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1.  Using Network Science to Evaluate Exercise-Associated Brain Changes in Older Adults 
Literature has shown that exercise is beneficial for cognitive function in older adults and that aerobic fitness is associated with increased hippocampal tissue and blood volumes. The current study used novel network science methods to shed light on the neurophysiological implications of exercise-induced changes in the hippocampus of older adults. Participants represented a volunteer subgroup of older adults that were part of either the exercise training (ET) or healthy aging educational control (HAC) treatment arms from the Seniors Health and Activity Research Program Pilot (SHARP-P) trial. Following the 4-month interventions, MRI measures of resting brain blood flow and connectivity were performed. The ET group's hippocampal cerebral blood flow (CBF) exhibited statistically significant increases compared to the HAC group. Novel whole-brain network connectivity analyses showed greater connectivity in the hippocampi of the ET participants compared to HAC. Furthermore, the hippocampus was consistently shown to be within the same network neighborhood (module) as the anterior cingulate cortex only within the ET group. Thus, within the ET group, the hippocampus and anterior cingulate were highly interconnected and localized to the same network neighborhood. This project shows the power of network science to investigate potential mechanisms for exercise-induced benefits to the brain in older adults. We show a link between neurological network features and CBF, and it is possible that this alteration of functional brain networks may lead to the known improvement in cognitive function among older adults following exercise.
doi:10.3389/fnagi.2010.00023
PMCID: PMC2893375  PMID: 20589103
hippocampus; exercise; fitness; aging; perfusion; networks; small-world; fMRI
2.  Multimodal intervention in older adults improves resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe† 
The prefrontal cortex and medial temporal lobe are particularly vulnerable to the effects of aging. The disconnection between them is suggested to be an important cause of cognitive decline in normal aging. Here, using multimodal intervention training, we investigated the functional plasticity in resting-state connectivity of these two regions in older adults. The multimodal intervention, comprised of cognitive training, Tai Chi exercise, and group counseling, was conducted to explore the regional connectivity changes in the default-mode network, as well as changes in prefrontal-based voxel-wise connectivity in the whole brain. Results showed that the intervention selectively affected resting-state functional connectivity between the medial prefrontal cortex and medial temporal lobe. Moreover, the strength of resting-state functional connectivity between these regions correlated with individual cognitive performance. Our results suggest that multimodal intervention could postpone the effects of aging and improve the function of the regions that are most heavily influenced by aging, as well as play an important role in preserving the brain and cognition during old age.
doi:10.3389/fnagi.2014.00039
PMCID: PMC3948107  PMID: 24653698
intervention; plasticity; aging; fMRI; functional connectivity
3.  Aging Brain from a Network Science Perspective: Something to Be Positive About? 
PLoS ONE  2013;8(11):e78345.
To better understand age differences in brain function and behavior, the current study applied network science to model functional interactions between brain regions. We observed a shift in network topology whereby for older adults subcortical and cerebellar structures overlapping with the Salience network had more connectivity to the rest of the brain, coupled with fragmentation of large-scale cortical networks such as the Default and Fronto-Parietal networks. Additionally, greater integration of the dorsal medial thalamus and red nucleus in the Salience network was associated with greater satisfaction with life for older adults, which is consistent with theoretical predictions of age-related increases in emotion regulation that are thought to help maintain well-being and life satisfaction in late adulthood. In regard to cognitive abilities, greater ventral medial prefrontal cortex coherence with its topological neighbors in the Default Network was associated with faster processing speed. Results suggest that large-scale organizing properties of the brain differ with normal aging, and this perspective may offer novel insight into understanding age-related differences in cognitive function and well-being.
doi:10.1371/journal.pone.0078345
PMCID: PMC3819386  PMID: 24223147
4.  Effects of a cognitive training on spatial learning and associated functional brain activations 
BMC Neuroscience  2013;14:73.
Background
Both cognitive and physical exercise have been discussed as promising interventions for healthy cognitive aging. The present study assessed the effects of cognitive training (spatial vs. perceptual training) and physical training (endurance training vs. non-endurance training) on spatial learning and associated brain activation in 33 adults (40–55 years). Spatial learning was assessed with a virtual maze task, and at the same time neural correlates were measured with functional magnetic resonance imaging (fMRI).
Results
Only the spatial training improved performance in the maze task. These behavioral gains were accompanied by a decrease in frontal and temporal lobe activity. At posttest, participants of the spatial training group showed lower activity than participants of the perceptual training group in a network of brain regions associated with spatial learning, including the hippocampus and parahippocampal gyrus. No significant differences were observed between the two physical intervention groups.
