Brain network connectivity–behavioral relationships exhibit trait‐like properties: Evidence from hippocampal connectivity and memory

Despite a growing number of studies showing relationships between behavior and resting‐state functional MRI measures of large‐scale brain network connectivity, no study to our knowledge has sought to investigate whether intrinsic connectivity–behavioral relationships are stable over time. In this study, we investigated the stability of such brain–behavior relationships at two timepoints, approximately 1 week apart. We focused on the relationship between the strength of hippocampal connectivity to posterior cingulate cortex and episodic memory performance. Our results showed that this relationship is stable across samples of a different age and reliable over two points in time. These findings provide the first evidence that the relationship between large‐scale intrinsic network connectivity and episodic memory performance is a stable characteristic that varies between individuals. © 2015 Wiley Periodicals, Inc.     

Functional brain connectivity at rest changes after working memory training

Networks of functional connectivity are highly consistent across participants, suggesting that functional connectivity is for a large part predetermined. However, several studies have shown that functional connectivity may change depending on instructions or previous experience. In the present study, we investigated whether 6 weeks of practice with a working memory task changes functional connectivity during a resting period preceding the task. We focused on two task‐relevant networks, the frontoparietal network and the default network, using seed regions in the right middle frontal gyrus (MFG) and the medial prefrontal cortex (PFC), respectively. After practice, young adults showed increased functional connectivity between the right MFG and other regions of the frontoparietal network, including bilateral superior frontal gyrus, paracingulate gyrus, and anterior cingulate cortex. In addition, they showed reduced functional connectivity between the medial PFC and right posterior middle temporal gyrus. Moreover, a regression with performance changes revealed a positive relation between performance increases and changes of frontoparietal connectivity, and a negative relation between performance increases and changes of default network connectivity. Next, to study whether experience‐dependent effects would be different during development, we also examined practice effects in a pilot sample of 12‐year‐old children. No practice effects were found in this group, suggesting that practice‐related changes of functional connectivity are age‐dependent. Nevertheless, future studies with larger samples are necessary to confirm this hypothesis. Hum Brain Mapp, 2013. © 2011 Wiley Periodicals, Inc.     

Functional network connectivity during rest and task conditions: A comparative study

Functional connectivity (FC) examines temporal statistical dependencies among distant brain regions by means of seed‐based analysis or independent component analysis (ICA). Spatial ICA also makes it possible to investigate FC at the network level, termed functional network connectivity (FNC). The dynamics of each network (ICA component), which may consist of several remote regions is described by the ICA time‐course of that network; hence, FNC studies statistical dependencies among ICA time‐courses. In this article, we compare comprehensively FNC in the resting state and during performance of an auditory oddball (AOD) task in 28 healthy subjects on relevant (nonartifactual) brain networks. The results show global FNC decrease during the performance of the task. In addition, we show that specific networks enlarge and/or demonstrate higher activity during the performance of the task. The results suggest that performing an active task like AOD may be facilitated by recruiting more neurons and higher activation of related networks rather than collaboration among different brain networks. We also evaluated the impact of temporal filtering on FNC analyses. Results showed that the results are not significantly affected by filtering. Hum Brain Mapp 34:2959–2971, 2013. © 2012 Wiley Periodicals, Inc.     

Default‐mode network functional connectivity is closely related to metabolic activity

Over the last decade, the brain's default‐mode network (DMN) and its function has attracted a lot of attention in the field of neuroscience. However, the exact underlying mechanisms of DMN functional connectivity, or more specifically, the blood‐oxygen level‐dependent (BOLD) signal, are still incompletely understood. In the present study, we combined 2‐deoxy‐2‐[¹⁸F]fluoroglucose positron emission tomography (FDG‐PET), proton magnetic resonance spectroscopy (¹H‐MRS), and resting‐state functional magnetic resonance imaging (rs‐fMRI) to investigate more directly the association between local glucose consumption, local glutamatergic neurotransmission and DMN functional connectivity during rest. The results of the correlation analyzes using the dorsal posterior cingulate cortex (dPCC) as seed region showed spatial similarities between fluctuations in FDG‐uptake and fluctuations in BOLD signal. More specifically, in both modalities the same DMN areas in the inferior parietal lobe, angular gyrus, precuneus, middle, and medial frontal gyrus were positively correlated with the dPCC. Furthermore, we could demonstrate that local glucose consumption in the medial frontal gyrus, PCC and left angular gyrus was associated with functional connectivity within the DMN. We did not, however, find a relationship between glutamatergic neurotransmission and functional connectivity. In line with very recent findings, our results lend further support for a close association between local metabolic activity and functional connectivity and provide further insights towards a better understanding of the underlying mechanism of the BOLD signal. Hum Brain Mapp 36:2027–2038, 2015. © 2015 Wiley Periodicals, Inc.     

