Intrinsic Functional Connectivity Networks Research Articles

Resting-state functional connectivity in children cooled for neonatal encephalopathy.

Therapeutic hypothermia improves outcomes following neonatal hypoxic-ischaemic encephalopathy, reducing cases of death and severe disability such as cerebral palsy compared with normothermia management. However, when cooled children reach early school-age, they have cognitive and motor impairments which are associated with underlying alterations to brain structure and white matter connectivity. It is unknown whether these differences in structural connectivity are associated with differences in functional connectivity between cooled children and healthy controls. Resting-state functional MRI has been used to characterize static and dynamic functional connectivity in children, both with typical development and those with neurodevelopmental disorders. Previous studies of resting-state brain networks in children with hypoxic-ischaemic encephalopathy have focussed on the neonatal period. In this study, we used resting-state fMRI to investigate static and dynamic functional connectivity in children aged 6-8 years who were cooled for neonatal hypoxic-ischaemic without cerebral palsy [n = 22, median age (interquartile range) 7.08 (6.85-7.52) years] and healthy controls matched for age, sex and socioeconomic status [n = 20, median age (interquartile range) 6.75 (6.48-7.25) years]. Using group independent component analysis, we identified 31 intrinsic functional connectivity networks consistent with those previously reported in children and adults. We found no case-control differences in the spatial maps of these intrinsic connectivity networks. We constructed subject-specific static functional connectivity networks by measuring pairwise Pearson correlations between component time courses and found no case-control differences in functional connectivity after false discovery rate correction. To study the time-varying organization of resting-state networks, we used sliding window correlations and deep clustering to investigate dynamic functional connectivity characteristics. We found k = 4 repetitively occurring functional connectivity states, which exhibited no case-control differences in dwell time, fractional occupancy or state functional connectivity matrices. In this small cohort, the spatiotemporal characteristics of resting-state brain networks in cooled children without severe disability were too subtle to be differentiated from healthy controls at early school-age, despite underlying differences in brain structure and white matter connectivity, possibly reflecting a level of recovery of healthy resting-state brain function. To our knowledge, this is the first study to investigate resting-state functional connectivity in children with hypoxic-ischaemic encephalopathy beyond the neonatal period and the first to investigate dynamic functional connectivity in any children with hypoxic-ischaemic encephalopathy.

Intrinsic connectivity within the affective salience network moderates adolescent susceptibility to negative and positive peer norms

Not all adolescents are equally susceptible to peer influence, and for some, peer influence exerts positive rather than negative effects. Using resting-state functional magnetic resonance imaging, the current study examined how intrinsic functional connectivity networks associated with processing social cognitive and affective stimuli predict adolescents’ (n = 87, ages 11–14 years) prosocial tendencies and risky behaviors in the context of positive and negative peer norms. We tested the moderating role of four candidate intrinsic brain networks—associated with mentalizing, cognitive control, motivational relevance, and affective salience—in peer influence susceptibility. Only intrinsic connectivity within the affective salience network significantly moderated the association between peer norms and adolescent behavior above and beyond the other networks. Adolescents with high intrinsic connectivity within the affective salience network reported greater prosocial tendencies in contexts with more positive peer norms but greater risk-taking behavior in contexts with more negative peer norms. In contrast, peer norms were not associated with adolescent behavior for individuals with low affective salience within-network intrinsic connectivity. The mentalizing network, cognitive control network, and motivational relevance network were not associated with individual differences in peer influence susceptibility. This study identifies key neural mechanisms underlying differential susceptibility to positive and negative peer influence in early adolescence, with a particular emphasis on the role of affective salience over traditional mentalizing, regulatory, and motivational processes.

The Functional Network of the Visual Cortex Is Altered in Migraine.

Migraine is a common neurological disorder characterized by recurrent episodes of headache, frequently accompanied by various reversible neurological disturbances. Some migraine patients experience visually triggered migraine headache, and most attacks of migraine with aura are associated with the disturbance of vision and photophobia, suggesting an abnormal neural activity in the visual cortex. Numerous studies have shown a large cortical hemodynamic response to visual stimulation and an altered intrinsic visual functional connectivity network in patients with migraine. In this interictal study, we applied a novel data-driven method with fMRI to identify the functional network in the visual cortex evoked by visual stimulation and investigated the effect of migraine on this network. We found that the distribution of the functional network along both the ventral and dorsal visual pathways differed between migraine patients and non-headache healthy control participants, providing evidence that the functional network was altered in migraine between headaches. The functional network was bilateral in the control participants but substantially lateralized in the migraine patients. The results also indicated different effects of colored lenses on the functional network for both participant groups.