Conclusions
Functional changes in neural systems associated with spatial navigation can be induced by cognitive interventions and seem to be stronger than effects of physical exercise in middle-aged adults.
doi:10.1186/1471-2202-14-73
PMCID: PMC3729599  PMID: 23870447
Exercise; Physical activity; Cognitive training; Cognition; Spatial memory; fMRI; Humans; Prevention
5.  Spatially Distributed Effects of Mental Exhaustion on Resting-State FMRI Networks 
PLoS ONE  2014;9(4):e94222.
Brain activity during rest is spatially coherent over functional connectivity networks called resting-state networks. In resting-state functional magnetic resonance imaging, independent component analysis yields spatially distributed network representations reflecting distinct mental processes, such as intrinsic (default) or extrinsic (executive) attention, and sensory inhibition or excitation. These aspects can be related to different treatments or subjective experiences. Among these, exhaustion is a common psychological state induced by prolonged mental performance. Using repeated functional magnetic resonance imaging sessions and spatial independent component analysis, we explored the effect of several hours of sustained cognitive performances on the resting human brain. Resting-state functional magnetic resonance imaging was performed on the same healthy volunteers in two days, with and without, and before, during and after, an intensive psychological treatment (skill training and sustained practice with a flight simulator). After each scan, subjects rated their level of exhaustion and performed an N-back task to evaluate eventual decrease in cognitive performance. Spatial maps of selected resting-state network components were statistically evaluated across time points to detect possible changes induced by the sustained mental performance. The intensive treatment had a significant effect on exhaustion and effort ratings, but no effects on N-back performances. Significant changes in the most exhausted state were observed in the early visual processing and the anterior default mode networks (enhancement) and in the fronto-parietal executive networks (suppression), suggesting that mental exhaustion is associated with a more idling brain state and that internal attention processes are facilitated to the detriment of more extrinsic processes. The described application may inspire future indicators of the level of fatigue in the neural attention system.
doi:10.1371/journal.pone.0094222
PMCID: PMC3976406  PMID: 24705397
6.  Intrinsic connectivity between the hippocampus and posteromedial cortex predicts memory performance in cognitively intact older individuals 
NeuroImage  2010;51(2):910-917.
Coherent fluctuations of spontaneous brain activity are present in distinct functional-anatomic brain systems during undirected wakefulness. However, the behavioral significance of this spontaneous activity has only begun to be investigated. Our previous studies have demonstrated that successful memory formation requires coordinated neural activity in a distributed memory network including the hippocampus and posteromedial cortices, specifically the precuneus and posterior cingulate (PPC), thought to be integral nodes of the default network. In this study, we examined whether intrinsic connectivity during the resting state between the hippocampus and PPC can predict individual differences in the performance of an associative memory task among cognitively intact older individuals. The intrinsic connectivity, between regions within the hippocampus and PPC that were maximally engaged during a subsequent memory fMRI task, was measured during a period of rest prior to the performance of the memory paradigm. Stronger connectivity between the hippocampal and posteromedial regions during rest predicted better performance on the memory task. Furthermore, hippocampal-PPC intrinsic connectivity was also significantly correlated with episodic memory measures on neuropsychological tests, but not with performance in non-memory domains. Whole brain exploratory analyses further confirmed the spatial specificity of the relationship between hippocampal-default network posteromedial cortical connectivity and memory performance in older subjects. Our findings provide support for the hypothesis that one of the functions of this large-scale brain network is to subserve episodic memory processes. Research is ongoing to determine if impaired connectivity between these regions may serve as a predictor of memory decline related to early Alzheimer’s disease.
doi:10.1016/j.neuroimage.2010.02.046
PMCID: PMC2856812  PMID: 20188183
7.  Disruptions in Brain Networks of Older Fallers Are Associated with Subsequent Cognitive Decline: A 12-Month Prospective Exploratory Study 
PLoS ONE  2014;9(4):e93673.