Effective brain connectivity at rest is associated with choice‐induced preference formation

Preferences can change as a consequence of making hard decisions whereby the value of chosen options increases and the value of rejected options decreases. Such choice‐induced preference changes have been associated with brain areas detecting choice conflict (anterior cingulate cortex, ACC), updating stimulus value (dorsolateral prefrontal cortex, dlPFC) and supporting memory of stimulus value (hippocampus and ventromedial prefrontal cortex, vmPFC). Here we investigated whether resting‐state neuronal activity within these regions is associated with the magnitude of individuals' preference updates. We fitted a dynamic causal model (DCM) to resting‐state neuronal activity in the spectral domain (spDCM) and estimated the causal connectivity among core regions involved in preference formation following hard choices. The extent of individuals' choice‐induced preference changes were found to be associated with a diminished resting‐state excitation between the left dlPFC and the vmPFC, whereas preference consistency was related to a higher resting‐state excitation from the ACC to the left hippocampus and vmPFC. Our results point to a model of preference formation during which the dynamic network configurations between left dlPFC, ACC, vmPFC and left hippocampus at rest are linked to preference change or stability.     

Reduced executive and default network functional connectivity in cigarette smokers

Altered functional connectivity has been associated with acute and chronic nicotine use. Connectivity alterations, specifically in the right and left executive control networks (RECN/LECN) and the default mode network (DMN), may contribute to the addiction cycle. The objective of this study was to determine if executive control network (ECN) and DMN connectivity is different between non‐smokers and smokers and whether reductions in connectivity are related to chronic cigarette use. The RECN, LECN, and DMN were identified in resting state functional magnetic resonance imaging data in 650 subjects. Analyses tested for group differences in network connectivity strength, controlling for age and alcohol use. There was a significant group effect on LECN and DMN connectivity strength with smokers (n = 452) having lower network strengths than non‐smokers (n = 198). Smokers had lower connectivity than non‐smokers associated with key network hubs: the dorsolateral prefrontal cortex, and parietal nodes within ECNs. Further, ECN connectivity strength was negatively associated with pack years of cigarette use. Our data suggest that chronic nicotine use negatively impacts functional connectivity within control networks that may contribute to the difficulty smokers have in quitting. Hum Brain Mapp 36:872–882, 2015. © 2014 Wiley Periodicals, Inc.     

Functional connectivity between posterior hippocampus and retrosplenial complex predicts individual differences in navigational ability

Individuals vary widely in their ability to orient and navigate within the environment. Previous neuroimaging research has shown that hippocampus (HC) and scene‐responsive regions (retrosplenial complex [RSC] and parahippocampal gyrus/parahippocampal place area [PPA]) were crucial for spatial orienting and navigation. Resting‐state functional connectivity and a self‐reported questionnaire of navigational ability were used to examine the hypothesis that the pattern of reciprocal connections between these regions reflects individual differences in spatial navigation. It was found that the functional connectivity between the posterior HC and RSC was significantly higher in good than in poor navigators. These results confirmed the crucial role of hippocampal and extra‐hippocampal regions in spatial navigation and provided new insight into how spontaneous brain activity may account for individual differences in spatial ability. © 2016 Wiley Periodicals, Inc.     