Atypical resting state functional connectivity in mild traumatic brain injury.

ObjectivesThis study aimed to investigate changes in three intrinsic functional connectivity networks (IFCNs; default mode network [DMN], salience network [SN], and task‐positive network [TPN]) in individuals who had sustained a mild traumatic brain injury (mTBI).MethodsResting‐state functional magnetic resonance imaging (rs‐fMRI) data were acquired from 27 mTBI patients with persistent postconcussive symptoms, along with 26 age‐ and sex‐matched controls. These individuals were recruited from a Level‐1 trauma center, at least 3 months after a traumatic episode. IFCNs were established based on seed‐to‐voxel, region‐of‐interest (ROI) to ROI, and independent component analyses (ICA). Subsequently, we analyzed the relationship between functional connectivity and postconcussive symptoms.ResultsSeed‐to‐voxel analysis of rs‐fMRI demonstrated decreased functional connectivity in the right lateral parietal lobe, part of the DMN, and increased functional connectivity in the supramarginal gyrus, part of the SN. Our TPN showed both hypo‐ and hyperconnectivity dependent on seed location. Within network hypoconnectivity was observed in the visual network also using group comparison. Using an ICA, we identified altered network functional connectivity in regions within four IFCNs (sensorimotor, visual, DMN, and dorsal attentional). A significant negative correlation between dorsal attentional network connectivity and behavioral symptoms score was also found.ConclusionsOur findings indicate that rs‐fMRI may be of use clinically in order to assess disrupted functional connectivity among IFCNs in mTBI patients. Improved mTBI diagnostic and prognostic information could be especially relevant for athletes looking to safely return to play, as well for individuals from the general population with persistent postconcussive symptoms months after injury, who hope to resume activity.

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.

Heterogeneous distribution of tau pathology in the behavioural variant of Alzheimer’s disease

ObjectiveThe clinical phenotype of the rare behavioural variant of Alzheimer’s disease (bvAD) is insufficiently understood. Given the strong clinico-anatomical correlations of tau pathology in AD, we investigated the distribution of...

The Relationship of Functional Connectivity of the Sensorimotor and Visual Cortical Networks Between Resting and Task States.

The intrinsic activity of the human brain maintains its general operation at rest, and this ongoing spontaneous activity exhibits a high level of spatiotemporally correlated activity among different cortical areas, showing intrinsically organized brain functional connectivity (FC) networks. Many functional network properties of the human brain have been investigated extensively for both rest and task states, but the relationship between these two states has been rarely investigated yet and remains unclear. Comparing well-defined task-specific networks with corresponding intrinsic FC networks may reveal their relationship and improve our understanding of the brain’s operations at both rest and task states. This study investigated the relationship of the sensorimotor and visual cortical FC networks between the resting and task states. The sensorimotor task was to rub right-hand fingers, and the visual task was to open and close eyes, respectively. Our study demonstrated a general relationship of the task-evoked FC network with its corresponding intrinsic FC network, regardless of the tasks. For each task type, the study showed that (1) the intrinsic and task-evoked FC networks shared a common network and the task enhanced the coactivity within that common network compared to the intrinsic activity; (2) some areas within the intrinsic FC network were not activated by the task, and therefore, the task activated only partial but not whole of the intrinsic FC network; and (3) the task activated substantial additional areas outside the intrinsic FC network and therefore recruited more intrinsic FC networks to perform the task.

Extended-amygdala intrinsic functional connectivity networks: A population study.

Pre‐clinical and human neuroimaging research implicates the extended‐amygdala (ExtA) (including the bed nucleus of the stria terminalis [BST] and central nucleus of the amygdala [CeA]) in networks mediating negative emotional states associated with stress and substance‐use behaviours. The extent to which individual ExtA structures form a functionally integrated unit is controversial. We utilised a large sample (n > 1,000 healthy young adult humans) to compare the intrinsic functional connectivity networks (ICNs) of the BST and CeA using task‐free functional magnetic resonance imaging (fMRI) data from the Human Connectome Project. We assessed whether inter‐individual differences within these ICNs were related to two principal components representing negative disposition and alcohol use. Building on recent primate evidence, we tested whether within BST‐CeA intrinsic functional connectivity (iFC) was heritable and further examined co‐heritability with our principal components. We demonstrate the BST and CeA to have discrete, but largely overlapping ICNs similar to previous findings. We found no evidence that within BST—CeA iFC was heritable; however, post hoc analyses found significant BST iFC heritability with the broader superficial and centromedial amygdala regions. There were no significant correlations or co‐heritability associations with our principal components either across the ICNs or for specific BST‐Amygdala iFC. Possible differences in phenotype associations across task‐free, task‐based, and clinical fMRI are discussed, along with suggestions for more causal investigative paradigms that make use of the now well‐established ExtA ICNs.

