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1.  Reduced hippocampal activity during encoding in cognitively normal adults carrying the APOE ε4 allele 
Neuropsychologia  2011;49(9):2448-2455.
Apolipoprotein (APOE) ε4-related differences in memory performance have been detected before age 65. The hippocampus and the surrounding medial temporal lobe (MTL) structures are the first site affected by Alzheimer’s disease (AD) and the MTL is the seat of episodic memory, including visuo-spatial memory. While reports of APOE ε4-related differences in these brain structures are not consistent in either cross-sectional or longitudinal structural and functional magnetic resonance imaging (fMRI) studies, there is increasing evidence that brain activity at baseline (defined as activity during fixation or rest) may differ in APOE ε4 carriers compared to non-carriers. In this fMRI study, cognitively normal APOE ε4 carriers and non-carriers engaged in a perspective-dependent spatial learning task (Shelton and Gabrieli, 2002) previously shown to activate MTL structures in older participants (Borghesani et al., 2008). A low-level, visually engaging dot-control task was used for comparison, in addition to fixation. APOE ε4 carriers showed less activation than non-carriers in the hippocampus proper during encoding. Specifically, when spatial encoding was contrasted against the dot-control task, encoding-related activation was significantly lower in carriers than non-carriers. By contrast, no ε4-related differences in the hippocampus were found when spatial encoding was compared with fixation. Lower activation, however, was not global since encoding-related activation in early visual cortex (left lingual gyrus) was not different between APOE ε4 carriers and non-carriers. The present data document APOE ε4-related differences in the hippocampus proper during encoding and underscore the role of low-level control contrasts for complex encoding tasks. These results have implications for fMRI studies that investigate the default-mode network (DMN) in middle -aged to older APOE ε4 carriers to help evaluate AD risk in this otherwise cognitively normal population.
doi:10.1016/j.neuropsychologia.2011.04.022
PMCID: PMC3137687  PMID: 21549723
Medial Temporal Lobe; Hippocampus; Learning; Visuo-spatial; APOE ε4; Memory
2.  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
3.  Hypometabolism in Alzheimer's-Affected Brain Regions in Cognitively Normal Latinos Carrying the Apolipoprotein E ε4 Allele 
Archives of neurology  2010;67(4):462-468.
Objective
The extent to which the apolipoprotein E (APOE) ε4 allele is a susceptibility gene for late-onset Alzheimer's disease (AD) in Latino individuals continues to be clarified. In this study, fluorodeoxyglucose positron emission tomography (PET) was used to investigate whether regional reductions in the cerebral metabolic rate for glucose (CMRgl) previously found in cognitively normal late-middle-aged APOE ε4 carriers extends to members of the Latino Mexican-American community.
Methods
A brain mapping algorithm (SPM5) was used to compare cross-sectional regional CMRgl in Latino APOE ε4 carriers versus noncarriers.
Subjects
11 APOE ε4 carriers and 16 noncarriers from Arizona's Latino community (mean age 54.6±6.4 years) matched for sex, mean age and educational level, and who were predominantly of self-designated Mexican origin.
Results
Participant groups had similar distributions for age, gender, education, family history of dementia, clinical ratings and neuropsychological test scores. Latino APOE ε4 carriers had lower CMRgl than the noncarriers in posterior cingulate, precuneus and parietal regions previously found to be preferentially affected in AD patients and cognitively normal non-Latino APOE ε4 carriers. Additionally, the Latino APOE ε4 carriers had lower CMRgl in middle and anterior cingulate cortex, hippocampus and thalamus.
Conclusions
This study provides support for the relationship between APOE ε4 and risk of AD in Latinos. It illustrates the role of PET as a presymptomatic endophenotype for the assessment of AD risk factors, and supports the inclusion of Latino APOE ε4 carriers in proof-of-concept studies using FDG PET to evaluate promising presymptomatic treatments in cognitively normal carriers of this common AD susceptibility gene.
doi:10.1001/archneurol.2010.30
PMCID: PMC2943432  PMID: 20385913
4.  Alzheimer’s disease family history impacts resting state functional connectivity 
Annals of neurology  2012;72(4):571-577.
Objective
Offspring whose parents have Alzheimer’s disease (AD) are at increased risk for developing dementia. Patients with AD typically exhibit disruptions in the default mode network (DMN). The aim of this study was to investigate the effect of a family history of late-onset AD on DMN integrity in cognitively normal individuals. In particular, we determined whether a family history effect is detectable in apolipoprotein E (APOE) ε4 allele non-carriers.
Method
We studied a cohort of 348 cognitively normal participants with or without family history of late-onset AD. DMN integrity was assessed by resting state functional connectivity magnetic resonance imaging.
Results
A family history of late-onset AD was associated with reduced resting state functional connectivity between particular nodes of the DMN, namely the posterior cingulate and medial temporal cortex. The observed functional connectivity reduction was not attributable to medial temporal structural atrophy. Importantly, we detected a family history effect on DMN functional connectivity in APOE ε4 allele non-carriers.
Interpretation
Unknown genetic factors, embodied in a family history of late-onset AD, may affect DMN integrity prior to cognitive impairment.
doi:10.1002/ana.23643
PMCID: PMC3490438  PMID: 23109152
5.  White Matter Alterations in Cognitively Normal apoE ε2 Carriers: Insight into Alzheimer Resistance? 
BACKGROUND AND PURPOSE
The basis for decreased vulnerability to AD among apoE ε2 carriers is unknown. The purpose of this study was to use diffusion tensor imaging to detect possible differences in white matter integrity between cognitively normal elderly apoE ε2 carriers and apoE ε3/ε3 controls.
