Age-Related Differences in Test-Retest Reliability in Resting-State Brain Functional Connectivity

Resting-state functional MRI (rs-fMRI) has emerged as a powerful tool for investigating brain functional connectivity (FC). Research in recent years has focused on assessing the reliability of FC across younger subjects within and between scan-sessions. Test-retest reliability in resting-state functional connectivity (RSFC) has not yet been examined in older adults. In this study, we investigated age-related differences in reliability and stability of RSFC across scans. In addition, we examined how global signal regression (GSR) affects RSFC reliability and stability. Three separate resting-state scans from 29 younger adults (18–35 yrs) and 26 older adults (55–85 yrs) were obtained from the International Consortium for Brain Mapping (ICBM) dataset made publically available as part of the 1000 Functional Connectomes project www.nitrc.org/projects/fcon_1000. 92 regions of interest (ROIs) with 5 cubic mm radius, derived from the default, cingulo-opercular, fronto-parietal and sensorimotor networks, were previously defined based on a recent study. Mean time series were extracted from each of the 92 ROIs from each scan and three matrices of z-transformed correlation coefficients were created for each subject, which were then used for evaluation of multi-scan reliability and stability. The young group showed higher reliability of RSFC than the old group with GSR (p-value = 0.028) and without GSR (p-value <0.001). Both groups showed a high degree of multi-scan stability of RSFC and no significant differences were found between groups. By comparing the test-retest reliability of RSFC with and without GSR across scans, we found significantly higher proportion of reliable connections in both groups without GSR, but decreased stability. Our results suggest that aging is associated with reduced reliability of RSFC which itself is highly stable within-subject across scans for both groups, and that GSR reduces the overall reliability but increases the stability in both age groups and could potentially alter group differences of RSFC.     

Effects of Low Doses of Pioglitazone on Resting-State Functional Connectivity in Conscious Rat Brain

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor-γ (PPARγ) agonist in clinical use for treatment of type 2 diabetes (T2DM). Accumulating evidence suggests PPARγ agonists may be useful for treating or delaying the onset of Alzheimer’s disease (AD), possibly via actions on mitochondria, and that dose strengths lower than those clinically used for T2DM may be efficacious. Our major objective was to determine if low doses of pioglitazone, administered orally, impacted brain activity. We measured blood-oxygenation-level dependent (BOLD) low-frequency fluctuations in conscious rats to map changes in brain resting-state functional connectivity due to daily, oral dosing with low-dose PIO. The connectivity in two neural circuits exhibited significant changes compared with vehicle after two days of treatment with PIO at 0.08 mg/kg/day. After 7 days of treatment with a range of PIO dose-strengths, connections between 17 pairs of brain regions were significantly affected. Functional connectivity with the CA1 region of the hippocampus, a region that is involved in memory and is affected early in the progression of AD, was specifically investigated in a seed-based analysis. This approach revealed that the spatial pattern of CA1 connectivity was consistent among all dose groups at baseline, prior to treatment with PIO, and in the control group imaged on day 7. Compared to baseline and controls, increased connectivity to CA1 was observed regionally in the hypothalamus and ventral thalamus in all PIO-treated groups, but was least pronounced in the group treated with the highest dose of PIO. These data support our hypothesis that PIO modulates neuronal and/or cerebrovascular function at dose strengths significantly lower than those used to treat T2DM and therefore may be a useful therapy for neurodegenerative diseases including AD.     

Functional Connectivity Alterations in Epilepsy from Resting-State Functional MRI

The study of functional brain connectivity alterations induced by neurological disorders and their analysis from resting state functional Magnetic Resonance Imaging (rfMRI) is generally considered to be a challenging task. The main challenge lies in determining and interpreting the large-scale connectivity of brain regions when studying neurological disorders such as epilepsy. We tackle this challenging task by studying the cortical region connectivity using a novel approach for clustering the rfMRI time series signals and by identifying discriminant functional connections using a novel difference statistic measure. The proposed approach is then used in conjunction with the difference statistic to conduct automatic classification experiments for epileptic and healthy subjects using the rfMRI data. Our results show that the proposed difference statistic measure has the potential to extract promising discriminant neuroimaging markers. The extracted neuroimaging markers yield 93.08% classification accuracy on unseen data as compared to 80.20% accuracy on the same dataset by a recent state-of-the-art algorithm. The results demonstrate that for epilepsy the proposed approach confirms known functional connectivity alterations between cortical regions, reveals some new connectivity alterations, suggests potential neuroimaging markers, and predicts epilepsy with high accuracy from rfMRI scans.     