Functional connectivity in amygdalar‐sensory/(pre)motor networks at rest: new evidence from the Human Connectome Project

The word ‘e‐motion’ derives from the Latin word ‘ex‐moveo’ which literally means ‘moving away from something/somebody’. Emotions are thus fundamental to prime action and goal‐directed behavior with obvious implications for individual's survival. However, the brain mechanisms underlying the interactions between emotional and motor cortical systems remain poorly understood. A recent diffusion tensor imaging study in humans has reported the existence of direct anatomical connections between the amygdala and sensory/(pre)motor cortices, corroborating an initial observation in animal research. Nevertheless, the functional significance of these amygdala‐sensory/(pre)motor pathways remain uncertain. More specifically, it is currently unclear whether a distinct amygdala‐sensory/(pre)motor circuit can be identified with resting‐state functional magnetic resonance imaging (rs‐fMRI). This is a key issue, as rs‐fMRI offers an opportunity to simultaneously examine distinct neural circuits that underpin different cognitive, emotional and motor functions, while minimizing task‐related performance confounds. We therefore tested the hypothesis that the amygdala and sensory/(pre)motor cortices could be identified as part of the same resting‐state functional connectivity network. To this end, we examined independent component analysis results in a very large rs‐fMRI data‐set drawn from the Human Connectome Project (n = 820 participants, mean age: 28.5 years). To our knowledge, we report for the first time the existence of a distinct amygdala‐sensory/(pre)motor functional network at rest. rs‐fMRI studies are now warranted to examine potential abnormalities in this circuit in psychiatric and neurological diseases that may be associated with alterations in the amygdala‐sensory/(pre)motor pathways (e.g. conversion disorders, impulse control disorders, amyotrophic lateral sclerosis and multiple sclerosis).     

Age differences in the default network at rest and the relation to self-referential processing

Older adults show a ‘positivity bias’ in tasks involving emotion and self-referential processing. A critical network that is involved in self-referencing and shows age-related decline is the default network (DN). The purpose of the current study was to investigate age differences in pre- and post-task DN functional connectivity (FC) and signal variability, and to examine whether they are predictive of the positivity bias in self-referencing. We measured FC and within-subject variability of the DN in resting-state scans preceding and following tasks involving personality judgements on the self and a close other. Older adults endorsed more positive traits than younger adults on both tasks. FC was weaker post-task in older vs younger adults, and younger adults had greater variability than older adults in DN nodes. Younger adults with higher post-task DN variability had more negative self-ratings. For both age groups, greater FC in the DN was associated with more negative self-ratings. Neither FC nor variability was related to other ratings, despite the potential for self-processing when making other judgements. Our findings suggest that ageing leads to reduced FC and variability in the DN, which is most apparent after task, and may be one mechanism underlying the positive bias with age.     

Extratemporal functional connectivity impairments at rest are related to memory performance in mesial temporal epilepsy

Mesial temporal lobe epilepsy (MTLE) is the most frequent form of focal epilepsy. At rest, there is evidence that brain abnormalities in MTLE are not limited to the epileptogenic region, but extend throughout the whole brain. It is also well established that MTLE patients suffer from episodic memory deficits. Thus, we investigated the relation between the functional connectivity seen at rest in fMRI and episodic memory impairments in MTLE. We focused on resting state BOLD activity and evaluated whether functional connectivity (FC) differences emerge from MTL seeds in left and right MTLE groups, compared with healthy controls. Results revealed significant FC reductions in both patient groups, localized in angular gyri, thalami, posterior cingulum and medial frontal cortex. We found that the FC between the left non‐pathologic MTL and the medial frontal cortex was positively correlated with the delayed recall score of a non‐verbal memory test in right MTLE patients, suggesting potential adaptive changes to preserve this memory function. In contrast, we observed a negative correlation between a verbal memory test and the FC between the left pathologic MTL and posterior cingulum in left MTLE patients, suggesting potential functional maladaptative changes in the pathologic hemisphere. Overall, the present study provides some indication that left MTLE may be more impairing than right MTLE patients to normative functional connectivity. Our data also indicates that the pattern of extra‐temporal FC may vary as a function of episodic memory material and each hemisphere's capacity for cognitive reorganization. Hum Brain Mapp 34:2202–2216, 2013. © 2012 Wiley Periodicals, Inc.     