MATERIALS AND METHODS
Thirty-nine cognitively normal elderly individuals (19 heterozygous carriers of the apoE ε2 allele, 20 apoE ε3/ε3 subjects as controls) underwent diffusion tensor MR imaging on a 4T scanner. Fractional anisotropy, MD, and axial and radial diffusivity were compared using a ROI approach. In addition, an exploratory whole-brain analysis of fractional anisotropy between the 2 groups was undertaken using TBSS.
RESULTS
apoE ε2 carriers had higher FA in the posterior cingulate white matter (P = .01) and anterior corpus callosum (P = .005) than apoE ε3/ε3 controls, secondary to lower radial diffusivity. No significant differences in the FA of the posterior corpus callosum, anterior cingulate white matter, or parahippocampal white matter were seen. Whole-brain TBSS analysis detected regions of higher FA in the apoE ε2 group in the superior longitudinal fasciculus, right thalamus, and the bilateral anterior limbs of the internal capsule, in addition to the posterior cingulum and corpus callosum (P < .005). There were no regions in which the apoE ε3/ε3 group had higher FA.
CONCLUSIONS
apoE ε2 carriers harbor more robust white matter integrity that may be associated with decreased vulnerability to developing AD. This provides further evidence that regional DTI metrics may serve as early imaging biomarkers of AD risk.
doi:10.3174/ajnr.A2984
PMCID: PMC3951461  PMID: 22383234
6.  Functional Network Endophenotypes Unravel the Effects of Apolipoprotein E Epsilon 4 in Middle-Aged Adults 
PLoS ONE  2013;8(2):e55902.
Apolipoprotein E-ε4 (APOE-ε4) accentuates memory decline, structural volume loss and cerebral amyloid deposition in cognitively healthy adults. We investigated whether APOE-ε4 carriers will show disruptions in the intrinsic cognitive networks, including the default mode (DMN), executive control (ECN) and salience (SN) networks, relative to noncarriers in middle-aged healthy adults; and the extent to which episodic-memory performance is related to the altered functional connectivity (Fc) in these networks. Resting-state functional connectivity MRI (R-fMRI) was used to measure the differences in the DMN, ECN and SN Fc between 20 APOE-ε4 carriers and 26 noncarriers. Multiple linear regression analyses were performed to determine the relationship between episodic-memory performance and Fc differences in the three resting-state networks across all subjects. There were no significant differences in the demographic and neuropsychological characteristics and the gray-matter volumes in the carriers and noncarriers. While mostly diminished DMN and ECN functional connectivities were seen, enhanced connections to the DMN structures were found in the SN in ε4 carriers. Altered DMN and ECN were associated with episodic memory performance. Significant Fc differences in the brain networks implicated in cognition were seen in middle-aged individuals with a genetic risk for AD, in the absence of cognitive decline and gray-matter atrophy. Prospective studies are essential to elucidate the potential of R-fMRI technique as a biomarker for predicting conversion from normal to early AD in healthy APOE-ε4 carriers.
doi:10.1371/journal.pone.0055902
PMCID: PMC3570545  PMID: 23424640
7.  Default-mode network connectivity and white matter burden in late-life depression 
Psychiatry research  2011;194(1):39-46.
The brain's default-mode network has been the focus of intense research. This study characterizes the default-mode network activity in late-life depression and the correlation of the default-mode network activity changes with the white-matter hyperintensities burden. We hypothesized that elderly depressed subjects would have altered default-mode network activity, which would correlate with the increased white-matter hyperintensities burden. Twelve depressed subjects (mean Hamilton Depression Rating Scale 19.8±4.1, mean age 70.5±4.9) and 12 non-depressed, comparison subjects (mean age 69±6.5) were included. Functional MRI data were collected while subjects performed a low cognitive load, event-related task. We compared the default-mode network activity in these groups (including depressed subjects pre and post antidepressant treatment). We analyzed the resting connectivity patterns of the posterior cingulate cortex. Deconvolution was used to evaluate the correlation of resting-state connectivity scores with the white-matter hyperintensities burden. Compared with non-depressed elderly, depressed subjects pretreatment had decreased connectivity in the subgenual anterior cingulate cortex and increased connectivity in the dorsomedial prefrontal cortex and the orbitofrontal cortex. The abnormal connectivity was significantly correlated with the white-matter hyperintensities burden. Remitted elderly depressed subjects had improved functional connectivity compared to pretreatment, although alterations persisted in the anterior cingulate and the prefrontal cortex when remitted elderly depressed subjects were compared with non-depressed elderly. Our study provides evidence for altered default-mode network connectivity in late-life depression. The correlation between white-matter hyperintensities burden and default-mode network connectivity emphasizes the role of vascular changes in late-life depression etiopathogenesis.
doi:10.1016/j.pscychresns.2011.04.003
PMCID: PMC3189685  PMID: 21824753
Late-life depression; resting state; connectivity; white matter burden
8.  Age-related changes in the default mode network are more advanced in Alzheimer disease 
Neurology  2011;77(16):1524-1531.
Objective:
To investigate age-related default mode network (DMN) connectivity in a large cognitively normal elderly cohort and in patients with Alzheimer disease (AD) compared with age-, gender-, and education-matched controls.