MiR‐9 could mediate the relationship between childhood maltreatment and depression

AbstractBackgroundChildhood maltreatment (CM) is regarded as an important risk factor for major disorder depression (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear.PurposeTo explore the neural basis of the effects of CM on MDD and the potential effects of microRNA‐9 (miR‐9) in mediating these processes.MethodForty unmedicated MDD patients and 34 healthy controls (HCs) completed resting‐state fMRI scans and peripheral blood miR‐9 tests. The neural substrates of CM, miR‐9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) network were investigated in MDD patients. Two‐step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR‐9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs.ResultMDD patients showed higher miR‐9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR‐9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal‐striatum pathway and limbic system. The connection of amygdala to prefrontal‐limbic circuits separately mediated the effects of CM severity on the miR‐9 levels, and the impacts of miR‐9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR‐9 levels, CM severity, and AFC strength in prefrontal‐limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%).ConclusionMiR‐9 may play a crucial role in the process of CM experience‐produced brain changes targeting prefrontal‐limbic regions and that subsequently leads to depression. The present neuroimaging‐epigenetic results provide new insight into our understanding of MDD pathophysiology.

Identification of microRNA-9 linking the effects of childhood maltreatment on depression using amygdala connectivity

Childhood maltreatment (CM) is regarded as an important risk factor for major depressive disorder (MDD). However, the neural links corresponding to the process of early CM experience producing brain alterations and then leading to depression later remain unclear. To explore the neural basis of the effects of CM on MDD and the potential role of microRNA-9 (miR-9) in these processes, we recruited 40 unmedicated MDD patients and 34 healthy controls (HCs) to complete resting-state fMRI scans and peripheral blood miR-9 tests. The neural substrates of CM, miR-9, and depression, as well as their interactive effects on intrinsic amygdala functional connectivity (AFC) networks were investigated in MDD patients. Two-step mediation analysis was separately employed to explore whether AFC strength mediates the association among CM severity, miR-9 levels, and depression. A support vector classifier (SVC) model of machine learning was used to distinguish MDD patients from HCs. MDD patients showed higher miR-9 levels that were negatively correlated with CM scores and depressive severity. Overlapping effects of CM, miR-9, and depressive severity on bilateral AFC networks in MDD patients were primarily located in the prefrontal-striatum pathway and limbic system. The connection of amygdala to prefrontal-limbic circuits could mediate the effects of CM severity on the miR-9 levels, as well as the impacts of miR-9 levels on the severity of depression in MDD patients. Furthermore, the SVC model, which integrated miR-9 levels, CM severity, and AFC strength in prefrontal-limbic regions, had good power in differentiating MDD patients from HCs (accuracy 85.1%). MiR-9 may play a crucial role in the process of CM experience-produced brain changes targeting prefrontal-limbic regions and that subsequently leads to depression. The present neuroimaging-epigenetic results provide new insight into our understanding of MDD pathophysiology.

The changes of brain functional networks in young adult smokers based on independent component analysis.

Intrinsic functional connectivity (FC) networks, including the default mode network (DMN), central executive network (CEN), and salience network (SN), have been implicated in nicotine addiction. However, litter evidence exists about the abnormalities in the three networks in young adult smokers. Forty-eight young adult smokers and 49 age- and gender-matched non-smokers were recruited in the present study. Resting-state functional magnetic resonance imaging (fMRI) data were analyzed by a combination of independent component analysis (ICA) and dual regression to identify potential differences of FC patterns in the DMN, CEN, and SN. Compared to non-smokers, young adult smokers showed enhanced FC of the left posterior cingulate cortex (LPCC), right medial prefrontal cortex (RMPFC) and right precuneus within the DMN network, of the right dorsolateral prefrontal cortex (DLPFC) within the right CEN, and of the left anterior insula (LAI) within the SN. We also found increased FC between the DMN, CEN and key node of the SN (anterior insula, AI). Correlation analysis showed that the increased FC within the networks was significantly correlated with smoking behaviors (pack-years, smoking duration, FTND, first smoking age, and number of cigarettes per day). Our findings may provide additional evidence for conceptualizing the framework of nicotine addiction as a disease of intercommunicating brain networks.

