Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (ß = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

Opposite Dynamics of GABA and Glutamate Levels in the Occipital Cortex during Visual Processing.

Magnetic resonance spectroscopy (MRS) measures the two most common inhibitory and excitatory neurotransmitters, GABA and glutamate, in the human brain. However, the role of MRS-derived GABA and glutamate signals in relation to system-level neural signaling and behavior is not fully understood. In this study, we investigated levels of GABA and glutamate in the visual cortex of healthy human participants (both genders) in three functional states with increasing visual input. Compared with a baseline state of eyes closed, GABA levels decreased after opening the eyes in darkness and Glx levels remained stable during eyes open but increased with visual stimulation. In relevant states, GABA and Glx correlated with amplitude of fMRI signal fluctuations. Furthermore, visual discriminatory performance correlated with the level of GABA, but not Glx. Our study suggests that differences in brain states can be detected through the contrasting dynamics of GABA and Glx, which has implications in interpreting MRS measurements.SIGNIFICANCE STATEMENT GABA and glutamate are the two most abundant neurotransmitters in human brain. Their interaction, known as inhibitory-excitatory balance, plays a crucial role in establishing spontaneous and stimulus-driven brain activity. Yet, the relationship between magnetic resonance spectroscopy (MRS)-derived levels of both metabolites and fMRI is still a matter of dispute. In this work, we study GABA and glutamate in three states of visual processing and in relation to fMRI and visual discriminatory performance in healthy people. We found that states of visual processing can be detected through the contrasting dynamics of GABA and glutamate and their correlation with fMRI signals. We also demonstrated that GABA, but not glutamate, in the visual system predicts visual performance. Our results provide insights into MRS-derived GABA and glutamate measurements.

Increased Global Interaction Across Functional Brain Modules During Cognitive Emotion Regulation.

Cognitive emotion regulation (CER) enables humans to flexibly modulate their emotions. While local theories of CER neurobiology suggest interactions between specialized local brain circuits underlying CER, e.g., in subparts of amygdala and medial prefrontal cortices (mPFC), global theories hypothesize global interaction increases among larger functional brain modules comprising local circuits. We tested the global CER hypothesis using graph-based whole-brain network analysis of functional MRI data during aversive emotional processing with and without CER. During CER, global between-module interaction across stable functional network modules increased. Global interaction increase was particularly driven by subregions of amygdala and cuneus-nodes of highest nodal participation-that overlapped with CER-specific local activations, and by mPFC and posterior cingulate as relevant connector hubs. Results provide evidence for the global nature of human CER, complementing functional specialization of embedded local brain circuits during successful CER.

Metabolic connectivity mapping reveals effective connectivity in the resting human brain.

Directionality of signaling among brain regions provides essential information about human cognition and disease states. Assessing such effective connectivity (EC) across brain states using functional magnetic resonance imaging (fMRI) alone has proven difficult, however. We propose a novel measure of EC, termed metabolic connectivity mapping (MCM), that integrates undirected functional connectivity (FC) with local energy metabolism from fMRI and positron emission tomography (PET) data acquired simultaneously. This method is based on the concept that most energy required for neuronal communication is consumed postsynaptically, i.e., at the target neurons. We investigated MCM and possible changes in EC within the physiological range using "eyes open" versus "eyes closed" conditions in healthy subjects. Independent of condition, MCM reliably detected stable and bidirectional communication between early and higher visual regions. Moreover, we found stable top-down signaling from a frontoparietal network including frontal eye fields. In contrast, we found additional top-down signaling from all major clusters of the salience network to early visual cortex only in the eyes open condition. MCM revealed consistent bidirectional and unidirectional signaling across the entire cortex, along with prominent changes in network interactions across two simple brain states. We propose MCM as a novel approach for inferring EC from neuronal energy metabolism that is ideally suited to study signaling hierarchies in the brain and their defects in brain disorders.

Impact of Global Mean Normalization on Regional Glucose Metabolism in the Human Brain.

