX-314-sensitive Na+ spikes. Unlike in the stem of the apical dendrite, Ca2+ spikes were not easily evoked in the distal apical tuft when Na+ channels were blocked. When triggered, the Cd2+-sensitive Ca2+ spikes in the dendritic tuft were nonregenerative and had very high activation thresholds (approximately +10 mV). These results suggested that the high voltage-activated Ca2+ potentials that amplify distal EPSPs are primarily generated in the proximal stem of the apical dendrite and not within the fine dendritic branches of the apical tuft of layers V-VI PFC neurons.
The purpose of this study was to evaluate the effects of age on D2 receptor binding with 123I-iodobenzofuran (IBF) SPECT.
Subjects were 40 healthy volunteers (age 19-83 yr), including 6 who had test/retest studies. Scans were acquired with a triple-head SPECT camera 3 hr postinjection of IBF (300 MBq). Striatal regions (caudate and putamen) were defined by two different region-of-interest (ROI) sets consisting of large volumes [(CLVs), 2.2 and 6.6 m] and small volumes [(SVs), 0.6 and 1.3 ml]. D2 binding (Rv=V3/V2) was quantified using our previously proposed multilinear regression technique. Effects of age on D2 binding were evaluated by fitting linear, exponential and logarithmic models.
The mean Rvs were 26% lower than LV for both putamen and caudate than the corresponding values from the SV due to the partial-volume effect. Although the identifiability of Rv using SV deteriorated slightly, the test/retest reproducibility of Rv measurements was equally excellent for LV and SV. The mean Rvs were 11% higher for putamen compared with those for caudate. D2 binding declined significantly with age (p < 10(-5)) for all three models. The nonlinear models were slightly superior to the linear model in describing the relationship between Rv and age. In these models, D2 binding declined with age, equally for caudate and putamen at 7%-13% per decade; the decline was progressively smaller with age.
IBF SPECT permitted reliable measurements of D2 binding in the caudate or putamen separately using small ROI volumes that significantly improved the quantitation loss from the partial-volume effect. Our results agreed with previous PET and postmortem findings of D2 binding losses with age. However, these age effects may be nonlinear. Age-related changes in D2 binding must be taken into consideration in clinical IBF SPECT investigations.
Younger and older adults were asked to find a single target in both feature- and conjunction- search conditions. Display size varied between 2 and 8 items, and target-distractor similarity ranged from relatively low to high levels. The accuracy data indicated that older adults had particular difficulty finding targets in high-similarity conjunction-search displays containing a large number of distractors. The reaction time (RT) analyses found larger age deficits in many of these same conditions. For both groups, predictions of conjunction search based on Treisman and Sato's additive model (Journal of Experimental Psychology: Human Perception and Performance, 1990: 16, 459-478) departed significantly from actual performance. The RT data of older observers were, in large part, predicted as a simple linear function of the young adults' data. These results are discussed with respect to age differences in selective attention, generalized slowing, and an age-related loss in search efficiency.
The temporal characteristics of the BOLD response in sensorimotor and auditory cortices were measured in subjects performing finger tapping while listening to metronome pacing tones. A repeated trial paradigm was used with stimulus durations of 167 ms to 16 s and intertrial times of 30 s. Both cortical systems were found to be nonlinear in that the response to a long stimulus could not be predicted by convolving the 1-s response with a rectangular function. In the short-time regime, the amplitude of the response varied only slowly with stimulus duration. It was found that this character was predicted with a modification to Buxton's balloon model. Wiener deconvolution was used to deblur the response to concatenated short episodes of finger tapping at different temporal separations and at rates from 1 to 4 Hz. While the measured response curves were distorted by overlap between the individual episodes, the deconvolved response at each rate was found to agree well with separate scans at each of the individual rates. Thus, although the impulse response cannot predict the response to fully overlapping stimuli, linear deconvolution is effective when the stimuli are separated by at least 4 s. The deconvolution filter must be measured for each subject using a short-stimulus paradigm. It is concluded that deconvolution may be effective in diminishing the hemodynamically imposed temporal blurring and may have potential applications in quantitating responses in eventrelated fMRI.