Characteristics of Resting-State Functional Connectivity in HIV-Associated Neurocognitive Disorder

BackgroundHIV-associated neurocognitive disorder (HAND) can occur in patients without prior AIDS defining illness and can be debilitating. This study aimed to evaluate the difference in the patterns of intrinsic brain activity between patients with or without HAND for deepening our understanding of HAND.MethodsWe evaluated 24 HIV-infected individuals, 12 with previously diagnosed HAND and 12 previously diagnosed without HAND, and 11 seronegative individuals. These individuals then underwent repeat NP testing and a functional brain MRI scan. For functional MRI analysis, seed-based analysis with bilateral precuneus cortex seed was applied.ResultsAmong the 12 individuals with previously diagnosed HAND, 3 showed improvement of their neurocognitive function and 1 was excluded for worsening liver disease. Among the 12 patients who previously had normal neurocognitive function, 2 showed neurocognitive impairment. Overall, the HAND group, who had impaired cognitive function at the time of MRI scan, showed significant decrease of resting status functional connectivity between bilateral precuneus and prefrontal cortex (PFC) compared with nonHAND group, those who had normal neurocognitive function (Corrected P<0.05). The functional connectivity with the right inferior frontal operculum and right superior frontal gyrus was positively correlated with memory and learning ability.ConclusionsThis cross-sectional study found a significant difference in fMRI patterns between patients with and without HAND. Decreased functional connectivity between precuneus and PFC could be possible functional substrate for cognitive dysfunction in HIV patients, which should be characterized in a longitudinal study.     

Resting-State Functional Connectivity Patterns Predict Chinese Word Reading Competency

Resting-state functional connectivity (RSFC) offers a novel approach to reveal the temporal synchronization of functionally related brain regions. Recent studies have identified several RSFCs whose strength was associated with reading competence in alphabetic languages. In the present study, we examined the role of intrinsic functional relations for reading a non-alphabetic language – Chinese – by correlating RSFC maps of nine Chinese reading-related seed regions and reaction time in the single-character reading task. We found that Chinese reading efficiency was positively correlated with the connection between left inferior occipital gyrus and left superior parietal lobule, between right posterior fusiform gyrus and right superior parietal lobule, and between left inferior temporal gyrus and left inferior parietal lobule. These results could not be attributed to inter-individual differences arising from the peripheral processes of the reading task such as visual input detection and articulation. The observed RSFC-reading correlation relationships are discussed in the framework of Chinese character reading, including visuospatial analyses and semantic/phonological processes.     

Correlation between Infraslow-Electrical Brain Activity and Resting-State Functional MRI Connectivity in Patients with Chronic Cerebral Ischaemia

Human Physiology - The problem of studying the relationship of infraslow electrical activity with neural networks has gained importance due to the new facts on the modulation mechanisms of these...     

Maximizing Negative Correlations in Resting-State Functional Connectivity MRI by Time-Lag

This paper aims to better understand the physiological meaning of negative correlations in resting state functional connectivity MRI (r-fcMRI). The correlations between anatomy-based brain regions of 18 healthy humans were calculated and analyzed with and without a correction for global signal and with and without spatial smoothing. In addition, correlations between anatomy-based brain regions of 18 naïve anesthetized rats were calculated and compared to the human data. T-statistics were used to differentiate between positive and negative connections. The application of spatial smoothing and global signal correction increased the number of significant positive connections but their effect on negative connections was complex. Positive connections were mainly observed between cortical structures while most negative connections were observed between cortical and non-cortical structures with almost no negative connections between non-cortical structures. In both human and rats, negative connections were never observed between bilateral homologous regions. The main difference between positive and negative connections in both the human and rat data was that positive connections became less significant with time-lags, while negative connections became more significant with time-lag. This effect was evident in all four types of analyses (with and without global signal correction and spatial smoothing) but was most significant in the analysis with no correction for the global signal. We hypothesize that the valence of r-fcMRI connectivity reflects the relative contributions of cerebral blood volume (CBV) and flow (CBF) to the BOLD signal and that these relative contributions are location-specific. If cerebral circulation is primarily regulated by CBF in one region and by CBV in another, a functional connection between these regions can manifest as an r-fcMRI negative and time-delayed correlation. Similarly, negative correlations could result from spatially inhomogeneous responses of rCBV or rCBF alone. Consequently, neuronal regulation of brain circulation may be deduced from the valence of r-fcMRI connectivity.     