Because the human brain consumes a disproportionate fraction of the resting body's energy, positron emission tomography (PET) measurements of absolute glucose metabolism (CMRglc) can serve as disease biomarkers. Global mean normalization (GMN) of PET data reveals disease-based differences from healthy individuals as fractional changes across regions relative to a global mean. To assess the impact of GMN applied to metabolic data, we compared CMRglc with and without GMN in healthy awake volunteers with eyes closed (i.e., control) against specific physiological/clinical states, including healthy/awake with eyes open, healthy/awake but congenitally blind, healthy/sedated with anesthetics, and patients with disorders of consciousness. Without GMN, global CMRglc alterations compared to control were detected in all conditions except in congenitally blind where regional CMRglc variations were detected in the visual cortex. However, GMN introduced regional and bidirectional CMRglc changes at smaller fractions of the quantitative delocalized changes. While global information was lost with GMN, the quantitative approach (i.e., a validated method for quantitative baseline metabolic activity without GMN) not only preserved global CMRglc alterations induced by opening eyes, sedation, and varying consciousness but also detected regional CMRglc variations in the congenitally blind. These results caution the use of GMN upon PET-measured CMRglc data in health and disease.

Cognitive emotion regulation modulates the balance of competing influences on ventral striatal aversive prediction error signals.

Cognitive emotion regulation (CER) is a critical human ability to face aversive emotional stimuli in a flexible way, via recruitment of specific prefrontal brain circuits. Animal research reveals a central role of ventral striatum in emotional behavior, for both aversive conditioning, with striatum signaling aversive prediction errors (aPE), and for integrating competing influences of distinct striatal inputs from regions such as the prefrontal cortex (PFC), amygdala, hippocampus and ventral tegmental area (VTA). Translating these ventral striatal findings from animal research to human CER, we hypothesized that successful CER would affect the balance of competing influences of striatal afferents on striatal aPE signals, in a way favoring PFC as opposed to 'subcortical' (i.e., non-isocortical) striatal inputs. Using aversive Pavlovian conditioning with and without CER during fMRI, we found that during CER, superior regulators indeed reduced the modulatory impact of 'subcortical' striatal afferents (hippocampus, amygdala and VTA) on ventral striatal aPE signals, while keeping the PFC impact intact. In contrast, inferior regulators showed an opposite pattern. Our results demonstrate that ventral striatal aPE signals and associated competing modulatory inputs are critical mechanisms underlying successful cognitive regulation of aversive emotions in humans.

Changes in resting-state connectivity in musicians with embouchure dystonia.

OBJECTIVE: Embouchure dystonia is a highly disabling task-specific dystonia in professional brass musicians leading to spasms of perioral muscles while playing the instrument. As they are asymptomatic at rest, resting-state functional magnetic resonance imaging in these patients can reveal changes in functional connectivity within and between brain networks independent from dystonic symptoms. METHODS: We therefore compared embouchure dystonia patients to healthy musicians with resting-state functional magnetic resonance imaging in combination with independent component analyses. RESULTS: Patients showed increased functional connectivity of the bilateral sensorimotor mouth area and right secondary somatosensory cortex, but reduced functional connectivity of the bilateral sensorimotor hand representation, left inferior parietal cortex, and mesial premotor cortex within the lateral motor function network. Within the auditory function network, the functional connectivity of bilateral secondary auditory cortices, right posterior parietal cortex and left sensorimotor hand area was increased, the functional connectivity of right primary auditory cortex, right secondary somatosensory cortex, right sensorimotor mouth representation, bilateral thalamus, and anterior cingulate cortex was reduced. Negative functional connectivity between the cerebellar and lateral motor function network and positive functional connectivity between the cerebellar and primary visual network were reduced. CONCLUSIONS: Abnormal resting-state functional connectivity of sensorimotor representations of affected and unaffected body parts suggests a pathophysiological predisposition for abnormal sensorimotor and audiomotor integration in embouchure dystonia. Altered connectivity to the cerebellar network highlights the important role of the cerebellum in this disease. © 2016 International Parkinson and Movement Disorder Society.

Changes in extra-striatal functional connectivity in patients with schizophrenia in a psychotic episode.