The topographic organization of cortical neurons is traditionally examined using histological procedures. Functional magnetic resonance imaging (fMRI) offers the potential noninvasively to detect interregional connectivity of human brain. In the brain, there is spontaneous firing of neurons even in the resting state. Such spontaneous firing will increase local blood flow, cause MRI signal fluctuations, and affect remotely located neurons through the efferent output. By calculating covariance of each voxel referenced to the time course of a selected brain region, it is possible to detect the neurons connected to the selected region. Using this covariance method, neural connectivity to primary motor cortex was assessed during a resting state in six healthy right-handed volunteers. This interregional connectivity is similar to connectivity established by other anatomical, histochemical, and physiological techniques. This method may offer in vivo noninvasive measurements of neural projections.
99mTc-TRODAT-1 is a new radiopharmaceutical that selectively binds the dopamine transporters. This study characterized the effects of aging on its regional cerebral distribution in healthy human volunteers.
The sample consisted of 27 men and 28 women with a mean age of 41.1 +/- 17.1 y (age range 18.7-73.8 y). Dynamic SPECT scans of the brain were obtained with a standardized acquisition and processing protocol on a triple-head camera. Mean counts per pixel were measured in multiple regions of interest within each basal ganglia. Regression analyses were used to relate the specific uptake values at 3-4 h after administration to age. Both linear and nonlinear models of aging were tested.
The relative concentration of radioactivity in most subregions of the basal ganglia decreased significantly with age (all P values < 0.0001). Nonlinear models of aging fit the data significantly better than a straight line. The rate of decline was significantly faster in young adults than in older volunteers (P < 0.001). The break-point age at which the rate of change slowed down and became more stable was 36 y old for the whole striatum and ranged from 32 to 44 y old depending on subregion.
The effects of aging on central nervous system dopamine transporters do not appear to be linear. Most effects seem to occur during young adulthood before people reach their 40s. The distribution then appears to remain relatively stable until late in life. The findings suggest that the adult life cycle is better characterized as a series of phases than as a continuum.
In two experiments, the effects of taxing selective attention processes on the efficiency of working memory processes were considered in relation to normal aging. In both experiments, the presence of task-irrelevant information disrupted the efficiency of working memory processes, and the effect was generally greater for older than for younger adults. The presence of distracting information increased the frequency of intrusion errors in both younger and older adults and of memory-based errors in older adults. These findings suggest that distraction disrupts both the ability to maintain a coherent stream of goal-directed thought and action in younger and older adults and the encoding and retention of relevant information in older adults.
Age-related decline in working memory figures prominently in theories of cognitive aging. However, the effects of aging on the neural substrate of working memory are largely unknown. Positron emission tomography (PET) was used to investigate verbal and spatial short-term storage (3 sec) in older and younger adults. Previous investigations with younger subjects performing these same tasks have revealed asymmetries in the lateral organization of verbal and spatial working memory. Using volume of interest (VOI) analyses that specifically compared activation at sites identified with working memory to their homologous twin in the opposite hemisphere, we show pronounced age differences in this organization, particularly in the frontal lobes: In younger adults, activation is predominantly left lateralized for verbal working memory, and right lateralized for spatial working memory, whereas older adults show a global pattern of anterior bilateral activation for both types of memory. Analyses of frontal subregions indicate that several underlying patterns contribute to global bilaterality in older adults: most notably, bilateral activation in areas associated with rehearsal, and paradoxical laterality in dorsolateral prefrontal sites (DLPFC; greater left activation for spatial and greater right activation for verbal). We consider several mechanisms that could account for these age differences including the possibility that bilateral activation reflects recruitment to compensate for neural decline.