Cognitive impairment and impaired mobility are major public health concerns. There is growing recognition that impaired mobility is an early biomarker of cognitive impairment and dementia. The neural basis for this association is currently unclear. We propose disrupted functional connectivity as a potential mechanism. In this 12-month prospective exploratory study, we compared functional connectivity of four brain networks– the default mode network (DMN), fronto-executive network (FEN), fronto-parietal network (FPN), and the primary motor sensory network (SMN) – between community-dwelling older adults with ≥ two falls in the last 12 months and their non-falling counterparts (≤ one fall in the last 12 months). Functional connectivity was examined both at rest and during a simple motor tapping task. Compared with non-fallers, fallers showed more connectivity between the DMN and FPN during right finger tapping (p = 0.04), and significantly less functional connectivity between the SMN and FPN during rest (p≤0.05). Less connectivity between the SMN and FPN during rest was significantly associated with greater decline in both cognitive function and mobility over the12-month period (r = −0.32 and 0.33 respectively; p≤0.04). Thus, a recent history of multiple falls among older adults without a diagnosis of dementia may indicate sub-clinical changes in brain function and increased risk for subsequent decline.
doi:10.1371/journal.pone.0093673
PMCID: PMC3977422  PMID: 24699668
8.  Echoes of the Brain within Default Mode, Association, and Heteromodal Cortices 
The Journal of Neuroscience  2013;33(35):14031-14039.
Intrinsic connectivity networks (ICNs), such as the default mode, frontoparietal control, and salience networks, provide a useful large-scale description of the functional architecture of the brain. Although ICNs are functionally specialized, the information that they process needs to be integrated for coherent cognition, perception, and behavior. A region capable of performing this integration might be expected to contain traces, or “echoes,” of the neural signals from multiple ICNs. Here, using fMRI in humans, we show the existence of specific “transmodal” regions containing echoes of multiple ICNs. These regions include core nodes of the default mode network, as well as multimodal association regions of the temporoparietal and temporo-occipito-parietal junction, right middle frontal gyrus, and dorsal anterior cingulate cortex. In contrast, “unimodal” regions such as the primary sensory and motor cortices show a much more singular pattern of activity, containing traces of few or even single ICNs. The presence of ICN echoes might explain how transmodal regions are involved in multiple different cognitive states. Our results suggest that these transmodal regions have a particular local spatial organization containing topographic maps that relate to multiple ICNs. This makes transmodal regions uniquely placed to be able to mediate the cross talk between the brain's functional networks through local modulation of adjacent regions that communicate with different ICNs.
doi:10.1523/JNEUROSCI.0570-13.2013
PMCID: PMC3810536  PMID: 23986239
9.  Shorter term aerobic exercise improves brain, cognition, and cardiovascular fitness in aging 
Physical exercise, particularly aerobic exercise, is documented as providing a low cost regimen to counter well-documented cognitive declines including memory, executive function, visuospatial skills, and processing speed in normally aging adults. Prior aging studies focused largely on the effects of medium to long term (>6 months) exercise training; however, the shorter term effects have not been studied. In the present study, we examined changes in brain blood flow, cognition, and fitness in 37 cognitively healthy sedentary adults (57–75 years of age) who were randomized into physical training or a wait-list control group. The physical training group received supervised aerobic exercise for 3 sessions per week 1 h each for 12 weeks. Participants' cognitive, cardiovascular fitness and resting cerebral blood flow (CBF) were assessed at baseline (T1), mid (T2), and post-training (T3). We found higher resting CBF in the anterior cingulate region in the physical training group as compared to the control group from T1 to T3. Cognitive gains were manifested in the exercise group's improved immediate and delayed memory performance from T1 to T3 which also showed a significant positive association with increases in both left and right hippocampal CBF identified earlier in the time course at T2. Additionally, the two cardiovascular parameters, VO2 max and rating of perceived exertion (RPE) showed gains, compared to the control group. These data suggest that even shorter term aerobic exercise can facilitate neuroplasticity to reduce both the biological and cognitive consequences of aging to benefit brain health in sedentary adults.
doi:10.3389/fnagi.2013.00075
PMCID: PMC3825180  PMID: 24282403
aging; CBF; exercise; memory; MRI
10.  Functional resting-state networks are differentially affected in schizophrenia 
Schizophrenia research  2011;130(1-3):86-93.
Neurobiological theories posit that schizophrenia relates to disturbances in connectivity between brain regions. Resting-state functional magnetic resonance imaging is a powerful tool for examining functional connectivity and has revealed several canonical brain networks, including the default mode, dorsal attention, executive control, and salience networks. The purpose of this study was to examine changes in these networks in schizophrenia. 42 patients with schizophrenia and 61 healthy subjects completed a RS-fMRI scanning session. Seed-based region-of-interest correlation analysis was used to identify the default mode, dorsal attention, executive control, and salience networks. Compared to healthy subjects, individuals with schizophrenia demonstrated greater connectivity between the posterior cingulate cortex, a key hub of the default mode, and the left inferior gyrus, left middle frontal gyrus, and left middle temporal gyrus. Interestingly, these regions were more strongly connected to the executive control network in healthy control subjects. In contrast to the default mode, patients demonstrated less connectivity in the executive control and dorsal attention networks. No differences were observed in the salience network. The results indicate that resting-state networks are differentially affected in schizophrenia. The alterations are characterized by reduced segregation between the default mode and executive control networks in the prefrontal cortex and temporal lobe, and reduced connectivity in the dorsal attention and executive control networks. The changes suggest that the process of functional specialization is altered in schizophrenia. Further work is needed to determine if the alterations are related to disturbances in white matter connectivity, neurodevelopmental abnormalities, and genetic risk for schizophrenia.