Abnormal Resting-State Connectivity at Functional MRI in Women with Premenstrual Syndrome

Objectives

Premenstrual syndrome (PMS) refers to a series of cycling and relapsing physical, emotion and behavior syndromes that occur in the luteal phase and resolve soon after the onset of menses. Although PMS is widely recognized, its neural mechanism is still unclear.

Design

To address this question, we measured brain activity for women with PMS and women without PMS (control group) using resting-state functional magnetic resonance imaging (rs-fMRI). In addition, the participants should complete the emotion scales (Beck Anxiety Inventory, BAI; Beck Depression Inventory, BDI, before the scanning) as well as the stress perception scale (Visual analog scale for stress, VAS, before and after the scanning).

Results

The results showed that compared with the control group, the PMS group had decreased connectivity in the middle frontal gyrus (MFG) and theparahippocampalgyrus (PHG), as well as increased connectivity in the left medial/superior temporal gyri (MTG/STG) and precentralgyrus within the default mode network (DMN); in addition, the PMS group had higher anxiety and depression scale scores, together with lower stress perception scores. Finally, there were significantly positive correlations between the stress perception scores and functional connectivity in the MFG and cuneus. The BDI scores in the PMS group were correlated negatively with the functional connectivity in the MFG and precuneus and correlated positively with the functional connectivity in the MTG.

Conclusion

These findings suggest that compared with normal women, women with PMS displayed abnormal stress sensitivity, which was reflected in the decreased and increased functional connectivity within the DMN, blunted stress perception and higher depression.     

Altered Resting-State Amygdala Functional Connectivity after 36 Hours of Total Sleep Deprivation

Objectives

Recent neuroimaging studies have identified a potentially critical role of the amygdala in disrupted emotion neurocircuitry in individuals after total sleep deprivation (TSD). However, connectivity between the amygdala and cerebral cortex due to TSD remains to be elucidated. In this study, we used resting-state functional MRI (fMRI) to investigate the functional connectivity changes of the basolateral amygdala (BLA) and centromedial amygdala (CMA) in the brain after 36 h of TSD.

Materials and Methods

Fourteen healthy adult men aged 25.9±2.3 years (range, 18–28 years) were enrolled in a within-subject crossover study. Using the BLA and CMA as separate seed regions, we examined resting-state functional connectivity with fMRI during rested wakefulness (RW) and after 36 h of TSD.

Results

TSD resulted in a significant decrease in the functional connectivity between the BLA and several executive control regions (left dorsolateral prefrontal cortex [DLPFC], right dorsal anterior cingulate cortex [ACC], right inferior frontal gyrus [IFG]). Increased functional connectivity was found between the BLA and areas including the left posterior cingulate cortex/precuneus (PCC/PrCu) and right parahippocampal gyrus. With regard to CMA, increased functional connectivity was observed with the rostral anterior cingulate cortex (rACC) and right precentral gyrus.

Conclusion

These findings demonstrate that disturbance in amygdala related circuits may contribute to TSD psychophysiology and suggest that functional connectivity studies of the amygdala during the resting state may be used to discern aberrant patterns of coupling within these circuits after TSD.     

研究报告: 大鼠感觉运动系统静息态脑网络研究

为了理解啮齿类动物的脑功能连接,本文利用9.4T fMRI获得轻度麻醉状态下大鼠静息状态及刺激激活的数据,通过互相关分析构建节点之间的相关系数矩阵并计算相应的网络参数．结果发现：给予前爪电刺激时,刺激对侧初级感觉皮层(S1)、丘脑(Tha)有较强的正激活,双侧尾状壳核(CPu)有较强的负激活．静息状态时大鼠感觉/运动皮层内部、丘脑内部的连接性较强,而感觉/运动皮层与丘脑之间的连接较弱,双侧感觉运动系统之间存在较强的同步低频振荡,感觉运动系统在静息态时的脑网络具有小世界属性．结果提示,啮齿类动物在大脑信息处理中的功能分离和整合可能与人类存在某些相似性,支持哺乳动物中枢神经系统的基本功能存在遗传保守性的观点．     

Altered Default Network Resting-State Functional Connectivity in Adolescents with Internet Gaming Addiction

Purpose

Excessive use of the Internet has been linked to a variety of negative psychosocial consequences. This study used resting-state functional magnetic resonance imaging (fMRI) to investigate whether functional connectivity is altered in adolescents with Internet gaming addiction (IGA).