Aging is an independent risk factor for the development of atherosclerosis, a vascular abnormality that plays a significant role in the development of many cardiovascular disorders. Animal experiments have demonstrated that aging predisposes the vasculature to advanced atherosclerotic disease and vessel injury and that this predisposition is a function of age-associated changes in the vessel wall itself. Because vascular smooth muscle cells play important roles in the pathogenesis of many vascular disorders, identifying age-associated differences in the way these cells respond to extracellular clues has been an area of active research. Currently, the most remarkable differences in intracellular signaling between vascular smooth muscle cells isolated from young and old animals are related to the control of cell migration through the CamKII pathways and the accelerated transition of older vascular smooth muscle cells from the contractile to the synthetic phenotype. These differences may be due to alternative signaling pathways revealed by the inability of older cells to respond to inhibitors, such as transforming growth factor (TGF)-beta1, or to altered interactions with the extracellular matrix resulting from age-associated shifts in integrin expression or changes in the matrix composition of blood vessels. The exact role that these alterations have in explaining age-associated differences in the response of the vessel wall to injury and its increased susceptibility to developing advanced atherosclerotic lesions remains to be determined but will be guided by studies on intracellular signaling mechanisms.
A baseline or control state is fundamental to the understanding of most complex systems. Defining a baseline state in the human brain, arguably our most complex system, poses a particular challenge. Many suspect that left unconstrained, its activity will vary unpredictably. Despite this prediction we identify a baseline state of the normal adult human brain in terms of the brain oxygen extraction fraction or OEF. The OEF is defined as the ratio of oxygen used by the brain to oxygen delivered by flowing blood and is remarkably uniform in the awake but resting state (e.g., lying quietly with eyes closed). Local deviations in the OEF represent the physiological basis of signals of changes in neuronal activity obtained with functional MRI during a wide variety of human behaviors. We used quantitative metabolic and circulatory measurements from positron-emission tomography to obtain the OEF regionally throughout the brain. Areas of activation were conspicuous by their absence. All significant deviations from the mean hemisphere OEF were increases, signifying deactivations, and resided almost exclusively in the visual system. Defining the baseline state of an area in this manner attaches meaning to a group of areas that consistently exhibit decreases from this baseline, during a wide variety of goal-directed behaviors monitored with positron-emission tomography and functional MRI. These decreases suggest the existence of an organized, baseline default mode of brain function that is suspended during specific goal-directed behaviors.
In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons activated by the attended stimulus showed increased gamma-frequency (35 to 90 hertz) synchronization but reduced low-frequency (<17 hertz) synchronization compared with neurons at nearby V4 sites activated by distracters. Because postsynaptic integration times are short, these localized changes in synchronization may serve to amplify behaviorally relevant signals in the cortex.
In crowded visual scenes, attention is needed to select relevant stimuli. To study the underlying mechanisms, we recorded
neurons in cortical area V4 while macaque monkeys attended to behaviorally relevant stimuli and ignored distracters. Neurons
activated by the attended stimulus showed increased gamma-frequency (35 to 90 hertz) synchronization but reduced low-frequency
(<17 hertz) synchronization compared with neurons at nearby V4 sites activated by distracters. Because postsynaptic integration
times are short, these localized changes in synchronization may serve to amplify behaviorally relevant signals in the cortex.
Introduction: Independent component analysis (ICA) has been used to analyze single-subject fMRI data sets (1,2). A principal advantage of this approach is its applicability to cognitive paradigms for which detailed models of brain activity are not available. However, unlike univariate methods (e.g., regression, K-S statistics), ICA does not naturally generalize to a method suitable for drawing inferences about groups of subjects. We present here for the first time a method for drawing group inferences using ICA of fMRI data, and its application to a simple visual paradigm. Theory: We assume a set of independent hemodynamic source locations in the brain (indicated by s_i(v) for the vth voxel in the ith subject) which are linearly mixed by their hemodynamic time courses. This linear mixing is represented by the matrix A_i and results in u_i(v). We assume K_i time points were acquired and that there are more time points than brain sources. The fMRI sampling of the brain's hemodynamics results in y_i(v). Our goal then is to estimate the hemodynamic sources. Our method contains three stages: (a) spatial normalization and data reduction, (b) independent source estimation, (c) group inference.