Methods:
We analyzed task-free–fMRI data with both independent component analysis and seed-based analysis to identify anterior and posterior DMNs. We investigated age-related changes in connectivity in a sample of 341 cognitively normal subjects. We then compared 28 patients with AD with 56 cognitively normal noncarriers of the APOE ϵ4 allele matched for age, education, and gender.
Results:
The anterior DMN shows age-associated increases and decreases in fontal lobe connectivity, whereas the posterior DMN shows mainly age-associated declines in connectivity throughout. Relative to matched cognitively normal controls, subjects with AD display an accelerated pattern of the age-associated changes described above, except that the declines in frontal lobe connectivity did not reach statistical significance. These changes survive atrophy correction and are correlated with cognitive performance.
Conclusions:
The results of this study indicate that the DMN abnormalities observed in patients with AD represent an accelerated aging pattern of connectivity compared with matched controls.
doi:10.1212/WNL.0b013e318233b33d
PMCID: PMC3198977  PMID: 21975202
9.  Temporal lobe functional activity and connectivity in young adult APOE e4 carriers 
Background
To determine if the APOE e4 allele influences both the functional activation and connectivity of the medial temporal lobes (MTL) during successful memory encoding in young adults.
Methods
Twenty-four healthy young adults, twelve carriers and twelve non-carriers of the APOE e4 allele, were scanned in a subsequent memory paradigm, using event-related functional magnetic resonance imaging (fMRI). The neuroanatomical correlates of successful encoding were measured as greater neural activity for subsequently remembered versus forgotten task items, or in short, encoding success activity (ESA). Group differences in ESA within the MTL, as well as whole brain functional connectivity with the MTL, were assessed.
Results
In the absence of demographic or performance differences, APOE e4 allele carriers exhibited greater bilateral MTL activity relative to the non-carriers to accomplish the same encoding task. Additionally, while e4 carriers demonstrated greater functional connectivity of ESA-related MTL activity with the posterior cingulate (PCC) and other peri-limbic regions, overall connectivity reductions were found across anterior and posterior cortices.
Conclusions
These results suggest that the APOE e4 allele may influence not only functional activations within the MTL, but functional connectivity of the MTL to other regions implicated in memory encoding. Enhanced functional connectivity of the MTL with the PCC in young adult e4 carriers suggests that APOE may be expressed early in brain regions known to be involved in Alzheimer's disease long before late-onset dementia is a practical risk or consideration. It is also possible that these functional connectivity differences reflect pleiotropic effects of APOE during early development.
doi:10.1016/j.jalz.2009.07.003
PMCID: PMC2891943  PMID: 19744893
fMRI; Memory; Genetics; Alzheimer's disease; Functional Connectivity; APOE
10.  Alterations of Resting State Functional Connectivity in the Default Network in Adolescents with Autism Spectrum Disorders 
Brain research  2009;1313:202.
Autism spectrum disorders (ASD) are associated with disturbances of neural connectivity. Functional connectivity between neural structures is typically examined within the context of a cognitive task, but also exists in the absence of a task (i.e., “rest”). Connectivity during rest is particularly active in a set of structures called the default network, which includes the posterior cingulate cortex (PCC), retrosplenial cortex, lateral parietal cortex/angular gyrus, medial prefrontal cortex, superior frontal gyrus, temporal lobe, and parahippocampal gyrus. We previously reported that adults with ASD relative to controls show areas of stronger and weaker connectivity within the default network. The objective of the present study was to examine the default network in adolescents with ASD. Sixteen adolescents with ASD and 15 controls participated in a functional MRI study. Functional connectivity was examined between a PCC seed and other areas of the default network. Both groups showed connectivity in the default network. Relative to controls, adolescents with ASD showed widespread weaker connectivity in nine of the eleven areas of the default network. Moreover, an analysis of symptom severity indicated that poorer social skills and increases in restricted and repetitive behaviors and interests correlated with weaker connectivity, whereas poorer verbal and non-verbal communication correlated with stronger connectivity in multiple areas of the default network. These findings indicate that adolescents with ASD show weaker connectivity in the default network than previously reported in adults with ASD. The findings also show that weaker connectivity within the default network is associated with specific impairments in ASD.
doi:10.1016/j.brainres.2009.11.057
PMCID: PMC2818723  PMID: 20004180
Functional Magnetic Resonance Imaging; development; symptom severity; Asperger’s syndrome; pervasive developmental disorder not otherwise specified
11.  Evidence of altered posteromedial cortical fMRI activity in subjects at risk for Alzheimer disease 
The posteromedial cortices and other regions of the “default network” are particularly vulnerable to the pathology of Alzheimer disease (AD). In this study, we performed fMRI to investigate whether the presence of apolipoprotein E (APOE) ε4 allele and degree of memory impairment were associated with dysfunction of these brain regions. Seventy-five elderly subjects ranging from cognitively normal to mild AD, divided into ε4 carriers and non-carriers, underwent fMRI during a memory encoding task. Across all subjects, posteromedial and ventral anterior cingulate cortices (key components of the default network) as well as right middle and inferior prefrontal regions demonstrated reduced task-induced deactivation in the ε4 carriers relative to non-carriers. Even among cognitively normal subjects, ε4 carriers demonstrated reduced posteromedial deactivation compared to non-carriers, in the same regions which demonstrated failure of deactivation in AD patients. Greater failure of posteromedial deactivation was related to worse memory performance (delayed recall) across all subjects and within the range of cognitively normal subjects. In summary, the posteromedial cortical fMRI response pattern is modulated both by the presence of APOE ε4 and episodic memory capability. Altered fMRI activity of the posteromedial areas of the brain default network may be an early indicator of risk for AD.
doi:10.1097/WAD.0b013e3181a785c9
PMCID: PMC2837131  PMID: 19571734
Alzheimer disease; apolipoprotein E (APOE); cognitive aging; functional magnetic resonance imaging (fMRI); mild cognitive impairment (MCI); memory
12.  Altered functional connectivity in asymptomatic MAPT subjects 
Neurology  2011;77(9):866-874.