BACKGROUND: In patients with schizophrenia in a psychotic episode, intra-striatal intrinsic connectivity is increased in the putamen but not ventral striatum. Furthermore, multimodal changes have been observed in the anterior insula that interact extensively with the putamen. AIMS: We hypothesised that during psychosis, putamen extra-striatal functional connectivity is altered with both the anterior insula and areas normally connected with the ventral striatum (i.e. altered functional connectivity distinctiveness of putamen and ventral striatum). METHOD: We acquired resting-state functional magnetic resonance images from 21 patients with schizophrenia in a psychotic episode and 42 controls. RESULTS: Patients had decreased functional connectivity: the putamen with right anterior insula and dorsal prefrontal cortex, the ventral striatum with left anterior insula. Decreased functional connectivity between putamen and right anterior insula was specifically associated with patients' hallucinations. Functional connectivity distinctiveness was impaired only for the putamen. CONCLUSIONS: Results indicate aberrant extra-striatal connectivity during psychosis and a relationship between reduced putamen-right anterior insula connectivity and hallucinations. Data suggest that altered intrinsic connectivity links striatal and insular pathophysiology in psychosis.

How do you make me feel better? Social cognitive emotion regulation and the default mode network.

Socially-induced cognitive emotion regulation (Social-Reg) is crucial for emotional well-being and social functioning; however, its brain mechanisms remain poorly understood. Given that both social cognition and cognitive emotion regulation engage key regions of the default-mode network (DMN), we hypothesized that Social-Reg would rely on the DMN, and that its effectiveness would be associated with social functioning. During functional MRI, negative emotions were elicited by pictures, and - via short instructions - a psychotherapist either down-regulated participants' emotions by employing reappraisal (Reg), or asked them to simply look at the pictures (Look). Adult Attachment Scale was used to measure social functioning. Contrasting Reg versus Look, aversive emotions were successfully reduced during Social-Reg, with increased activations in the prefrontal and parietal cortices, precuneus and the left temporo-parietal junction. These activations covered key nodes of the DMN and were associated with Social-Reg success. Furthermore, participants' attachment security was positively correlated with both Social-Reg success and orbitofrontal cortex involvement during Social-Reg. In addition, specificity of the neural correlates of Social-Reg was confirmed by comparisons with participants' DMN activity at rest and their brain activations during a typical emotional self-regulation task based on the same experimental paradigm without a psychotherapist. Our results provide first evidence for the specific involvement of the DMN in Social-Reg, and the association of Social-Reg with individual differences in attachment security. The findings suggest that DMN dysfunction, found in many neuropsychiatric disorders, may impair the ability to benefit from Social-Reg.

Imbalance in subregional connectivity of the right temporoparietal junction in major depression.

Major depressive disorder (MDD) involves impairment in cognitive and interpersonal functioning. The right temporoparietal junction (RTPJ) is a key brain region subserving cognitive-attentional and social processes. Yet, findings on the involvement of the RTPJ in the pathophysiology of MDD have so far been controversial. Recent connectivity-based parcellation data revealed a topofunctional dualism within the RTPJ, linking its anterior and posterior part (aRTPJ/pRTPJ) to antagonistic brain networks for attentional and social processing, respectively. Comparing functional resting-state connectivity of the aRTPJ and pRTPJ in 72 MDD patients and 76 well-matched healthy controls, we found a seed (aRTPJ/pRTPJ) × diagnosis (MDD/controls) interaction in functional connectivity for eight regions. Employing meta-data from a large-scale neuroimaging database, functional characterization of these regions exhibiting differentially altered connectivity with the aRTPJ/pRTPJ revealed associations with cognitive (dorsolateral prefrontal cortex, parahippocampus) and behavioral (posterior medial frontal cortex) control, visuospatial processing (dorsal visual cortex), reward (subgenual anterior cingulate cortex, medial orbitofrontal cortex, posterior cingulate cortex), as well as memory retrieval and social cognition (precuneus). These findings suggest that an imbalance in connectivity of subregions, rather than disturbed connectivity of the RTPJ as a whole, characterizes the connectional disruption of the RTPJ in MDD. This imbalance may account for key symptoms of MDD in cognitive, emotional, and social domains. Hum Brain Mapp 37:2931-2942, 2016. © 2016 Wiley Periodicals, Inc.