Methods

Seventeen adolescents with IGA and 24 normal control adolescents underwent a 7.3 minute resting-state fMRI scan. Posterior cingulate cortex (PCC) connectivity was determined in all subjects by investigating synchronized low-frequency fMRI signal fluctuations using a temporal correlation method. To assess the relationship between IGA symptom severity and PCC connectivity, contrast images representing areas correlated with PCC connectivity were correlated with the scores of the 17 subjects with IGA on the Chen Internet Addiction Scale (CIAS) and Barratt Impulsiveness Scale-11 (BIS-11) and their hours of Internet use per week.

Results

There were no significant differences in the distributions of the age, gender, and years of education between the two groups. The subjects with IGA showed longer Internet use per week (hours) (p<0.0001) and higher CIAS (p<0.0001) and BIS-11 (p = 0.01) scores than the controls. Compared with the control group, subjects with IGA exhibited increased functional connectivity in the bilateral cerebellum posterior lobe and middle temporal gyrus. The bilateral inferior parietal lobule and right inferior temporal gyrus exhibited decreased connectivity. Connectivity with the PCC was positively correlated with CIAS scores in the right precuneus, posterior cingulate gyrus, thalamus, caudate, nucleus accumbens, supplementary motor area, and lingual gyrus. It was negatively correlated with the right cerebellum anterior lobe and left superior parietal lobule.

Conclusion

Our results suggest that adolescents with IGA exhibit different resting-state patterns of brain activity. As these alterations are partially consistent with those in patients with substance addiction, they support the hypothesis that IGA as a behavioral addiction that may share similar neurobiological abnormalities with other addictive disorders.     

Altered Resting-State Functional Connectivity of the Frontal-Striatal Reward System in Social Anxiety Disorder

We investigated differences in the intrinsic functional brain organization (functional connectivity) of the human reward system between healthy control participants and patients with social anxiety disorder. Functional connectivity was measured in the resting-state via functional magnetic resonance imaging (fMRI). 53 patients with social anxiety disorder and 33 healthy control participants underwent a 6-minute resting-state fMRI scan. Functional connectivity of the reward system was analyzed by calculating whole-brain temporal correlations with a bilateral nucleus accumbens seed and a ventromedial prefrontal cortex seed. Patients with social anxiety disorder, relative to the control group, had (1) decreased functional connectivity between the nucleus accumbens seed and other regions associated with reward, including ventromedial prefrontal cortex; (2) decreased functional connectivity between the ventromedial prefrontal cortex seed and lateral prefrontal regions, including the anterior and dorsolateral prefrontal cortices; and (3) increased functional connectivity between both the nucleus accumbens seed and the ventromedial prefrontal cortex seed with more posterior brain regions, including anterior cingulate cortex. Social anxiety disorder appears to be associated with widespread differences in the functional connectivity of the reward system, including markedly decreased functional connectivity between reward regions and between reward regions and lateral prefrontal cortices, and markedly increased functional connectivity between reward regions and posterior brain regions.     

Functional Connectivity Changes in Resting-State EEG as Potential Biomarker for Amyotrophic Lateral Sclerosis

Background

Amyotrophic Lateral Sclerosis (ALS) is heterogeneous and overlaps with frontotemporal dementia. Spectral EEG can predict damage in structural and functional networks in frontotemporal dementia but has never been applied to ALS.

Methods

18 incident ALS patients with normal cognition and 17 age matched controls underwent 128 channel EEG and neuropsychology assessment. The EEG data was analyzed using FieldTrip software in MATLAB to calculate simple connectivity measures and scalp network measures. sLORETA was used in nodal analysis for source localization and same methods were applied as above to calculate nodal network measures. Graph theory measures were used to assess network integrity.

Results

Cross spectral density in alpha band was higher in patients. In ALS patients, increased degree values of the network nodes was noted in the central and frontal regions in the theta band across seven of the different connectivity maps (p<0.0005). Among patients, clustering coefficient in alpha and gamma bands was increased in all regions of the scalp and connectivity were significantly increased (p=0.02). Nodal network showed increased assortativity in alpha band in the patients group. The Clustering Coefficient in Partial Directed Connectivity (PDC) showed significantly higher values for patients in alpha, beta, gamma, theta and delta frequencies (p=0.05).