Objective:
To determine whether functional connectivity is altered in subjects with mutations in the microtubule associated protein tau (MAPT) gene who were asymptomatic but were destined to develop dementia, and to compare these findings to those in subjects with behavioral variant frontotemporal dementia (bvFTD).
Methods:
In this case-control study, we identified 8 asymptomatic subjects with mutations in MAPT and 8 controls who screened negative for mutations in MAPT. Twenty-one subjects with a clinical diagnosis of bvFTD were also identified and matched to 21 controls. All subjects had resting-state fMRI. In-phase functional connectivity was assessed between a precuneus seed in the default mode network (DMN) and a fronto-insular cortex seed in the salience network, and the rest of the brain. Atlas-based parcellation was used to assess functional connectivity and gray matter volume across specific regions of interest.
Results:
The asymptomatic MAPT subjects and subjects with bvFTD showed altered functional connectivity in the DMN, with reduced in-phase connectivity in lateral temporal lobes and medial prefrontal cortex, compared to controls. Increased in-phase connectivity was also observed in both groups in the medial parietal lobe. Only the bvFTD group showed altered functional connectivity in the salience network, with reduced connectivity in the fronto-insular cortex and anterior cingulate. Gray matter loss was observed across temporal, frontal, and parietal regions in bvFTD, but not in the asymptomatic MAPT subjects.
Conclusions:
Functional connectivity in the DMN is altered in MAPT subjects before the occurrence of both atrophy and clinical symptoms, suggesting that changes in functional connectivity are early features of the disease.
doi:10.1212/WNL.0b013e31822c61f2
PMCID: PMC3162637  PMID: 21849646
13.  Altered PET Functional Brain Responses in Cognitively Intact Elderly Persons at Risk for Alzheimer Disease (Carriers of the ε4 Allele) 
Objective
Few previous studies have investigated the association between APOE genotype and brain activation during performance of cognitive tasks in healthy middle-aged and elderly subjects, and the results have been mixed. The authors investigated APOE-mediated differential brain activation in a group of healthy elderly subjects.
Methods
Using H2 15O positron emission tomography (PET), they imaged 32 healthy subjects (26 non-ε4 carriers and 6 ε4 carriers) performing a serial shape-recognition memory task under two conditions: Simple Demand (SD), in which one shape was presented in each study trial, and Titrated Demand (TD), in which study list length was adjusted so that each subject recognized words at approximately 75% accuracy. Multiple-regression analyses were performed, with the “activation” difference (TD–SD PET counts) as the dependent variable and the APOE genotype (presence versus absence of the ε4 allele) as the independent variable.
Results
Compared with non-carriers, ε4 carriers exhibited significantly decreased TD–SD activation differences in the left superior temporal, right superior frontal, left postcental, left precuneus, and posterior cingulate gyrus because ε4 carriers (versus non-carriers) showed increased activation during the SD and decreased activation during the TD condition.
Conclusion
Patterns of brain activation during a nonverbal memory task differed as a function of APOE genotype and, therefore, of genetic risk for Alzheimer disease (AD). Differences in activation were not a reflection of task difficulty, but indicate memory-related altered cognitive processing. Brain regions with decreased activation in the ε4 subjects may result from subclinical incipient AD pathology and/or APOE-related neurophysiologic heterogeneity.
doi:10.1176/appi.ajgp.12.6.596
PMCID: PMC3025285  PMID: 15545327
14.  Switching between executive and default mode networks in posttraumatic stress disorder: alterations in functional connectivity 
Background
Working memory processing and resting-state connectivity in the default mode network are altered in patients with post-traumatic stress disorder (PTSD). Because the ability to effortlessly switch between concentration on a task and an idling state during rest is implicated in both these alterations, we undertook a functional magnetic resonance imaging study with a block design to analyze task-induced modulations in connectivity.
Methods
We performed a working memory task and psychophysiologic interaction analyses with the posterior cingulate cortex and the medial prefrontal cortex as seed regions during fixation in 12 patients with severe, chronic PTSD and 12 healthy controls.
Results
During the working memory task, the control group showed significantly stronger connectivity with areas implicated in the salience and executive networks, including the right inferior frontal gyrus and the right inferior parietal lobule. The PTSD group showed stronger connectivity with areas implicated in the default mode network, namely enhanced connectivity between the posterior cingulate cortex and the right superior frontal gyrus and between the medial prefrontal cortex and the left parahip-pocampal gyrus.
Limitations
Because we were studying alterations in patients with severe, chronic PTSD, we could not exclude patients taking medication. The small sample size may have limited the power of our analyses. To avoid multiple testing in a small sample, we only used 2 seed regions for our analyses.