Because of the sharp curvature of the retrosplenial region around the splenium of the corpus callosum, standard coronal sections are not appropriate for architectonic analysis of its posteroventral part. In the present study, examination of the posteroventral retrosplenial region of the rhesus monkey in sections that were orthogonal to its axis of curvature (and therefore appropriate for architectonic analysis) has permitted definition of its architecture and precise extent. This analysis demonstrated that areas 29 and 30 of the retrosplenial cortex, as well as adjacent area 23 of the posterior cingulate cortex, extend together as an arch around the splenium of the corpus callosum and maintain their topographical relationship with one another throughout their entire course. Injections of anterograde and retrograde tracers confined to retrosplenial area 30 revealed that this area has reciprocal connections with adjacent areas 23, 19 and PGm, with the mid-dorsolateral part of the prefrontal cortex (areas 9, 9/46 and 46), with multimodal area TPO in the superior temporal sulcus, as well as the posterior parahippocampal cortex, the presubiculum and the entorhinal cortex. There are also bidirectional connections with the lateroposterior thalamic nucleus, as well as the laterodorsal and the anteroventral limbic thalamic nuclei. The connectivity of area 30 suggests that it may play a role in working memory processes subserved by the mid-dorsolateral frontal cortex in interaction with the hippocampal system.
Statistical parametric maps are spatially extended statistical processes that are used to test hypotheses about regionally specific effects in neuroimaging data. The most established sorts of statistical parametric maps (e.g., Friston et al. [1991]: J Cereb Blood Flow Metab 11:690–699; Worsley et al. [1992]: J Cereb Blood Flow Metab 12:900–918) are based on linear models, for example ANCOVA, correlation coefficients and t tests. In the sense that these examples are all special cases of the general linear model it should be possible to implement them (and many others) within a unified framework. We present here a general approach that accomodates most forms of experimental layout and ensuing analysis (designed experiments with fixed effects for factors, covariates and interaction of factors). This approach brings together two well established bodies of theory (the general linear model and the theory of Gaussian fields) to provide a complete and simple framework for the analysis of imaging data.
The importance of this framework is twofold: (i) Conceptual and mathematical simplicity, in that the same small number of operational equations is used irrespective of the complexity of the experiment or nature of the statistical model and (ii) the generality of the framework provides for great latitude in experimental design and analysis.
Functional magnetic resonance imaging (fMRI) was conducted to observe the effects of cocaine administration on the physiological fluctuations of fMRI signal in two brain regions. Seven long-term cocaine users with an average age of 32 years and 8 years of cocaine use history were recruited for the study. A T2*-weighted fast echo-planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three sets of brain images for each subject under three conditions (at rest, after saline injection, and after cocaine injection [0.57 mg/kg]). Cross-correlation maps were constructed using the synchronous, low frequency signal from voxel time courses after filtering respiratory, cardiac, and other physiological noise. A quantitative evaluation of the changes in functional connectivity was made using spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC values in the region of primary visual cortex and 43% reduction in SCC values in the region of primary motor cortex were observed after cocaine administration. This significant reduction in SCC values in these cortical regions is a reflection of changes in neuronal activity. It is suggested that the observed changes in low frequency components after acute cocaine administration during a resting, no-task situation may be used as a baseline reference source when assessing the effects of cocaine on task-driven activation or on mesolimbic dopamine pathways. Magn Reson Med 43:45–51, 2000. © 2000 Wiley-Liss, Inc.
An MRI time course of 512 echo-planar images (EPI) in resting human brain obtained every 250 ms reveals fluctuations in signal intensity in each pixel that have a physiologic origin. Regions of the sensorimotor cortex that were activated secondary to hand movement were identified using functional MRI methodology (FMRI). Time courses of low frequency (<0.1 Hz) fluctuations in resting brain were observed to have a high degree of temporal correlation (P < 10−3) within these regions and also with time courses in several other regions that can be associated with motor function. It is concluded that correlation of low frequency fluctuations, which may arise from fluctuations in blood oxygenation or flow, is a manifestation of functional connectivity of the brain.
We study dynamical synchronization in a model of a neural system constituted by local networks of densely interconnected excitatory and inhibitory neurons. Neural dynamics are determined by voltage- and ligand-gated ion channels. Coupling between the local networks is introduced via sparse excitatory connectivity. With modulation of this long-range synaptic coupling the system undergoes a transition from independent oscillations to chaotic synchronization. Between these states exists a 'weakly’ stable state with epochs of synchronization and complex intermittent desynchronization. This may facilitate adaptive brain function by engendering a diverse repertoire of dynamics and contribute to the genesis of complexity in the EEG.