doi:10.1016/j.schres.2011.03.010
PMCID: PMC3139756  PMID: 21458238
Schizophrenia; Resting-state; fMRI; Default Mode; Dorsal Attention; Executive Control
11.  Resting State Networks' Corticotopy: The Dual Intertwined Rings Architecture 
PLoS ONE  2013;8(7):e67444.
How does the brain integrate multiple sources of information to support normal sensorimotor and cognitive functions? To investigate this question we present an overall brain architecture (called “the dual intertwined rings architecture”) that relates the functional specialization of cortical networks to their spatial distribution over the cerebral cortex (or “corticotopy”). Recent results suggest that the resting state networks (RSNs) are organized into two large families: 1) a sensorimotor family that includes visual, somatic, and auditory areas and 2) a large association family that comprises parietal, temporal, and frontal regions and also includes the default mode network. We used two large databases of resting state fMRI data, from which we extracted 32 robust RSNs. We estimated: (1) the RSN functional roles by using a projection of the results on task based networks (TBNs) as referenced in large databases of fMRI activation studies; and (2) relationship of the RSNs with the Brodmann Areas. In both classifications, the 32 RSNs are organized into a remarkable architecture of two intertwined rings per hemisphere and so four rings linked by homotopic connections. The first ring forms a continuous ensemble and includes visual, somatic, and auditory cortices, with interspersed bimodal cortices (auditory-visual, visual-somatic and auditory-somatic, abbreviated as VSA ring). The second ring integrates distant parietal, temporal and frontal regions (PTF ring) through a network of association fiber tracts which closes the ring anatomically and ensures a functional continuity within the ring. The PTF ring relates association cortices specialized in attention, language and working memory, to the networks involved in motivation and biological regulation and rhythms. This “dual intertwined architecture” suggests a dual integrative process: the VSA ring performs fast real-time multimodal integration of sensorimotor information whereas the PTF ring performs multi-temporal integration (i.e., relates past, present, and future representations at different temporal scales).
doi:10.1371/journal.pone.0067444
PMCID: PMC3722222  PMID: 23894288
12.  Amyloid deposition is associated with impaired default network function in older persons without dementia 
Neuron  2009;63(2):178-188.
Summary
Alzheimer's disease (AD) has been associated with functional alterations in a distributed network of brain regions linked to memory function, with a recent focus on the cortical regions collectively known as the default network. Posterior components of the default network, including the precuneus and posterior cingulate, are particularly vulnerable to early deposition of amyloid β-protein, one of the hallmark pathologies of AD. In this study, we use in vivo amyloid imaging to demonstrate that high levels of amyloid deposition are associated with aberrant default network functional magnetic resonance imaging (fMRI) activity in asymptomatic and minimally impaired older individuals, similar to the pattern of dysfunction reported in AD patients. These findings suggest that amyloid pathology is linked to neural dysfunction in brain regions supporting memory function and provide support for the hypothesis that cognitively intact older individuals with evidence of amyloid pathology may be in early stages of AD.
doi:10.1016/j.neuron.2009.07.003
PMCID: PMC2738994  PMID: 19640477
13.  The default mode network and altered consciousness in epilepsy 
Behavioural neurology  2011;24(1):55-65.
The default mode network has been hypothesized following the observation that specific regions of the brain are consistently activated during the resting state and deactivated during engagement with task. The primary nodes of this network, which typically include the precuneus / posterior cingulate, the medial frontal and lateral parietal cortices, are thought to be involved in introspective and social cognitive functions. Interestingly, this same network has been shown to be selectively impaired during epileptic seizures associated with loss of consciousness. Using a wide range of neuroimaging and electrophysiological modalities, decreased activity in the default state has been confirmed during complex partial, generalized tonic-clonic, and absence seizures. In this review we will discuss these three seizure types and will focus on possible mechanisms by which decreased default mode network activity occurs. Although the specific mechanisms of onset and propagation differ considerably across these seizure types, we propose that the resulting loss of consciousness in all three types of seizures is due to active inhibition of subcortical arousal systems that normally maintain default mode network activity in the awake state. Further, we suggest that these findings support a general “network inhibition hypothesis,” by which active inhibition of arousal systems leads to cortical deactivation resembling other states of reduced consciousness.
doi:10.3233/BEN-2011-0310
PMCID: PMC3150226  PMID: 21447899
Epilepsy; Consciousness; Default Mode Network
14.  Large-scale directional connections among multi resting-state neural networks in human brain: A functional MRI and Bayesian network modeling study 
Neuroimage  2011;56(3):1035-1042.