Discussion

There is increased connectivity in the fronto-central regions of the scalp and areas corresponding to Salience and Default Mode network in ALS, suggesting a pathologic disruption of neuronal networking in early disease states. Spectral EEG has potential utility as a biomarker in ALS.     

Multimodal fMRI Resting-State Functional Connectivity in Granulin Mutations: The Case of Fronto-Parietal Dementia

Background

Monogenic dementias represent a great opportunity to trace disease progression from preclinical to symptomatic stages. Frontotemporal Dementia related to Granulin (GRN) mutations presents a specific framework of brain damage, involving fronto-temporal regions and long inter-hemispheric white matter bundles. Multimodal resting-state functional MRI (rs-fMRI) is a promising tool to carefully describe disease signature from the earliest disease phase.

Objective

To define local connectivity alterations in GRN related pathology moving from the presymptomatic (asymptomatic GRN mutation carriers) to the clinical phase of the disease (GRN- related Frontotemporal Dementia).

Methods

Thirty-one GRN Thr272fs mutation carriers (14 patients with Frontotemporal Dementia and 17 asymptomatic carriers) and 38 healthy controls were recruited. Local connectivity measures (Regional Homogeneity (ReHo), Fractional Amplitude of Low Frequency Fluctuation (fALFF) and Degree Centrality (DC)) were computed, considering age and gender as nuisance variables as well as the influence of voxel-level gray matter atrophy.

Results

Asymptomatic GRN carriers had selective reduced ReHo in the left parietal region and increased ReHo in frontal regions compared to healthy controls. Considering Frontotemporal Dementia patients, all measures (ReHo, fALFF and DC) were reduced in inferior parietal, frontal lobes and posterior cingulate cortex. Considering GRN mutation carriers, an inverse correlation with age in the posterior cingulate cortex, inferior parietal lobule and orbitofrontal cortex was found.

Conclusions

GRN pathology is characterized by functional brain network alterations even decades before the clinical onset; they involve the parietal region primarily and then spread to the anterior regions of the brain, supporting the concept of molecular nexopathies.     

Glutamate Concentration in the Medial Prefrontal Cortex Predicts Resting-State Cortical-Subcortical Functional Connectivity in Humans

Communication between cortical and subcortical regions is integral to a wide range of psychological processes and has been implicated in a number of psychiatric conditions. Studies in animals have provided insight into the biochemical and connectivity processes underlying such communication. However, to date no experiments that link these factors in humans in vivo have been carried out. To investigate the role of glutamate in individual differences in communication between the cortex – specifically the medial prefrontal cortex (mPFC) – and subcortical regions in humans, a combination of resting-state fMRI, DTI and MRS was performed. The subcortical target regions were the nucleus accumbens (NAc), dorsomedial thalamus (DMT), and periaqueductal grey (PAG). It was found that functional connectivity between the mPFC and each of the NAc and DMT was positively correlated with mPFC glutamate concentrations, whilst functional connectivity between the mPFC and PAG was negatively correlated with glutamate concentration. The correlations involving mPFC glutamate and FC between the mPFC and each of the DMT and PAG were mirrored by correlations with structural connectivity, providing evidence that the glutamatergic relationship may, in part, be due to direct connectivity. These results are in agreement with existing results from animal studies and may have relevance for MDD and schizophrenia.     

The Functional Connectivity Landscape of the Human Brain

Functional brain networks emerge and dissipate over a primarily static anatomical foundation. The dynamic basis of these networks is inter-regional communication involving local and distal regions. It is assumed that inter-regional distances play a pivotal role in modulating network dynamics. Using three different neuroimaging modalities, 6 datasets were evaluated to determine whether experimental manipulations asymmetrically affect functional relationships based on the distance between brain regions in human participants. Contrary to previous assumptions, here we show that short- and long-range connections are equally likely to strengthen or weaken in response to task demands. Additionally, connections between homotopic areas are the most stable and less likely to change compared to any other type of connection. Our results point to a functional connectivity landscape characterized by fluid transitions between local specialization and global integration. This ability to mediate functional properties irrespective of spatial distance may engender a diverse repertoire of cognitive processes when faced with a dynamic environment.     