This paper presents a general approach to the analysis of functional MRI time-series from one or more subjects. The approach is predicated on an extension of the general linear model that allows for correlations between error terms due to physiological noise or correlations that ensue after temporal smoothing. This extension uses the effective degrees of freedom associated with the error term. The effective degrees of freedom are a simple function of the number of scans and the temporal autocorrelation function. A specific form for the latter can be assumed if the data are smoothed, in time, to accentuate hemodynamic responses with a neural basis. This assumption leads to an expedient implementation of a flexible statistical framework. The importance of this small extension is that, in contradistinction to our previous approach, any parametric statistical analysis can be implemented. We demonstrate this point using a multiple regression analysis that tests for effects of interest (activations due to word generation), while taking explicit account of some obvious confounds.
Responses of neurons in monkey visual cortex are modulated when attention is directed into the receptive field of the neuron: the gain or sensitivity of the response is increased or the synchronization of the spikes to the local field potential (LFP) is increased. We investigated, using model simulations, whether the synchrony of inhibitory networks could link these observations. We found that, indeed, an increase in inhibitory synchrony could enhance the coherence of the model neurons with the simulated LFP, and could have different effects on the firing rate. When the firing rate vs. current (f-I) response curves saturated at high I, attention yielded a shift in sensitivity; alternatively, when the f-I curves were non-saturating, the most significant effect was on the gain of the response. This suggests that attention may act through changes in the synchrony of inhibitory networks.
A fundamental characteristic of working memory is that its capacity to handle information is limited. While there have been many brain mapping studies of working memory, the physiological basis of its capacity limitation has not been explained. We identified characteristics of working memory capacity using functional magnetic resonance imaging (fMRI) in healthy subjects. Working memory capacity was studied using a parametric ‘ n -back’ working memory task involving increasing cognitive load and ultimately decreasing task performance. Loci within dorsolateral prefrontal cortex (DLPFC) evinced exclusively an ‘inverted-U’ shaped neuro- physiological response from lowest to highest load, consistent with a capacity-constrained response. Regions outside of DLPFC, in contrast, were more heterogeneous in response and often showed early plateau or continuously increasing responses, which did not reflect capacity constraints. However, sporadic loci, including in the premotor cortex, thalamus and superior parietal lobule, also demon- strated putative capacity-constrained responses, perhaps arising as an upstream effect of DLPFC limitations or as part of a broader network-wide capacity limitation. These results demonstrate that regionally specific nodes within the working memory network are capacity-constrained in the physiological domain, providing a missing link in current explorations of the capacity characteristics of working memory.
The effects of age (19-100 years) upon dopamine uptake sites labeled with [3H]GBR-12935 in human postmortem putamen from 20 individuals were studied. There was a 70% decrease in binding density (Bmax) over the adult age range. No significant changes in binding affinity (Kd) were detected, the mean Kd being 1.0 +/- 0.2 nM (mean +/- S.E.M.). Nor were there any changes in binding related to the postmortem delay. Based on the findings that [3H]GBR-12935 labels the uptake site for dopamine, it is suggested that the age-related loss of [3H]GBR-12935 binding in human putamen reflects a degeneration of dopamine neurites.
Since spontaneous oral dyskinesias are more prevalent in the elderly, and since these movements may be controlled by the balance of brain dopamine D1 and D2 dopamine receptors, we measured the densities of these receptors in 247 postmortem brain striata. In childhood, the densities of D1 and D2 dopamine receptors in the brain striatum rise and fall together. After age 20 years, D1 receptors disappear at 3.2% per decade while D2 receptors disappear at about 2.2% per decade. Overall, therefore, the D1/D2 ratio falls with age. Since perioral motion in rats is dominated by a high D1/D2 ratio, the observed decline in the human D1/D2 ratio with age suggests that the perioral control mechanisms for humans and rats may be different.