This study examined the large-scale connectivity among multiple resting-state networks (RSNs) in the human brain. Independent component analysis was first applied to the resting-state functional MRI (fMRI) data acquired from 12 healthy young subjects for the separation of RSNs. Four sensory (lateral and medial visual, auditory, sensory-motor) RSNs and four cognitive (default-mode, self-referential, dorsal and ventral attention) RSNs were identified. Gaussian Bayesian network (BN) learning approach was then used for the examination of the conditional dependencies among these RSNs and the construction of the network-to-network directional connectivity patterns. The BN based results demonstrated that sensory networks and cognitive networks were hierarchically organized. Specially, we found the sensory networks were highly intra-dependent and the cognitive networks were strongly intra-influenced. In addition, the results depicted dominant bottom-up connectivity from sensory networks to cognitive networks in which the self-referential and the default-mode networks might play respectively important roles in the process of resting-state information transfer and integration. The present study characterized the global connectivity relations among RSNs and delineated more characteristics of spontaneous activity dynamics.
doi:10.1016/j.neuroimage.2011.03.010
PMCID: PMC3319766  PMID: 21396456
Bayesian network; fMRI; connectivity; resting-state network; spontaneous activity
15.  Brain Network Connectivity in Individuals with Schizophrenia and their Siblings 
Biological psychiatry  2010;69(10):967-973.
Background
Research on brain activity in schizophrenia has shown that changes in the function of any single region cannot explain the range of cognitive and affective impairments in this illness. Rather, neural circuits that support sensory, cognitive and emotional processes are now being investigated as substrates for cognitive and affective impairments in schizophrenia, a shift in focus consistent with long-standing hypotheses about schizophrenia as a “dysconnection” syndrome. Our goal was to further examine alterations in functional connectivity within and between the default mode network, and three cognitive control networks (frontal-parietal, cingulo-opercular and cerebellar) as a basis for such impairments.
Methods
Resting state fMRI was collected from 40 individuals with DSM-IV-TR schizophrenia, 31 siblings of individuals with schizophrenia, 15 healthy controls, and 18 siblings of healthy controls while they rested quietly with their eyes closed. Connectivity metrics were compared between patients and controls for both within and between network connections, and were used to predict clinical symptoms and cognitive function.
Results
Individuals with schizophrenia showed reduced distal and somewhat enhanced local connectivity between the cognitive control networks as compared to controls. Additionally, greater connectivity between the frontal-parietal and cerebellar regions was robustly predictive of better cognitive performance across groups, and predictive of fewer disorganization symptoms among patients.
Conclusions
These results are consistent with the hypothesis that impairments of executive function and cognitive control result from disruption in the coordination of activity across brain networks, and additionally suggest that these might reflect impairments in normal pattern of brain connectivity development.
doi:10.1016/j.biopsych.2010.11.009
PMCID: PMC3081915  PMID: 21193174
Schizophrenia; Functional Connectivity; Cognitive Control; Cerebellum; Risk
16.  Age-related changes in neural functional connectivity and its behavioral relevance 
BMC Neuroscience  2012;13:16.
Background
Resting-state recordings are characterized by widely distributed networks of coherent brain activations. Disturbances of the default network - a set of regions that are deactivated by cognitive tasks and activated during passive states - have been detected in age-related disorders such as Alzheimer's or Parkinson's disease but alterations in the course of healthy aging still need to be explored.
Results
Using magnetoencephalography (MEG), the present study investigated how age-related functional resting-state brain connectivity links to cognitive performance in healthy aging in fifty-three participants ranging in age from 18 to 89 years. A beamforming technique was used to reconstruct the brain activity in source space and the interregional coupling was investigated using partial directed coherence (PDC). We found significant age-related alterations of functional resting-state connectivity. These are mainly characterized by reduced information input into the posterior cingulum/precuneus region together with an enhanced information flow to the medial temporal lobe. Furthermore, higher inflow in the medial temporal lobe subsystem was associated with weaker cognitive performance whereas stronger inflow in the posterior cluster was related to better cognitive performance.