Conclusion
The different patterns of connectivity imply significant group differences with task-induced switches (i.e., engaging and disengaging the default mode network and the central-executive network).
doi:10.1503/jpn.090175
PMCID: PMC2895156  PMID: 20569651
15.  Divergent network connectivity changes in behavioural variant frontotemporal dementia and Alzheimer’s disease 
Brain  2010;133(5):1352-1367.
Resting-state or intrinsic connectivity network functional magnetic resonance imaging provides a new tool for mapping large-scale neural network function and dysfunction. Recently, we showed that behavioural variant frontotemporal dementia and Alzheimer’s disease cause atrophy within two major networks, an anterior ‘Salience Network’ (atrophied in behavioural variant frontotemporal dementia) and a posterior ‘Default Mode Network’ (atrophied in Alzheimer’s disease). These networks exhibit an anti-correlated relationship with each other in the healthy brain. The two diseases also feature divergent symptom-deficit profiles, with behavioural variant frontotemporal dementia undermining social-emotional function and preserving or enhancing visuospatial skills, and Alzheimer’s disease showing the inverse pattern. We hypothesized that these disorders would exert opposing connectivity effects within the Salience Network (disrupted in behavioural variant frontotemporal dementia but enhanced in Alzheimer’s disease) and the Default Mode Network (disrupted in Alzheimer’s disease but enhanced in behavioural variant frontotemporal dementia). With task-free functional magnetic resonance imaging, we tested these ideas in behavioural variant frontotemporal dementia, Alzheimer’s disease and healthy age-matched controls (n = 12 per group), using independent component analyses to generate group-level network contrasts. As predicted, behavioural variant frontotemporal dementia attenuated Salience Network connectivity, most notably in frontoinsular, cingulate, striatal, thalamic and brainstem nodes, but enhanced connectivity within the Default Mode Network. Alzheimer’s disease, in contrast, reduced Default Mode Network connectivity to posterior hippocampus, medial cingulo-parieto-occipital regions and the dorsal raphe nucleus, but intensified Salience Network connectivity. Specific regions of connectivity disruption within each targeted network predicted intrinsic connectivity enhancement within the reciprocal network. In behavioural variant frontotemporal dementia, clinical severity correlated with loss of right frontoinsular Salience Network connectivity and with biparietal Default Mode Network connectivity enhancement. Based on these results, we explored whether a combined index of Salience Network and Default Mode Network connectivity might discriminate between the three groups. Linear discriminant analysis achieved 92% clinical classification accuracy, including 100% separation of behavioural variant frontotemporal dementia and Alzheimer’s disease. Patients whose clinical diagnoses were supported by molecular imaging, genetics, or pathology showed 100% separation using this method, including four diagnostically equivocal ‘test’ patients not used to train the algorithm. Overall, the findings suggest that behavioural variant frontotemporal dementia and Alzheimer’s disease lead to divergent network connectivity patterns, consistent with known reciprocal network interactions and the strength and deficit profiles of the two disorders. Further developed, intrinsic connectivity network signatures may provide simple, inexpensive, and non-invasive biomarkers for dementia differential diagnosis and disease monitoring.
doi:10.1093/brain/awq075
PMCID: PMC2912696  PMID: 20410145
functional magnetic resonance imaging; frontotemporal dementia; Alzheimer’s disease; functional connectivity; biomarker
16.  Default-Mode Network Changes in Huntington’s Disease: An Integrated MRI Study of Functional Connectivity and Morphometry 
PLoS ONE  2013;8(8):e72159.
Previous MRI studies of functional connectivity in pre-symptomatic mutation carriers of Huntington’s disease (HD) have shown dysfunction of the Default-Mode Network (DMN). No data however are currently available on the DMN alterations in the symptomatic stages of the disease, which are characterized by cortical atrophy involving several DMN nodes. We assessed DMN integrity and its possible correlations with motor and cognitive symptoms in 26 symptomatic HD patients as compared to 22 normal volunteers, by analyzing resting state functional MRI data, using the Precuneal Cortex/Posterior Cingulate Cortices (PC/PCC) as seed, controlling at voxel level for the effect of atrophy by co-varying for gray matter volume. Direct correlation with PC/PCC was decreased, without correlation with atrophy, in the ventral medial prefrontal cortex (including anterior cingulate and subgenual cortex), right dorso-medial prefrontal cortex, and in the right inferior parietal cortex (mainly involving the angular gyrus). Negative correlations with PC/PCC were decreased bilaterally in the inferior parietal cortices, while a cluster in the right middle occipital gyrus presented increased correlation with PC/PCC. DMN changes in the ventral medial prefrontal cortex significantly correlated with the performance at the Stroop test (p = .0002). Widespread DMN changes, not correlating with the atrophy of the involved nodes, are present in symptomatic HD patients, and correlate with cognitive disturbances.
doi:10.1371/journal.pone.0072159
PMCID: PMC3747049  PMID: 23977239
17.  Changes in Functional Integration with the Non-Epileptic Temporal Lobe of Patients with Unilateral Mesiotemporal Epilepsy 
PLoS ONE  2013;8(6):e67053.
Purpose
To investigate epilepsy-induced changes in effective connectivity between the non-epileptic amygdalo-hippocampal complex (AHC) and the rest of the brain in patients with unilateral mesiotemporal lobe epilepsy (MTLE) associated with hippocampal sclerosis (HS).