The need for a simply applied quantitative assessment of handedness is discussed and some previous forms reviewed. An inventory of 20 items with a set of instructions and response- and computational-conventions is proposed and the results obtained from a young adult population numbering some 1100 individuals are reported. The separate items are examined from the point of view of sex, cultural and socio-economic factors which might appertain to them and also of their inter-relationship to each other and to the measure computed from them all. Criteria derived from these considerations are then applied to eliminate 10 of the original 20 items and the results recomputed to provide frequency-distribution and cumulative frequency functions and a revised item-analysis. The difference of incidence of handedness between the sexes is discussed.
Anterograde and retrograde tracing methods including autoradiography, horseradish peroxidase histochemistry and fluorescent dye transport were used to demonstrate that the dorsolateral prefrontal cortex is connected with the hippocampal formation and associated cortical regions by two distinct pathways. Fibers forming a lateral pathway travel in the fronto-occipital fasciculus and connect the dorsolateral prefrontal cortex with the fundus of the rhinal sulcus, posterior subdivisions of the parahippocampal gyrus, and the presubiculum. A larger medial pathway forms in the cingulum bundle and terminates in the most caudal part of the presubiculum, as well as in adjacent transitional cortices. These cortices form a caudomedial promontory that is located between the posterior cingulate and prestriate areas. In all allo- and mesocortical targets of prefrontal cortex, labeled terminals form banding patterns reminiscent of the columnar organization of afferent fiber columns in neocortex. The same cytoarchitectonic areas that receive prefrontal afferents issue reciprocal projections. The largest source is the caudomedial lobule including its presubicular portion. Neurons in the parahippocampal gyrus and adjacent presubiculum also are retrogradely labeled following implants of horseradish peroxidase or injection of fluorescent dyes into prefrontal cortex. In addition, subicular neurons project to the prefrontal cortex although the subiculum does not appear to receive prefrontal afferent input. These findings emphasize that multiple channels of communication link the dorsolateral prefrontal cortex and the hippocampus via the parahippocampal gyrus, subiculum, presubiculum and adjacent transitional cortices. We speculate that each of these prefrontal projections may carry highly specific information into the hippocampus, whereas the reciprocal projections may allow retrieval by prefrontal cortex of memories stored in the hippocampus.
Administered a modified Stroop Color-Word Test to 80 healthy males aged 21-90 years as part of a study of neuropsychological functioning. No age differences were demonstrated on simple reading tasks; however, significant age effects were observed for the color naming and interference tasks (ps less than .001). Ss in the oldest age groups (61-70 and 71-90 years) performed more slowly than younger individuals on both of these. Of a variety of tests administered, performance on the Stroop Test was most affected by age. Because impairment on Stroop color naming and interference tests appears to be a concomitant of normal aging, caution should be exercised when one is interpreting Stroop test results from older patients with suspected cerebral dysfunction.
According to most behavioural, electrophysiological, and clinical studies, the cingulate gyrus is widely thought to be involved in regulation of emotional life, reactivity to painful stimuli, memory processing, and attention to sensory stimuli. Anatomically the cingulate cortex is composed of two distinct areas numbered 24 and 23 in Brodmann's classification. We have investigated the connections of the cingulate gyrus in monkeys, using horseradish peroxydase and radioautographic techniques, in order to verify the hypothesis of an anatomical complementarity of these cytoarchitectonic subdivisions. The posterior cingulate gyrus (area 23) is specifically connected with the associative temporal cortex, the medial temporal and orbitofrontal cortices, and with the medial pulvinar. The anterior cingulate gyrus (area 24) is related to the intralaminar, mediodorsal, and ventral anterior thalamic nuclei, the amygdala, and the nucleus accumbens septi. The two cingulate areas were found to be interconnected and to have, in common, connections with the 'limbic' thalamic nuclei (AM, AV, LD), the caudate nucleus, the claustrum, the lateral frontal and the posterior parietal (area 7) cortices.
In this study, the impact of two perceptual factors, feature similarity and spacing, on age-related differences in performance and psychophysiological measures were investigated within a focused attention paradigm. Young and old subjects performed an Eriksen letter identification task, in which centrally presented targets were flanked by response-compatible or response-incompatible letters. In feature similarity conditions, targets and flankers had a low or high amount of feature overlap. In spacing conditions, flankers were presented at four different lateral positions from the target. In the condition with high feature overlap and shortest target-flanker distance, old subjects showed greater interference by incompatible flankers than young subjects. Feature similarity was of little influence on age-related differences. However, spacing turned out to be of critical importance. Age-related interference effects disappeared when the target-flanker distance increased. This appears to be due to a decrease in response competition.