Conclusion
This is the first study to show age-related alterations in subsystems of the resting state network that are furthermore associated with cognitive performance.
doi:10.1186/1471-2202-13-16
PMCID: PMC3305677  PMID: 22333511
17.  The Effect of Three Months of Aerobic Training on Stroop Performance in Older Adults 
Journal of Aging Research  2012;2012:269815.
Growing evidence supports the use of physical training interventions to improve both physical and cognitive performances in healthy older adults. Few studies have examined the impact of aerobic exercise on Stroop task performance, a measure of executive functions. In the current 3-month aerobic training study, 50 older adults (mean age = 67.96 ± 6.25 years) were randomly assigned to either a three-month physical training group or to a control group (waiting list). Training sessions were 3 times per week for 60 minutes. All participants completed pre- and post-test measures of cognitive performance using the modified Stroop task and physical performance (Rockport one-mile test). Compared to controls, the training group showed significant improvements in physical capacity (P < 0.001) and enhanced Stroop performance, but only in the inhibition/switching condition (P < 0.03). Furthermore, the increase in aerobic capacity induced by the training regimen correlated negatively with reaction time in the inhibition/switching condition of the Stroop task at posttest (r = −0.538; P = 0.007). Importantly, the reported gains in cognitive performance were observed after only three months of physical training. Taken together, the results suggest that even short-term physical interventions can enhance older adults' executive functions.
doi:10.1155/2012/269815
PMCID: PMC3530182  PMID: 23304504
18.  Default Network Connectivity in Medial Temporal Lobe Amnesia 
There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting functional magnetic resonance imaging (fMRI) was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex was observed in amnesia. In contrast, somatomotor network connectivity was intact in amnesia, indicating bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia.
doi:10.1523/JNEUROSCI.0700-12.2012
PMCID: PMC3573849  PMID: 23077048
fMRI; default mode network; amnesia; episodic memory; hippocampus; prefrontal cortex; posterior cingulate; parietal lobe; diaschisis
19.  Auditory Oddball Deficits in Schizophrenia: An Independent Component Analysis of the fMRI Multisite Function BIRN Study 
Schizophrenia Bulletin  2009;35(1):67-81.
Deficits in the connectivity between brain regions have been suggested to play a major role in the pathophysiology of schizophrenia. A functional magnetic resonance imaging (fMRI) analysis of schizophrenia was implemented using independent component analysis (ICA) to identify multiple temporally cohesive, spatially distributed regions of brain activity that represent functionally connected networks. We hypothesized that functional connectivity differences would be seen in auditory networks comprised of regions such as superior temporal gyrus as well as executive networks that consisted of frontal-parietal areas. Eight networks were found to be implicated in schizophrenia during the auditory oddball paradigm. These included a bilateral temporal network containing the superior and middle temporal gyrus; a default-mode network comprised of the posterior cingulate, precuneus, and middle frontal gyrus; and multiple dorsal lateral prefrontal cortex networks that constituted various levels of between-group differences. Highly task-related sensory networks were also found. These results indicate that patients with schizophrenia show functional connectivity differences in networks related to auditory processing, executive control, and baseline functional activity. Overall, these findings support the idea that the cognitive deficits associated with schizophrenia are widespread and that a functional connectivity approach can help elucidate the neural correlates of this disorder.
doi:10.1093/schbul/sbn133
PMCID: PMC2643962  PMID: 19074498
fMRI; DLPFC; schizophrenia; default-mode; independent component analysis; auditory oddball
20.  Beneficial effects of short-term combination exercise training on diverse cognitive functions in healthy older people: study protocol for a randomized controlled trial 
Trials  2012;13:200.
Background
Results of previous studies have shown that exercise training can improve cognitive functions in healthy older people. Some studies have demonstrated that long-term combination exercise training can facilitate memory function improvement better than either aerobic or strength exercise training alone. Nevertheless, it remains unclear whether short-term combination exercise training can improve diverse cognitive functions in healthy older people or not. We investigate the effects of four weeks of short-term combination exercise training on various cognitive functions (executive functions, episodic memory, short-term memory, working memory, attention, reading ability, and processing speed) of healthy older people.
Methods
A single-blinded intervention with two parallel groups (combination exercise training; waiting list control) is used. Testers are blind to the study hypothesis and the participants’ group membership. Through an advertisement in a local newspaper, 64 healthy older adults are recruited and then assigned randomly to a combination exercise training group or a waiting list control group. Participants in the combination exercise training group must participate in the short-term combination exercise training (aerobic and strength exercise training) three days per week during the four weeks (12 workouts in total). The waiting list group does not participate in the combination exercise training. The primary outcome measure is the Stroop test score: a measure of executive function. Secondary outcome measures are assessments including the Verbal Fluency Task, Logical Memory, First and Second Names, Digit Span Forward, Digit span backward, Japanese Reading Test, Digit Cancellation Task, Digit Symbol Coding, and Symbol Search. We assess these outcome measures before and after the intervention.