Neural Correlates of Sevoflurane-induced Unconsciousness Identified by Simultaneous Functional Magnetic Resonance Imaging and Electroencephalography.

BACKGROUND: The neural correlates of anesthetic-induced unconsciousness have yet to be fully elucidated. Sedative and anesthetic states induced by propofol have been studied extensively, consistently revealing a decrease of frontoparietal and thalamocortical connectivity. There is, however, less understanding of the effects of halogenated ethers on functional brain networks. METHODS: The authors recorded simultaneous resting-state functional magnetic resonance imaging and electroencephalography in 16 artificially ventilated volunteers during sevoflurane anesthesia at burst suppression and 3 and 2 vol% steady-state concentrations for 700 s each to assess functional connectivity changes compared to wakefulness. Electroencephalographic data were analyzed using symbolic transfer entropy (surrogate of information transfer) and permutation entropy (surrogate of cortical information processing). Functional magnetic resonance imaging data were analyzed by an independent component analysis and a region-of-interest-based analysis. RESULTS: Electroencephalographic analysis showed a significant reduction of anterior-to-posterior symbolic transfer entropy and global permutation entropy. At 2 vol% sevoflurane concentrations, frontal and thalamic networks identified by independent component analysis showed significantly reduced within-network connectivity. Primary sensory networks did not show a significant change. At burst suppression, all cortical networks showed significantly reduced functional connectivity. Region-of-interest-based thalamic connectivity at 2 vol% was significantly reduced to frontoparietal and posterior cingulate cortices but not to sensory areas. CONCLUSIONS: Sevoflurane decreased frontal and thalamocortical connectivity. The changes in blood oxygenation level dependent connectivity were consistent with reduced anterior-to-posterior directed connectivity and reduced cortical information processing. These data advance the understanding of sevoflurane-induced unconsciousness and contribute to a neural basis of electroencephalographic measures that hold promise for intraoperative anesthesia monitoring.

Disrupted Intrinsic Networks Link Amyloid-ß Pathology and Impaired Cognition in Prodromal Alzheimer's Disease.

Amyloid-ß pathology (Aß) and impaired cognition characterize Alzheimer's disease (AD); however, neural mechanisms that link Aß-pathology with impaired cognition are incompletely understood. Large-scale intrinsic connectivity networks (ICNs) are potential candidates for this link: Aß-pathology affects specific networks in early AD, these networks show disrupted connectivity, and they process specific cognitive functions impaired in AD, like memory or attention. We hypothesized that, in AD, regional changes of ICNs, which persist across rest- and cognitive task-states, might link Aß-pathology with impaired cognition via impaired intrinsic connectivity. Pittsburgh compound B (PiB)-positron emission tomography reflecting in vivo Aß-pathology, resting-state fMRI, task-fMRI, and cognitive testing were used in patients with prodromal AD and healthy controls. In patients, default mode network's (DMN) functional connectivity (FC) was reduced in the medial parietal cortex during rest relative to healthy controls, relatively increased in the same region during an attention-demanding task, and associated with patients' cognitive impairment. Local PiB-uptake correlated negatively with DMN connectivity. Importantly, corresponding results were found for the right lateral parietal region of an attentional network. Finally, structural equation modeling confirmed a direct influence of DMN resting-state FC on the association between Aß-pathology and cognitive impairment. Data provide evidence that disrupted intrinsic network connectivity links Aß-pathology with cognitive impairment in early AD.

Local activity determines functional connectivity in the resting human brain: a simultaneous FDG-PET/fMRI study.