Friston et al. (1995, NeuroImage 2:45-53) presented a method for detecting activations in fMRI time-series based on the general linear model and a heuristic analysis of the effective degrees of freedom. In this communication we present corrected results that replace those of the previous paper and solve the same problem without recourse to heuristic arguments. Specifically we introduce a proper and unbiased estimator for the error terms and provide a more generally correct expression for the effective degrees of freedom. The previous estimates of error variance were biased and, in some instances, could have led to a 10-20% overestimate of Z values. Although the previous results are almost correct for the random regressors chosen for validation, the present theoretical results are exact for any covariate or waveform. We comment on some aspects of experimental design and data analysis, in the light of the theoretical framework discussed here.
Striatal dopamine reuptake sites were studied with PET in Alzheimer's disease (AD). A cocaine analogue, [11C]beta-CFT was used as a radioligand. In patients with AD, the reduction in [11C]beta-CFT uptake was about 20% from the age-adjusted mean value in control subjects, both in the putamen (p = 0.002) and in the caudate nucleus (p = 0.002). Thus, the putamen and the caudate nucleus were equally affected, in contrast to Parkinson's disease, which shows predominantly putaminal reduction. We found that the smaller the [11C]beta-CFT uptake in the putamen or in the caudate nucleus, the more severe the extrapyramidal symptoms. In healthy volunteers (nine women, six men; aged 23 to 70 years), [11C]beta-CFT uptake was reduced with age, both in the putamen (r = -0.70, p < 0.01) and in the caudate nucleus (r = -0.77, p < 0.001). The average decline per decade was 4.4% in the putamen and 4.7% in the caudate nucleus. We conclude that the brain dopaminergic system is affected in AD because the striatal uptake of the dopamine reuptake ligand [11C]beta-CFT is decreased. This reduction in [11C]beta-CFT uptake correlates with the severity of the extrapyramidal symptoms of the patients.
Aging of the human brain is associated with a decline in dopamine (DA) function, generally interpreted as reflecting DA cell loss. Positron emission tomography studies revealed that in healthy individuals, the age-related losses in DA transporters (presynaptic marker) were associated with losses in D2 receptors (postsynaptic marker) rather than with increases as is known to occur with DA cell loss. This association was specific for DA synaptic markers, because they were not correlated with striatal metabolism. Furthermore, the association was independent of age, suggesting that a common mechanism regulates the expression of receptors and transporters irrespective of age.
We measured the time lags between the start or end of tasks and signal changes in functional MRI (fMRI) for various age groups and evaluated the age correlation of the time lags.
Forty subjects, 20-76 years old, were evaluated. fMRI was performed with and echo planar imaging sequence at 0.5 s intervals. We measured the time for the signal of the precentral gyrus to make a half-maximal increase after starting the task (T-inc) and the time to reach the initial level after ceasing the task (T-dec).
Average T-inc was 3.09 s and T-dec was 6.63 s. The values of T-inc could be correlated to age. T-dec had no age correlation.
The time lag in fMRI was revealed to be prolonged with increasing age. Our results suggest that the time lag in fMRI is influenced by some factors associated with aging.