Discussion
This report is the first of a study that investigates the beneficial effects of short-term combination exercise training on diverse cognitive functions of older people. Our study is expected to provide sufficient evidence of short-term combination exercise’s effectiveness.
Trial registration
This trial was registered in The University Hospital Medical Information Network Clinical Trials Registry (Number UMIN000007828).
doi:10.1186/1745-6215-13-200
PMCID: PMC3495024  PMID: 23107038
21.  Promotion of the mind through exercise (PROMoTE): a proof-of-concept randomized controlled trial of aerobic exercise training in older adults with vascular cognitive impairment 
BMC Neurology  2010;10:14.
Background
Sub-cortical vascular ischaemia is the second most common etiology contributing to cognitive impairment in older adults, and is frequently under-diagnosed and under-treated. Although evidence is mounting that exercise has benefits for cognitive function among seniors, very few randomized controlled trials of exercise have been conducted in populations at high-risk for progression to dementia. Aerobic-based exercise training may be of specific benefit in delaying the progression of cognitive decline among seniors with vascular cognitive impairment by reducing key vascular risk factors associated with metabolic syndrome. Thus, we aim to carry out a proof-of-concept single-blinded randomized controlled trial primarily designed to provide preliminary evidence of efficacy aerobic-based exercise training program on cognitive and everyday function among older adults with mild sub-cortical ischaemic vascular cognitive impairment.
Methods/Design
A proof-of-concept single-blinded randomized trial comparing a six-month, thrice-weekly, aerobic-based exercise training group with usual care on cognitive and everyday function. Seventy older adults who meet the diagnostic criteria for sub-cortical ischaemic vascular cognitive impairment as outlined by Erkinjuntti and colleagues will be recruited from a memory clinic of a metropolitan hospital. The aerobic-based exercise training will last for 6 months. Participants will be followed for an additional six months after the cessation of exercise training.
Discussion
This research will be an important first step in quantifying the effect of an exercise intervention on cognitive and daily function among seniors with sub-cortical ischaemic vascular cognitive impairment, a recognized risk state for progression to dementia. Exercise has the potential to be an effective, inexpensive, and accessible intervention strategy with minimal adverse effects. Reducing the rate of cognitive decline among seniors with sub-cortical ischaemic vascular cognitive impairment could preserve independent functioning and health related quality of life in this population. This, in turn, could lead to reduced health care resource utilization costs and avoidance of early institutional care.
Trial Registration
ClinicalTrials.gov Protocol Registration System: NCT01027858.
doi:10.1186/1471-2377-10-14
PMCID: PMC2830197  PMID: 20158920
22.  Large-Scale Cortical Functional Organization and Speech Perception across the Lifespan 
PLoS ONE  2011;6(1):e16510.
Aging is accompanied by substantial changes in brain function, including functional reorganization of large-scale brain networks. Such differences in network architecture have been reported both at rest and during cognitive task performance, but an open question is whether these age-related differences show task-dependent effects or represent only task-independent changes attributable to a common factor (i.e., underlying physiological decline). To address this question, we used graph theoretic analysis to construct weighted cortical functional networks from hemodynamic (functional MRI) responses in 12 younger and 12 older adults during a speech perception task performed in both quiet and noisy listening conditions. Functional networks were constructed for each subject and listening condition based on inter-regional correlations of the fMRI signal among 66 cortical regions, and network measures of global and local efficiency were computed. Across listening conditions, older adult networks showed significantly decreased global (but not local) efficiency relative to younger adults after normalizing measures to surrogate random networks. Although listening condition produced no main effects on whole-cortex network organization, a significant age group x listening condition interaction was observed. Additionally, an exploratory analysis of regional effects uncovered age-related declines in both global and local efficiency concentrated exclusively in auditory areas (bilateral superior and middle temporal cortex), further suggestive of specificity to the speech perception tasks. Global efficiency also correlated positively with mean cortical thickness across all subjects, establishing gross cortical atrophy as a task-independent contributor to age-related differences in functional organization. Together, our findings provide evidence of age-related disruptions in cortical functional network organization during speech perception tasks, and suggest that although task-independent effects such as cortical atrophy clearly underlie age-related changes in cortical functional organization, age-related differences also demonstrate sensitivity to task domains.
doi:10.1371/journal.pone.0016510
PMCID: PMC3031590  PMID: 21304991
23.  Large-Scale Brain Networks in Board Game Experts: Insights from a Domain-Related Task and Task-Free Resting State 
PLoS ONE  2012;7(3):e32532.