Cerebellar dentate nucleus functional connectivity with cerebral cortex in Alzheimer's disease and memory: a seed-based approach

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by specific patterns of gray and white matter damage and cognitive/behavioral manifestations. The cerebellum has also been implicated in the pathophysiology of AD. Because the cerebellum is known to have strong functional connectivity (FC) with associative cerebral cortex regions, it is possible to hypothesize that it is incorporated into intrinsic FC networks relevant to cognitive manifestation of AD. In the present study, the cerebellar dentate nucleus, the largest cerebellar nucleus and the major output channel to the cerebral cortex, was chosen as the region of interest to test potential cerebellocerebral FC alterations and correlations with patients' memory impairment in a group of patients with AD. Compared to controls, patients with AD showed an increase in FC between the dentate nucleus and regions of the lateral temporal lobe. This study demonstrates that lower memory performances in AD may be related to altered FC within specific cerebellocortical functional modules, thus suggesting the cerebellar contribution to AD pathophysiology and typical memory dysfunctions.

Typical and Aberrant Functional Brain Flexibility: Lifespan Development and Aberrant Organization in Traumatic Brain Injury and Dyslexia.

Intrinsic functional connectivity networks derived from different neuroimaging methods and connectivity estimators have revealed robust developmental trends linked to behavioural and cognitive maturation. The present study employed a dynamic functional connectivity approach to determine dominant intrinsic coupling modes in resting-state neuromagnetic data from 178 healthy participants aged 8–60 years. Results revealed significant developmental trends in three types of dominant intra- and inter-hemispheric neuronal population interactions (amplitude envelope, phase coupling, and phase-amplitude synchronization) involving frontal, temporal, and parieto-occipital regions. Multi-class support vector machines achieved 89% correct classification of participants according to their chronological age using dynamic functional connectivity indices. Moreover, systematic temporal variability in functional connectivity profiles, which was used to empirically derive a composite flexibility index, displayed an inverse U-shaped curve among healthy participants. Lower flexibility values were found among age-matched children with reading disability and adults who had suffered mild traumatic brain injury. The importance of these results for normal and abnormal brain development are discussed in light of the recently proposed role of cross-frequency interactions in the fine-grained coordination of neuronal population activity.

Abnormal amygdala resting-state functional connectivity in primary dysmenorrhea.

Neuroimaging studies have manifested functional abnormalities in pain-related brain regions in patients with primary dysmenorrhea (PDM). However, as the key region in brain pain matrix, whether and how the amygdala functional network alteration in PDM is unclear. In this study, we aimed to investigate the intrinsic amygdala functional connectivity (AFC) network alteration in patients with PDM during ovulatory period. Thirty-six PDM patients and 35 matched healthy controls were enrolled in this study. The AFC was constructed using amygdala-based functional connectivity using resting-state functional MRI data. The plasma prostaglandin E2 level was measured during ovulatory period. The group difference on AFC network was conducted and further explored the clinical significant of the abnormal AFC network in PDM patients. Compared to the healthy control group, PDM patients showed increased left AFC in default mode network, including medial prefrontal cortex, posterior cingulate cortex/precuneus, angular gyrus, and inferior temporal gyrus, while, decreased left AFC at bilateral nucleus accumbens/orbital frontal cortex, and decreased right AFC network in right orbital frontal cortex and insula, ventral tegmental area (VTA), left hippocampal, and insula. In addition, the decreased right AFC in VTA was associated with higher plasma prostaglandin E2 level in the PDM group. The AFC network was disrupted in PDM patients, mainly in default mode network and reward system. The disrupted connectivity between amygdala and VTA might contribute to the prostaglandins associated pathological mechanism of PDM.

A review of hippocampal activation in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) is often characterized by deficits in memory encoding and retrieval and aberrant fear and extinction learning. The hippocampus plays a critical role in memory and contextual processing and has been implicated in intrinsic functional connectivity networks involved in self-referential thought and memory-related processes. This review focuses on hippocampal activation findings during memory and fear and extinction learning tasks, as well as resting state hippocampal connectivity in individuals with PTSD. A preponderance of functional neuroimaging studies to date, using memory, fear learning, and extinction tasks, report decreased or "controls comparable" hippocampal activation in individuals with PTSD, which is usually associated with poorer performance on the task imaged. Existing evidence thus raises the possibility that greater hippocampal recruitment in PTSD participants may be required for similar performance levels. Studies of resting state functional connectivity in PTSD predominantly report reduced within-network connectivity in the default mode network (DMN), as well as greater coupling between the DMN and salience network (SN) via the hippocampus. Together, these findings suggest that deficient hippocampal activation in PTSD may be associated with poorer performance during memory, extinction recall, and fear renewal tasks. Furthermore, studies of resting state connectivity implicate the hippocampus in decreased within-network DMN connectivity and greater coupling with SN regions characteristic of PTSD.