Methods
Thirty-three patients with unilateral MTLE associated with HS (20 females, mean age: 36 years, 19 left HS) and 33 adult controls matched for age and gender underwent 18F-Fluorodeoxyglucose positron emission tomography (FDG-PET). Right-HS patients' FDG-PET data were flipped to obtain a left–epileptic–focus–lateralized group of patients. Voxels of interest (VOI) were selected within the cytoarchitectonic probabilistic maps of the non-epileptic AHC (probability level  = 100%, SPM8 Anatomy toolbox v1.7). Patients and controls were compared using VOI metabolic activity as covariate of interest to search for epilepsy-induced changes in the contribution of the non-epileptic AHC to the level of metabolic activity in other brain areas. Age, gender, duration of epilepsy, seizure type and frequency were used as covariates of no-interest for connectivity analyses.
Key findings
Significant decrease in effective connectivity was found between the non-epileptic AHC and ventral prefrontal cortical areas bilaterally, as well as with the temporal pole and the posterior cingulate cortex contralateral to HS. Significant increase in connectivity was found between the non-epileptic AHC and midline structures, such as the anterior cingulate and dorsal medial prefrontal cortices, as well as the temporo-parietal junction bilaterally. Connectivity analyses also revealed a preserved positive connectivity between the non-epileptic and the epileptic AHC in the patients' group.
Significance
This study evidences epilepsy-induced changes in connectivity between the non-epileptic AHC and some limbic and default mode network areas. These changes in connectivity probably account for emotional, cognitive and decision-making impairments frequently observed in MTLE patients. The preserved neurometabolic connectivity between the non-epileptic and the epileptic AHC in MTLE patients is pivotal to explain the epilepsy-induced changes found in this study.
doi:10.1371/journal.pone.0067053
PMCID: PMC3688582  PMID: 23818976
18.  Altered resting-state connectivity in subjects at ultra-high risk for psychosis: an fMRI study 
Background
Individuals at ultra-high risk (UHR) for psychosis have self-disturbances and deficits in social cognition and functioning. Midline default network areas, including the medial prefrontal cortex and posterior cingulate cortex, are implicated in self-referential and social cognitive tasks. Thus, the neural substrates within the default mode network (DMN) have the potential to mediate self-referential and social cognitive information processing in UHR subjects.
Methods
This study utilized functional magnetic resonance imaging (fMRI) to investigate resting-state DMN and task-related network (TRN) functional connectivity in 19 UHR subjects and 20 matched healthy controls. The bilateral posterior cingulate cortex was selected as a seed region, and the intrinsic organization for all subjects was reconstructed on the basis of fMRI time series correlation.
Results
Default mode areas included the posterior/anterior cingulate cortices, the medial prefrontal cortex, the lateral parietal cortex, and the inferior temporal region. Task-related network areas included the dorsolateral prefrontal cortex, supplementary motor area, the inferior parietal lobule, and middle temporal cortex. Compared to healthy controls, UHR subjects exhibit hyperconnectivity within the default network regions and reduced anti-correlations (or negative correlations nearer to zero) between the posterior cingulate cortex and task-related areas.
Conclusions
These findings suggest that abnormal resting-state network activity may be related with the clinical features of UHR subjects. Neurodevelopmental and anatomical alterations of cortical midline structure might underlie altered intrinsic networks in UHR subjects.
doi:10.1186/1744-9081-6-58
PMCID: PMC2959003  PMID: 20932348
19.  Large-Scale Brain Network Coupling Predicts Acute Nicotine Abstinence Effects on Craving and Cognitive Function 
JAMA psychiatry  2014;71(5):523-530.
IMPORTANCE
Interactions of large-scale brain networks may underlie cognitive dysfunctions in psychiatric and addictive disorders.
OBJECTIVES
To test the hypothesis that the strength of coupling among 3 large-scale brain networks–salience, executive control, and default mode–will reflect the state of nicotine withdrawal (vs smoking satiety) and will predict abstinence-induced craving and cognitive deficits and to develop a resource allocation index (RAI) that reflects the combined strength of interactions among the 3 large-scale networks.
DESIGN, SETTING, AND PARTICIPANTS
A within-subject functional magnetic resonance imaging study in an academic medical center compared resting-state functional connectivity coherence strength after 24 hours of abstinence and after smoking satiety. We examined the relationship of abstinence-induced changes in the RAI with alterations in subjective, behavioral, and neural functions. We included 37 healthy smoking volunteers, aged 19 to 61 years, for analyses.
INTERVENTIONS
Twenty-four hours of abstinence vs smoking satiety.
MAIN OUTCOMES AND MEASURES
Inter-network connectivity strength (primary) and the relationship with subjective, behavioral, and neural measures of nicotine withdrawal during abstinence vs smoking satiety states (secondary).
RESULTS
The RAI was significantly lower in the abstinent compared with the smoking satiety states (left RAI, P = .002; right RAI, P = .04), suggesting weaker inhibition between the default mode and salience networks. Weaker inter-network connectivity (reduced RAI) predicted abstinence-induced cravings to smoke (r = −0.59; P = .007) and less suppression of default mode activity during performance of a subsequent working memory task (ventromedial prefrontal cortex, r = −0.66, P = .003; posterior cingulate cortex, r = −0.65, P = .001).
CONCLUSIONS AND RELEVANCE
Alterations in coupling of the salience and default mode networks and the inability to disengage from the default mode network may be critical in cognitive/affective alterations that underlie nicotine dependence.
doi:10.1001/jamapsychiatry.2013.4091
PMCID: PMC4097018  PMID: 24622915
20.  Altered Cerebellar Functional Connectivity with Intrinsic Connectivity Networks in Adults with Major Depressive Disorder 
PLoS ONE  2012;7(6):e39516.