Cognitive performance relies on the coordination of large-scale networks of brain regions that are not only temporally correlated during different tasks, but also networks that show highly correlated spontaneous activity during a task-free state. Both task-related and task-free network activity has been associated with individual differences in cognitive performance. Therefore, we aimed to examine the influence of cognitive expertise on four networks associated with cognitive task performance: the default mode network (DMN) and three other cognitive networks (central-executive network, dorsal attention network, and salience network). During fMRI scanning, fifteen grandmaster and master level Chinese chess players (GM/M) and fifteen novice players carried out a Chinese chess task and a task-free resting state. Modulations of network activity during task were assessed, as well as resting-state functional connectivity of those networks. Relative to novices, GM/Ms showed a broader task-induced deactivation of DMN in the chess problem-solving task, and intrinsic functional connectivity of DMN was increased with a connectivity pattern associated with the caudate nucleus in GM/Ms. The three other cognitive networks did not exhibit any difference in task-evoked activation or intrinsic functional connectivity between the two groups. These findings demonstrate the effect of long-term learning and practice in cognitive expertise on large-scale brain networks, suggesting the important role of DMN deactivation in expert performance and enhanced functional integration of spontaneous activity within widely distributed DMN-caudate circuitry, which might better support high-level cognitive control of behavior.
doi:10.1371/journal.pone.0032532
PMCID: PMC3299676  PMID: 22427852
24.  Strength of default mode resting state connectivity relates to white matter integrity in children 
Developmental science  2010;14(4):738-751.
A default mode network of brain regions is known to demonstrate coordinated activity during the resting state. While the default mode network is well characterized in adults, few investigations have focused upon its development. We scanned 9–13 year old children with diffusion tensor imaging and resting-state functional magnetic resonance imaging. We identified resting state networks using Independent Component Analysis and tested whether the functional connectivity between the medial prefrontal cortex (mPFC) and posterior cingulate cortex (PCC) depends upon the maturation of the underlying cingulum white matter tract. To determine the generalizability of this relationship, we also tested whether functional connectivity depends on white matter maturity between bilateral lateral prefrontal cortex (lateral PFC) within the executive control network. We found a positive relationship between mPFC-PCC connectivity and fractional anisotropy of the cingulum bundle; this positive relationship was moderated by the age of the subjects such that it was stronger in older children. By contrast, no such structure-function relationship emerged between right and left lateral PFC. However, functional and structural connectivity of this tract related positively with cognitive speed, fluency, and set-switching neuropsychological measures.
doi:10.1111/j.1467-7687.2010.01020.x
PMCID: PMC3117440  PMID: 21676094
Brain networks; cognition; development; DTI; fMRI
25.  Cerebral Blood Flow in Posterior Cortical Nodes of the Default Mode Network Decreases with Task Engagement but Remains Higher than in Most Brain Regions 
Cerebral Cortex (New York, NY)  2010;21(1):233-244.
Functional neuroimaging studies provide converging evidence for existence of intrinsic brain networks activated during resting states and deactivated with selective cognitive demands. Whether task-related deactivation of the default mode network signifies depressed activity relative to the remaining brain or simply lower activity relative to its resting state remains controversial. We employed 3D arterial spin labeling imaging to examine regional cerebral blood flow (CBF) during rest, a spatial working memory task, and a second rest. Change in regional CBF from rest to task showed significant normalized and absolute CBF reductions in posterior cingulate, posterior-inferior precuneus, and medial frontal lobes . A Statistical Parametric Mapping connectivity analysis, with an a priori seed in the posterior cingulate cortex, produced deactivation connectivity patterns consistent with the classic “default mode network” and activation connectivity anatomically consistent with engagement in visuospatial tasks. The large task-related CBF decrease in posterior-inferior precuneus relative to its anterior and middle portions adds evidence for the precuneus' heterogeneity. The posterior cingulate and posterior-inferior precuneus were also regions of the highest CBF at rest and during task performance. The difference in regional CBF between intrinsic (resting) and evoked (task) activity levels may represent functional readiness or reserve vulnerable to diminution by conditions affecting perfusion.
doi:10.1093/cercor/bhq090
PMCID: PMC3000573  PMID: 20484322
ASL; cerebral blood flow; cingulate; default mode network; precuneus

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