Over the last decade, synchronized resting-state fluctuations of blood oxygenation level-dependent (BOLD) signals between remote brain areas [so-called BOLD resting-state functional connectivity (rs-FC)] have gained enormous relevance in systems and clinical neuroscience. However, the neural underpinnings of rs-FC are still incompletely understood. Using simultaneous positron emission tomography/magnetic resonance imaging we here directly investigated the relationship between rs-FC and local neuronal activity in humans. Computational models suggest a mechanistic link between the dynamics of local neuronal activity and the functional coupling among distributed brain regions. Therefore, we hypothesized that the local activity (LA) of a region at rest determines its rs-FC. To test this hypothesis, we simultaneously measured both LA (glucose metabolism) and rs-FC (via synchronized BOLD fluctuations) during conditions of eyes closed or eyes open. During eyes open, LA increased in the visual system, and the salience network (i.e., cingulate and insular cortices) and the pattern of elevated LA coincided almost exactly with the spatial pattern of increased rs-FC. Specifically, the voxelwise regional profile of LA in these areas strongly correlated with the regional pattern of rs-FC among the same regions (e.g., LA in primary visual cortex accounts for ∼ 50%, and LA in anterior cingulate accounts for ∼ 20% of rs-FC with the visual system). These data provide the first direct evidence in humans that local neuronal activity determines BOLD FC at rest. Beyond its relevance for the neuronal basis of coherent BOLD signal fluctuations, our procedure may translate into clinical research particularly to investigate potentially aberrant links between local dynamics and remote functional coupling in patients with neuropsychiatric disorders.

Cognitive emotion regulation enhances aversive prediction error activity while reducing emotional responses.

Cognitive emotion regulation is a powerful way of modulating emotional responses. However, despite the vital role of emotions in learning, it is unknown whether the effect of cognitive emotion regulation also extends to the modulation of learning. Computational models indicate prediction error activity, typically observed in the striatum and ventral tegmental area, as a critical neural mechanism involved in associative learning. We used model-based fMRI during aversive conditioning with and without cognitive emotion regulation to test the hypothesis that emotion regulation would affect prediction error-related neural activity in the striatum and ventral tegmental area, reflecting an emotion regulation-related modulation of learning. Our results show that cognitive emotion regulation reduced emotion-related brain activity, but increased prediction error-related activity in a network involving ventral tegmental area, hippocampus, insula and ventral striatum. While the reduction of response activity was related to behavioral measures of emotion regulation success, the enhancement of prediction error-related neural activity was related to learning performance. Furthermore, functional connectivity between the ventral tegmental area and ventrolateral prefrontal cortex, an area involved in regulation, was specifically increased during emotion regulation and likewise related to learning performance. Our data, therefore, provide first-time evidence that beyond reducing emotional responses, cognitive emotion regulation affects learning by enhancing prediction error-related activity, potentially via tegmental dopaminergic pathways.

Aberrant topology of striatum's connectivity is associated with the number of episodes in depression.

In major depressive disorder, depressive episodes reoccur in ∼60% of cases; however, neural mechanisms of depressive relapse are poorly understood. Depressive episodes are characterized by aberrant topology of the brain's intrinsic functional connectivity network, and the number of episodes is one of the most important predictors for depressive relapse. In this study we hypothesized that specific changes of the topology of intrinsic connectivity interact with the course of episodes in recurrent depressive disorder. To address this hypothesis, we investigated which changes of connectivity topology are associated with the number of episodes in patients, independently of current symptoms and disease duration. Fifty subjects were recruited including 25 depressive patients (two to 10 episodes) and 25 gender- and age-matched control subjects. Resting-state functional magnetic resonance imaging, Harvard-Oxford brain atlas, wavelet-transformation of atlas-shaped regional time-series, and their pairwise Pearson's correlation were used to define individual connectivity matrices. Matrices were analysed by graph-based methods, resulting in outcome measures that were used as surrogates of intrinsic network topology. Topological scores were subsequently compared across groups, and, for patients only, related with the number of depressive episodes and current symptoms by partial correlation analysis. Concerning the whole brain connectivity network of patients, small-world topology was preserved but global efficiency was reduced and global betweenness-centrality increased. Aberrant nodal efficiency and centrality of regional connectivity was found in the dorsal striatum, inferior frontal and orbitofrontal cortex as well as in the occipital and somatosensory cortex. Inferior frontal changes were associated with current symptoms, whereas aberrant right putamen network topology was associated with the number of episodes. Results were controlled for effects of total grey matter volume, medication, and total disease duration. This finding provides first evidence that in major depressive disorder aberrant topology of the right putamen's intrinsic connectivity pattern is associated with the course of depressive episodes, independently of current symptoms, medication status and disease duration. Data suggest that the reorganization of striatal connectivity may interact with the course of episodes in depression thereby contributing to depressive relapse risk.