Background
Numerous studies have demonstrated the higher-order functions of the cerebellum, including emotion regulation and cognitive processing, and have indicated that the cerebellum should therefore be included in the pathophysiological models of major depressive disorder. The aim of this study was to compare the resting-state functional connectivity of the cerebellum in adults with major depression and healthy controls.
Methods
Twenty adults with major depression and 20 gender-, age-, and education-matched controls were investigated using seed-based resting-state functional connectivity magnetic resonance imaging.
Results
Compared with the controls, depressed patients showed significantly increased functional connectivity between the cerebellum and the temporal poles. However, significantly reduced cerebellar functional connectivity was observed in the patient group in relation to both the default-mode network, mainly including the ventromedial prefrontal cortex and the posterior cingulate cortex/precuneus, and the executive control network, mainly including the superior frontal cortex and orbitofrontal cortex. Moreover, the Hamilton Depression Rating Scale score was negatively correlated with the functional connectivity between the bilateral Lobule VIIb and the right superior frontal gyrus in depressed patients.
Conclusions
This study demonstrated increased cerebellar coupling with the temporal poles and reduced coupling with the regions in the default-mode and executive control networks in adults with major depression. These differences between patients and controls could be associated with the emotional disturbances and cognitive control function deficits that accompany major depression. Aberrant cerebellar connectivity during major depression may also imply a substantial role for the cerebellum in the pathophysiological models of depression.
doi:10.1371/journal.pone.0039516
PMCID: PMC3377654  PMID: 22724025
21.  Aberrant default mode network in subjects with amnestic mild cognitive impairment using resting-state functional MRI 
Magnetic resonance imaging  2011;30(1):48-61.
Amnestic mild cognitive impairment (aMCI) is a syndrome associated with faster memory decline than normal aging, and frequently represents the prodromal phase of Alzheimer’s disease. When a person is not actively engaged in a goal-directed task, spontaneous functional magnetic resonance imaging (fMRI) signals can reveal functionally connected brain networks, including the so-called default mode network (DMN). To date, only a few studies have investigated DMN functions in aMCI populations. In this study, group independent component analysis was conducted for resting-state fMRI data, with slices acquired perpendicular to the long axis of the hippocampus, from eight subjects with aMCI and eight normal control subjects. Subjects with aMCI showed increased DMN activity in middle cingulate cortex, medial prefrontal cortex, and left inferior parietal cortex compared to the normal control group. Decreased DMN activity for the aMCI group compared to the normal control group was noted in lateral prefrontal cortex, left medial temporal lobe (MTL), left medial temporal gyrus, posterior cingulate cortex/retrosplenial cortex/precuneus, and right angular gyrus. Although MTL volume difference between the two groups was not statistical significant, decreased activity in left MTL was observed for the aMCI group. Positive correlations between DMN activity and memory scores were noted for left lateral prefrontal cortex, left medial temporal gyrus, and right angular gyrus. These findings support the premise that alterations of the DMN occur in aMCI and may indicate deficiencies in functional, intrinsic brain architecture, that correlate with memory function, even before significant medial temporal lobe atrophy is detectable by structural MRI.
doi:10.1016/j.mri.2011.07.007
PMCID: PMC3232317  PMID: 21982164
default mode network (DMN); amnestic mild cognitive impairment (aMCI); resting-state fMRI; medial temporal lobe (MTL)
22.  Interaction of Age and APOE Genotype on Cerebral Blood Flow at Rest 
We investigated the impact of APOE genotype on cerebral blood flow (CBF) in older and younger adults. Forty cognitively normal older adults (16 ε4 carriers, 24 non-ε4 carriers) and 30 younger adults (15 ε4 carriers, 15 non-ε4 carriers) completed a resting-state whole-brain pulsed arterial spin labeling magnetic resonance scan. Main effects of aging were demonstrated wherein older adults had decreased gray matter CBF corrected for partial volume effects compared to younger adults in widespread brain regions. Main effects of APOE genotype were also observed wherein ε4 carriers displayed greater CBF in the left lingual gyrus and precuneus than non-carriers. An interaction between age and APOE genotype in the left anterior cingulate cortex (ACC) was characterized by reduced CBF in older ε4 carriers and increased CBF in young ε4 carriers. Increased CBF in the left ACC resulting from the interaction of age group and APOE genotype was positively correlated with executive functioning in young ε4 adults (r = 0.61, p = 0.04). Results demonstrate APOE genotype differentially impacts cerebrovascular function across the lifespan and may modify the relationship between CBF and cognition. Findings may partially support suggestions that the gene exerts antagonistic pleiotropic effects.
doi:10.3233/JAD-121897
PMCID: PMC4124882  PMID: 23302659
Aging; antagonistic pleiotropy; apolipoprotein E; cerebral blood flow; cerebrovascular function
23.  The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway 
Brain and Behavior  2014;4(3):408-417.
Introduction
Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus.
Methods
Using functional magnetic resonance imaging, we compared 11 smokers after 11 h of abstinence from nicotine and after satiation, with 10 nonsmoking controls, using independent component analysis for brain network comparisons as well as a whole brain resting-state functional connectivity analysis using the anterior cingulate cortex as a seed.