Revealing Topological Organization of Human Brain Functional Networks with Resting-State Functional near Infrared Spectroscopy

Background

The human brain is a highly complex system that can be represented as a structurally interconnected and functionally synchronized network, which assures both the segregation and integration of information processing. Recent studies have demonstrated that a variety of neuroimaging and neurophysiological techniques such as functional magnetic resonance imaging (MRI), diffusion MRI and electroencephalography/magnetoencephalography can be employed to explore the topological organization of human brain networks. However, little is known about whether functional near infrared spectroscopy (fNIRS), a relatively new optical imaging technology, can be used to map functional connectome of the human brain and reveal meaningful and reproducible topological characteristics.

Results

We utilized resting-state fNIRS (R-fNIRS) to investigate the topological organization of human brain functional networks in 15 healthy adults. Brain networks were constructed by thresholding the temporal correlation matrices of 46 channels and analyzed using graph-theory approaches. We found that the functional brain network derived from R-fNIRS data had efficient small-world properties, significant hierarchical modular structure and highly connected hubs. These results were highly reproducible both across participants and over time and were consistent with previous findings based on other functional imaging techniques.

Conclusions

Our results confirmed the feasibility and validity of using graph-theory approaches in conjunction with optical imaging techniques to explore the topological organization of human brain networks. These results may expand a methodological framework for utilizing fNIRS to study functional network changes that occur in association with development, aging and neurological and psychiatric disorders.     

Resting-State fMRI Functional Connectivity Is Associated with Sleepiness,Imagery, and Discontinuity of Mind

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the functional architecture of the healthy human brain and how it is affected by learning, lifelong development, brain disorders or pharmacological intervention. Non-sensory experiences are prevalent during rest and must arise from ongoing brain activity, yet little is known about this relationship. Here, we used two runs of rs-fMRI both immediately followed by the Amsterdam Resting-State Questionnaire (ARSQ) to investigate the relationship between functional connectivity within ten large-scale functional brain networks and ten dimensions of thoughts and feelings experienced during the scan in 106 healthy participants. We identified 11 positive associations between brain-network functional connectivity and ARSQ dimensions. ‘Sleepiness’ exhibited significant associations with functional connectivity within Visual, Sensorimotor and Default Mode networks. Similar associations were observed for ‘Visual Thought’ and ‘Discontinuity of Mind’, which may relate to variation in imagery and thought control mediated by arousal fluctuations. Our findings show that self-reports of thoughts and feelings experienced during a rs-fMRI scan help understand the functional significance of variations in functional connectivity, which should be of special relevance to clinical studies.     

Resting-State Network Disruption and APOE Genotype in Alzheimer's Disease: A lagged Functional Connectivity Study

Background

The apolipoprotein E epsilon 4 (APOE-4) is associated with a genetic vulnerability to Alzheimer''s disease (AD) and with AD-related abnormalities in cortical rhythms. However, it is unclear whether APOE-4 is linked to a specific pattern of intrinsic functional disintegration of the brain after the development of the disease or during its different stages. This study aimed at identifying spatial patterns and effects of APOE genotype on resting-state oscillations and functional connectivity in patients with AD, using a physiological connectivity index called “lagged phase synchronization”.

Methodology/Principal Findings

Resting EEG was recorded during awake, eyes-closed state in 125 patients with AD and 60 elderly controls. Source current density and functional connectivity were determined using eLORETA. Patients with AD exhibited reduced parieto-occipital alpha oscillations compared with controls, and those carrying the APOE-4 allele had reduced alpha activity in the left inferior parietal and temporo-occipital cortex relative to noncarriers. There was a decreased alpha2 connectivity pattern in AD, involving the left temporal and bilateral parietal cortex. Several brain regions exhibited increased lagged phase synchronization in low frequencies, specifically in the theta band, across and within hemispheres, where temporal lobe connections were particularly compromised. Areas with abnormal theta connectivity correlated with cognitive scores. In patients with early AD, we found an APOE-4-related decrease in interhemispheric alpha connectivity in frontal and parieto-temporal regions.

Conclusions/Significance

In addition to regional cortical dysfunction, as indicated by abnormal alpha oscillations, there are patterns of functional network disruption affecting theta and alpha bands in AD that associate with the level of cognitive disturbance or with the APOE genotype. These functional patterns of nonlinear connectivity may potentially represent neurophysiological or phenotypic markers of AD, and aid in early detection of the disorder.