Neuroimaging study of the amygdala functional connectivity network on the co-existence of depression and cognitive impairment in nondemented elderly

Objective To investigate the characteristics of amygdala neural circuitry in comorbidity of late-life depression (LLD) and cognitive impairment. Methods Twenty-four LLD, eighteen amnestic mild cognitive impairments (aMCI), thirteen aMCI with depression (dMCI) and thirty cognitive normal (CN) subjects completed resting-state functional magnetic resonance imaging scan.Main effects of depression and MCI and their interactions on the intrinsic amygdala functional connectivity network (AFCN) connectivity were examined.Behavioral significance of AFCN that voxel-wised amygdala connectivity correlating with depression severity and memory scores were also tested after controlling the effects of covariates, including age, gender, education, gray matter atrophy, and group. Results The immediate memory and delayed memory function in the aMCI group (-0.75±0.77 and -1.13±0.56) and the dMCI group (-1.07±0.79 and -1.00±0.52) were significantly lower than those of the CN group (0.46±0.73 and 0.60±0.61), and the difference was statistically significant (P<0.01). Depression and anxiety in the LLD group (1.00±0.53 and 0.93±0.98) and the dMCI group (0.86±0.80 and 0.78±0.82) were significantly higher than those of the CN group (-0.92±0.25 and -0.74±0.22), and the difference was statistically significant (P<0.01). Brain network analysis showed that separated neural circuits were implicated in the depression and cognitive impairment.Importantly, interactive effects of depression and MCI on the AFCN were also identified, especially in the bilateral somatomotor area, inferior parietal cortex/precuneus, posterior cingulate cortex, right medial prefrontal cortex/dorsolateral prefrontal cortex and hippocampus.Behavioral significance of AFCN also revealed the distinctive neural circuits involved in the depression severity and memory deficits, respectively.Conjunction analysis further identified the overlapped neural circuits associated with depression and memory deficits were primarily in the left DLPFC, insula, hippocampus, right inferior prefrontal cortex and dorsomedial prefrontal cortex. Conclusions Depression and cognitive impairment synergistically facilitate functional decoupling of AFCN and thus compromise the integrity of amygdala networks.Distinct depression-related or MCI-related neural constructs represent the characteristics of clinical phenotype of depression or MCI alone, while overlapped circuits probably reveal the neural basis of comorbidity of LLD and MCI. Key words: Late-life depression; Amnestic mild cognitive impairment; Comorbidity; Resting-state functional magnetic resonance imaging; Amygdala; Functional connectivity

P.3.017 - Differential effects of left and right prefrontal magnetic stimulation on resting state connectivity in healthy individuals

Introduction High frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained great interest in multiple clinical and research fields. With HF-rTMS a coil – wherein an alternating current is running – is placed on top of the skull, creating a magnetic field that influences the perpendicular neural tissue, thereby stimulating the neuronal activity of the targeted cortical area [1]. Although it is believed that HF-rTMS accomplishes its effect by influencing entire neuronal networks [2]. One cortical area frequently chosen as stimulation target is the dorsolateral prefrontal cortex (dlPFC), as it is part of the control network. However, despite its popularity and frequent use, very little is known about the differential effect of HF-rTMS over the left and right dlPFC on intrinsic functional connectivity networks in healthy individuals. Therefore the current study will address this issue. Methods The current study assessed the differential effects of left or right dlPFC HF-rTMS (corrected for sham) on intrinsic functional connectivity networks in a sample of 45 healthy individuals. The study was a randomized, single-blind trial with two sessions. During the first session demographic data were obtained and a baseline resting state functional magnetic resonance imaging (rsfMRI) scan was performed. During the second session subjects were randomized to either sham dlPFC HF-rTMS (n=15), left active dlPFC HF-rTMS (n=15) or right active dlPFC HF-rTMS (n=15) directly followed by a second rsfMRI scan. A HF-rTMS session consisted of sixty trains of 5 seconds at a frequency of 10Hz. During the sham condition the coil was tilted 90 degrees relative to the skull. This condition was used in order to correct for time and placebo effects. Independent Component Analysis (ICA) were performed to assess baseline differences and stimulation effects on within and between network functional connectivity. The five components of interest were the left frontal parietal network, right frontal parietal network, default mode network, salience network and reward network. Results The three stimulation groups did not differ on within as well as between functional connectivity of the five components of interest at baseline. Regarding the stimulation effects on within network connectivity, stimulation of the left dlPFC resulted in decreased functional connectivity in the salience network whereas right dlPFC stimulation resulted in increased functional connectivity within this network. Regarding the stimulation effects on between network connectivity, no differences between left or right dlPFC stimulation were found. Discussion Stimulation of either the left or the right dlPFC (compared to sham stimulation) thus seems to lead to opposite effects within the salience network. Since the role of this network in directing attention between internal and external processes [3], and decreased functional connectivity is associated with worsened cognitive functioning in aging [4], the results of this study might have implications for the clinical effects of HF-rTMS over the dlPFC. Therefore future (clinical) studies should implement questionnaires and/ or neurocognitive tasks in order to be able to relate changes in functional connectivity to changes in cognitive functioning.