Results
Independent component analysis demonstrated increased functional connectivity in brain networks such as the default mode network associated with the withdrawal state in multiple brain regions. In seed-based analysis, smokers in the withdrawal state showed stronger functional connectivity than nonsmoking controls between the anterior cingulate cortex and the precuneus, caudate, putamen, and frontal cortex (P < 0.05). Among smokers, compared to the satiated state, nicotine withdrawal was associated with increased connectivity between the anterior cingulate cortex and the precuneus, insula, orbital frontal gyrus, superior frontal gyrus, posterior cingulate cortex, superior temporal, and inferior temporal lobe (P < 0.02). The intensity of withdrawal-induced craving correlated with the strength of connectivity between the anterior cingulate cortex and the precuneus, insula, caudate, putamen, middle cingulate gyrus, and precentral gyrus (r = 0.60–0.76; P < 0.05).
Conclusions
In concordance with our previous report that structural neural connectivity between the anterior cingulate area and the precuneus increased in proportion to the progression of physical dependence, resting-state functional connectivity in this pathway increases during nicotine withdrawal in correlation with the intensity of withdrawal-induced craving. These findings suggest that smoking triggers structural and functional neural adaptations in the brain that support withdrawal-induced craving.
doi:10.1002/brb3.227
PMCID: PMC4055191  PMID: 24944870
Addiction; nicotine; resting-state functional connectivity
24.  Association Between Nicotine Dependence Severity, BOLD Response to Smoking Cues, and Functional Connectivity 
Neuropsychopharmacology  2013;38(12):2363-2372.
Enhanced motivational salience towards smoking cues is a consequence of chronic nicotine use, but the degree to which this value increases beyond that of other appetitive cues is unknown. In addition, it is unclear how connectivity between brain regions influences cue reactivity and how cue reactivity and functional connectivity are related to nicotine dependence severity. This study examined neural responses during the presentation of smoking cues and appetitive control cues, as well as functional connectivity in 116 smokers with a range of nicotine dependence severity. Smoking cues elicited greater response above baseline than food cues in orbitofrontal cortex (OFC) and supplementary motor area (SMA) and less deactivation below baseline in middle frontal gyrus, inferior parietal lobe, and middle temporal gyrus. Psychophysiological interaction (PPI) analysis using right OFC as a seed revealed increased connectivity with somatosensory cortex and lateral inferior parietal lobe during smoking cues compared with food cues. Similarly, a PPI analysis using left insula as a seed showed stronger connectivity with somatosensory cortex, right insula, OFC, and striatum. Finally, relationships with nicotine dependence scores showed enhanced response in insula and dorsal anterior cingulate cortex in the smoking vs food comparison, and increased connectivity between insula and circuits involved in motivated behavior. Combined, these results suggest that smokers engage attentional networks and default mode networks involved in self-referential processing to a greater degree during smoking cues. In addition, individuals with greater nicotine dependence severity show increased engagement of sensorimotor and motor preparation circuits, suggesting increased reliance on habitual behavior.
doi:10.1038/npp.2013.134
PMCID: PMC3799055  PMID: 23708507
abuse; biological psychiatry; craving; functional connectivity; imaging; clinical or preclinical; insula; nicotine dependence; psychiatry & behavioral sciences; craving; insula; functional connectivity; nicotine dependence
25.  Greater medial temporal hypometabolism and lower cortical amyloid burden in ApoE4-positive AD patients 
Background
ApoE4 has been associated with an increased risk of Alzheimer’s disease (AD), amyloid deposition and hypometabolism. ApoE4 is less prevalent in non-amnestic AD variants suggesting a direct effect on the clinical phenotype. However, the impact of ApoE4 on amyloid burden and glucose metabolism across different clinical AD syndromes is not well understood. We aimed to assess the relationship between amyloid deposition, glucose metabolism and ApoE4 genotype in a clinically heterogeneous population of AD patients.
Methods
Fifty-two patients with probable AD (NIA-AA) underwent [11C]Pittsburgh compound B (PIB) and [18F]fluorodeoxyglucose (FDG) PET scans. All patients had positive PIB-PET scans. 23 were ApoE4+ (14 heterozygous, 9 homozygous) and 29 were ApoE4−. Groups consisted of language-variant AD, visual-variant AD, and AD patients with amnestic and dysexecutive deficits. 52 healthy controls were included for comparison. FDG and PIB uptake was compared between groups on a voxel-wise basis and in regions-of-interest.
Results
Whilst PIB patterns were diffuse in both patient groups, ApoE4− patients showed higher PIB uptake than ApoE4+ patients across the cortex. Higher PIB uptake in ApoE4− patients was particularly significant in right lateral frontotemporal regions. In contrast, similar patterns of hypometabolism relative to controls were found in both patient groups, mainly involving lateral temporoparietal cortex, precuneus, posterior cingulate cortex, and middle frontal gyrus. Comparing patient groups, ApoE4+ subjects showed greater hypometabolism in bilateral medial temporal and right lateral temporal regions, and ApoE4− patients showed greater hypometabolism in cortical areas including supplementary motor cortex and superior frontal gyrus.
Conclusions
ApoE4+ AD patients showed lower global amyloid burden and greater medial temporal hypometabolism compared to matched ApoE4− patients. These findings suggest that ApoE4 may increase susceptibility to molecular pathology and modulate the anatomic pattern of neurodegeneration in AD.
doi:10.1136/jnnp-2013-305858
PMCID: PMC3946299  PMID: 23965289
Alzheimer’s disease; PET; amyloid; glucose metabolism; apolipoprotein E

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