Within-patient correspondence of amyloid-ß and intrinsic network connectivity in Alzheimer's disease.

There is striking overlap between the spatial distribution of amyloid-ß pathology in patients with Alzheimer's disease and the spatial distribution of high intrinsic functional connectivity in healthy persons. This overlap suggests a mechanistic link between amyloid-ß and intrinsic connectivity, and indeed there is evidence in patients for the detrimental effects of amyloid-ß plaque accumulation on intrinsic connectivity in areas of high connectivity in heteromodal hubs, and particularly in the default mode network. However, the observed spatial extent of amyloid-ß exceeds these tightly circumscribed areas, suggesting that previous studies may have underestimated the negative impact of amyloid-ß on intrinsic connectivity. We hypothesized that the known positive baseline correlation between patterns of amyloid-ß and intrinsic connectivity may mask the larger extent of the negative effects of amyloid-ß on connectivity. Crucially, a test of this hypothesis requires the within-patient comparison of intrinsic connectivity and amyloid-ß distributions. Here we compared spatial patterns of amyloid-ß-plaques (measured by Pittsburgh compound B positron emission tomography) and intrinsic functional connectivity (measured by resting-state functional magnetic resonance imaging) in patients with prodromal Alzheimer's disease via spatial correlations in intrinsic networks covering fronto-parietal heteromodal cortices. At the global network level, we found that amyloid-ß and intrinsic connectivity patterns were positively correlated in the default mode and several fronto-parietal attention networks, confirming that amyloid-ß aggregates in areas of high intrinsic connectivity on a within-network basis. Further, we saw an internetwork gradient of the magnitude of correlation that depended on network plaque-load. After accounting for this globally positive correlation, local amyloid-ß-plaque concentration in regions of high connectivity co-varied negatively with intrinsic connectivity, indicating that amyloid-ß pathology adversely reduces connectivity anywhere in an affected network as a function of local amyloid-ß-plaque concentration. The local negative association between amyloid-ß and intrinsic connectivity was much more pronounced than conventional group comparisons of intrinsic connectivity would suggest. Our findings indicate that the negative impact of amyloid-ß on intrinsic connectivity in heteromodal networks is underestimated by conventional analyses. Moreover, our results provide first within-patient evidence for correspondent patterns of amyloid-ß and intrinsic connectivity, with the distribution of amyloid-ß pathology following functional connectivity gradients within and across intrinsic networks.

Link between hippocampus' raised local and eased global intrinsic connectivity in AD.

BACKGROUND: The hippocampus (HP) is part of the default mode network (DMN), and both are key targets of Alzheimer's disease (AD). Because of widespread network degeneration, it has been suggested that increasing HP disconnection from the DMN may lead to progressive disinhibition of intra-HP synchronized activity. METHODS: To analyze HP local (i.e., within HP) and global (i.e., within DMN) intrinsic functional connectivity (local/global intrinsic functional connectivity [iFC]), healthy controls and patients with mild cognitive impairment and AD dementia were assessed by spatial high and normal resolution resting-state functional magnetic resonance imaging. RESULTS: Although patients' parietal local-iFC was reduced and positively correlated with reduced global-iFC within the DMN, HP local connectivity was progressively increased and negatively correlated with HP decreased global connectivity. Increased intra-HP connectivity was associated with impaired memory. CONCLUSION: Our result demonstrates a link between increased local and reduced global hippocampal connectivity in AD. Increased intra-HP synchrony may contribute to distinct symptoms such as memory impairment or more speculatively epileptic seizure.