Unbiased disector stereologic cell counting was applied to sections from the human substantia nigra that were immunostained by using a monoclonal antibody against the dopamine transporter (DAT). This antibody was found to penetrate the full thickness of the stained section. Quantification of the number of DAT immunostained neurons was performed in human cases stratified into three age groups, young (ages 0-49 years), middle aged (ages 50-69 years), and aged (ages 70-85 years). The number of DAT-immunoreactive nigral neurons was normalized for each case by constructing a ratio of the number of DAT-containing neurons to total number of neuromelanin-containing cells in each subject's sample. Three types of DAT nigral neurons were seen: type 1, intensely stained; type 2, lightly stained; and type 3, DAT-immunonegative neuromelanin-containing perikarya. By 50 years of age, the number of type 1 neurons decreased significantly (P < 0.0001), whereas the number of type 2 neurons increased with age (P < 0.0001). Type 3 neurons also increased with age (P < 0.01), although less robustly than type 2 neurons. Type 1 neurons decreased by 11.2% per decade, and the total number of nigral neurons (types 1-3) decreased by 6.7% per decade. Relative to the young group, there were 75% and 88% reductions in type 1 neurons in the middle-aged and aged groups, respectively. This contrasts with the 35% and 41% reductions in total number of neuromelanin-containing neurons seen in middle-aged and aged groups, respectively. The young group had significantly more type 1 neurons and fewer type 2 neurons compared with middle-aged and aged participants. Post-hoc analyses indicated that the young group had significantly fewer type 3 neurons compared with middle-aged and aged participants. These findings demonstrate an age-related reduction in the number of substantia nigra DAT-immunoreactive neurons. Therefore, insight into the mechanisms regulating the rate of DAT synthesis may aid in our understanding of the decline of DATs with aging and its functional significance.
Because of the sharp curvature of the retrosplenial region around the splenium of the corpus callosum, standard coronal sections are not appropriate for architectonic analysis of its posteroventral part. In the present study, examination of the posteroventral retrosplenial region of the rhesus monkey in sections that were orthogonal to its axis of curvature (and therefore appropriate for architectonic analysis) has permitted definition of its architecture and precise extent. This analysis demonstrated that areas 29 and 30 of the retrosplenial cortex, as well as adjacent area 23 of the posterior cingulate cortex, extend together as an arch around the splenium of the corpus callosum and maintain their topographical relationship with one another throughout their entire course. Injections of anterograde and retrograde tracers confined to retrosplenial area 30 revealed that this area has reciprocal connections with adjacent areas 23, 19 and PGm, with the mid-dorsolateral part of the prefrontal cortex (areas 9, 9/46 and 46), with multimodal area TPO in the superior temporal sulcus, as well as the posterior parahippocampal cortex, the presubiculum and the entorhinal cortex. There are also bidirectional connections with the lateroposterior thalamic nucleus, as well as the laterodorsal and the anteroventral limbic thalamic nuclei. The connectivity of area 30 suggests that it may play a role in working memory processes subserved by the mid-dorsolateral frontal cortex in interaction with the hippocampal system.
Functional magnetic resonance imaging (fMRI) was conducted to observe the effects of cocaine administration on the physiological fluctuations of fMRI signal in two brain regions. Seven long-term cocaine users with an average age of 32 years and 8 years of cocaine use history were recruited for the study. A T2*-weighted fast echo-planar imaging (EPI) pulse sequence was employed at 1.5 T to acquire three sets of brain images for each subject under three conditions (at rest, after saline injection, and after cocaine injection [0.57 mg/kg]). Cross-correlation maps were constructed using the synchronous, low frequency signal from voxel time courses after filtering respiratory, cardiac, and other physiological noise. A quantitative evaluation of the changes in functional connectivity was made using spatial correlation coefficient (SCC) analysis. A marked 50% reduction in SCC values in the region of primary visual cortex and 43% reduction in SCC values in the region of primary motor cortex were observed after cocaine administration. This significant reduction in SCC values in these cortical regions is a reflection of changes in neuronal activity. It is suggested that the observed changes in low frequency components after acute cocaine administration during a resting, no-task situation may be used as a baseline reference source when assessing the effects of cocaine on task-driven activation or on mesolimbic dopamine pathways.
The study examined the influence of losses in dopaminergic function on age-related cognitive deficits.
Eleven healthy subjects (21-68 years of age) completed a set of cognitive tasks used to assess perceptual speed and episodic memory. D(2) receptor binding was measured in the caudate and the putamen by using positron emission tomography.
A gradual age-related deterioration was found for all cognitive tasks and for D(2) binding in both striatal structures. Statistical control of D(2) binding eliminated the age-related cognitive variation, whereas residual effects of D(2) binding were seen after the analysis controlled for age.
D(2) receptor binding is a more important factor than chronological age in accounting for variation in cognitive performance across the adult lifespan. Changes in dopaminergic neurotransmission play an important role in aging-related cognitive decline.