Distinct neural correlates of episodic memory among apolipoprotein E alleles in cognitively normal elderly.

The apolipoprotein E (APOE) ε4 and ε2 alleles are acknowledged genetic factors modulating Alzheimer's disease (AD) risk and episodic memory (EM) deterioration in an opposite manner. Mounting neuroimaging studies describe EM-related brain activity differences among APOE alleles but remain limited in elucidating the underlying mechanism. Here, we hypothesized that the APOE ε2, ε3, and ε4 alleles have distinct EM neural substrates, as a manifestation of degeneracy, underlying their modulations on EM-related brain activity and AD susceptibility. To test the hypothesis, we identified neural correlates of EM function by correlating intrinsic hippocampal functional connectivity networks with neuropsychological EM performances in a voxelwise manner, with 129 cognitively normal elderly subjects (36 ε2 carriers, 44 ε3 homozygotes, and 49 ε4 carriers). We demonstrated significantly different EM neural correlates among the three APOE allele groups. Specifically, in the ε3 homozygotes, positive EM neural correlates were characterized in the Papez circuit regions; in the ε4 carriers, positive EM neural correlates involved the lateral temporal cortex, premotor cortex/sensorimotor cortex/superior parietal lobule, and cuneus; and in the ε2 carriers, negative EM neural correlates appeared in the bilateral frontopolar, posteromedial, and sensorimotor cortex. Further, in the ε4 carriers, the interaction between age and EM function occurred in the temporoparietal junction and prefrontal cortex. Our findings suggest that the underlying mechanism of APOE polymorphism modulations on EM function and AD susceptibility is genetically related to the neural degeneracy of EM function across APOE alleles.

Differential Effects of Left and Right Prefrontal High-Frequency Repetitive Transcranial Magnetic Stimulation on Resting-State Functional Magnetic Resonance Imaging in Healthy Individuals.

High-frequency repetitive transcranial magnetic stimulation (HF-rTMS) has gained great interest in multiple clinical and research fields and is believed to accomplish its effect by influencing neuronal networks. The dorsolateral prefrontal cortex (dlPFC) is frequently chosen as the cortical target for HF-rTMS. However, very little is known about the differential effect of HF-rTMS over the left and right dlPFC on intrinsic functional connectivity networks in patients or in healthy individuals. The current study assessed the differential effects of left or right HF-rTMS (corrected for sham) on intrinsic independent component analysis (ICA)-defined functional connectivity networks in a sample of 45 healthy individuals. All subjects had a first scanning session in which baseline functional connectivity was assessed. During the second session, individuals received one session of left, right, or sham dlPFC HF-rTMS (60 5-sec trains of 10 Hz at 110% motor threshold). The sham condition was used to correct for time and placebo effects. ICAs were performed to assess baseline differences and stimulation effects on within- and between-network functional connectivity. Stimulation of the left dlPFC resulted in decreased functional connectivity in the salience network, whereas right dlPFC stimulation resulted in increased functional connectivity within this network. No differences between left or right dlPFC stimulation were found in between-network connectivity. These results suggest that left and right HF-rTMS may have differential effects, and more research is needed on the clinical consequences.

Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer's disease.

Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer's disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer's disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer's disease network degeneration phenotype.