Predicting effective connectivity from resting-state networks in healthy elderly and patients with prodromal Alzheimer's disease.

Using functional neuroimaging techniques two aspects of functional integration in the human brain have been investigated, functional connectivity and effective connectivity. In this study we examined both connectivity types in parallel within an executive attention network during rest and while performing an attention task. We analyzed the predictive value of resting-state functional connectivity on task-induced effective connectivity in patients with prodromal Alzheimer's disease (AD) and healthy elderly. We found that in healthy elderly, functional connectivity was a significant predictor for effective connectivity, however, it was frequency-specific. Effective top-down connectivity emerging from prefrontal areas was related with higher frequencies of functional connectivity (e.g., 0.08-0.15 Hz), in contrast to effective bottom-up connectivity going to prefrontal areas, which was related to lower frequencies of functional connectivity (e.g., 0.001-0.03 Hz). In patients, the prediction of effective connectivity by functional connectivity was disturbed. We conclude that functional connectivity and effective connectivity are interrelated in healthy brains but this relationship is aberrant in very early AD.

Intrinsic network connectivity reflects consistency of synesthetic experiences.

Studying cognitive processes underlying synesthesia, a condition in which stimulation of one sensory modality automatically leads to abnormal additional sensory perception, allows insights into the neural mechanisms of normal and abnormal cross-modal sensory processing. Consistent with the notion that synesthesia results from hyperconnectivity, functional connectivity analysis (adopting independent component analysis and seed-based correlation analysis) of resting-state functional magnetic resonance imaging data of 12 grapheme-color synesthetes and 12 nonsynesthetic control subjects revealed, in addition to increased intranetwork connectivity, both a global and a specific (medial and lateral visual networks to a right frontoparietal network) increase of intrinsic internetwork connectivity in grapheme-color synesthesia. Moreover, this increased intrinsic network connectivity reflected the strength of synesthetic experiences. These findings constitute the first direct evidence of increased functional network connectivity in synesthesia. In addition to this significant contribution to the understanding of the neural mechanisms of synesthesia, our results have important general implications. In combination with data derived from clinical populations, our data strongly suggest that altered differences in intrinsic network connectivity are directly related to the phenomenology of human experiences.

Simultaneous electroencephalographic and functional magnetic resonance imaging indicate impaired cortical top-down processing in association with anesthetic-induced unconsciousness.

BACKGROUND: In imaging functional connectivity (FC) analyses of the resting brain, alterations of FC during unconsciousness have been reported. These results are in accordance with recent electroencephalographic studies observing impaired top-down processing during anesthesia. In this study, simultaneous records of functional magnetic resonance imaging (fMRI) and electroencephalogram were performed to investigate the causality of neural mechanisms during propofol-induced loss of consciousness by correlating FC in fMRI and directional connectivity (DC) in electroencephalogram. METHODS: Resting-state 63-channel electroencephalogram and blood oxygen level-dependent 3-Tesla fMRI of 15 healthy subjects were simultaneously registered during consciousness and propofol-induced loss of consciousness. To indicate DC, electroencephalographic symbolic transfer entropy was applied as a nonlinear measure of mutual interdependencies between underlying physiological processes. The relationship between FC of resting-state networks of the brain (z values) and DC was analyzed by a partial correlation. RESULTS: Independent component analyses of resting-state fMRI showed decreased FC in frontoparietal default networks during unconsciousness, whereas FC in primary sensory networks increased. DC indicated a decline in frontal-parietal (area under the receiver characteristic curve, 0.92; 95% CI, 0.68-1.00) and frontooccipital (0.82; 0.53-1.00) feedback DC (P<0.05 corrected). The changes of FC in the anterior default network correlated with the changes of DC in frontal-parietal (rpartial=+0.62; P=0.030) and frontal-occipital (+0.63; 0.048) electroencephalographic electrodes (P<0.05 corrected). CONCLUSION: The simultaneous propofol-induced suppression of frontal feedback connectivity in the electroencephalogram and of frontoparietal FC in the fMRI indicates a fundamental role of top-down processing for consciousness.