Multimodal investigation of triple network connectivity in patients with 22q11DS and association with executive functions

Large‐scale brain networks play a prominent role in cognitive abilities and their activity is impaired in psychiatric disorders, such as schizophrenia. Patients with 22q11.2 deletion syndrome (22q11DS) are at high risk of developing schizophrenia and present similar cognitive impairments, including executive functions deficits. Thus, 22q11DS represents a model for the study of neural biomarkers associated with schizophrenia. In this study, we investigated structural and functional connectivity within and between the Default Mode (DMN), the Central Executive (CEN), and the Saliency network (SN) in 22q11DS using resting‐state fMRI and DTI. Furthermore, we investigated if triple network impairments were related to executive dysfunctions or the presence of psychotic symptoms. Sixty‐three patients with 22q11DS and sixty‐eighty controls (age 6–33 years) were included in the study. Structural connectivity between main nodes of DMN, CEN, and SN was computed using probabilistic tractography. Functional connectivity was computed as the partial correlation between the time courses extracted from each node. Structural and functional connectivity measures were then correlated to executive functions and psychotic symptom scores. Our results showed mainly reduced structural connectivity within the CEN, DMN, and SN, in patients with 22q11DS compared with controls as well as reduced between‐network connectivity. Functional connectivity appeared to be more preserved, with impairments being evident only within the DMN. Structural connectivity impairments were also related to executive dysfunctions. These findings show an association between triple network structural alterations and executive deficits in patients with the microdeletion, suggesting that 22q11DS and schizophrenia share common psychopathological mechanisms. Hum Brain Mapp 38:2177–2189, 2017. © 2017 Wiley Periodicals, Inc.     

Resting state connectivity differences in eyes open versus eyes closed conditions

Functional magnetic resonance imaging data are commonly collected during the resting state. Resting state functional magnetic resonance imaging (rs‐fMRI) is very practical and applicable for a wide range of study populations. Rs‐fMRI is usually collected in at least one of three different conditions/tasks, eyes closed (EC), eyes open (EO), or eyes fixated on an object (EO‐F). Several studies have shown that there are significant condition‐related differences in the acquired data. In this study, we compared the functional network connectivity (FNC) differences assessed via group independent component analysis on a large rs‐fMRI dataset collected in both EC and EO‐F conditions, and also investigated the effect of covariates (e.g., age, gender, and social status score). Our results indicated that task condition significantly affected a wide range of networks; connectivity of visual networks to themselves and other networks was increased during EO‐F, while EC was associated with increased connectivity of auditory and sensorimotor networks to other networks. In addition, the association of FNC with age, gender, and social status was observed to be significant only in the EO‐F condition (though limited as well). However, statistical analysis did not reveal any significant effect of interaction between eyes status and covariates. These results indicate that resting‐state condition is an important variable that may limit the generalizability of clinical findings using rs‐fMRI.     

Altered resting state connectivity of the default mode network in alexithymia

Alexithymia is a trait characterized by a diminished capacity to describe and distinguish emotions and to fantasize; it is associated with reduced introspection and problems in emotion processing. The default mode network (DMN) is a network of brain areas that is normally active during rest and involved in emotion processing and self-referential mental activity, including introspection. We hypothesized that connectivity of the DMN might be altered in alexithymia. Twenty alexithymic and 18 non-alexithymic healthy volunteers underwent a resting state fMRI scan. Independent component analysis was used to identify the DMN. Differences in connectivity strength were compared between groups. Within the DMN, alexithymic participants showed lower connectivity within areas of the DMN (medial frontal and temporal areas) as compared to non-alexithymic participants. In contrast, connectivity in the high-alexithymic participants was higher for the sensorimotor cortex, occipital areas and right lateral frontal cortex than in the low-alexithymic participants. These results suggest a diminished connectivity within the DMN of alexithymic participants, in brain areas that may also be involved in emotional awareness and self-referential processing. On the other hand, alexithymia was associated with stronger functional connections of the DMN with brain areas involved in sensory input and control of emotion.     

Functional connectivity maps based on hippocampal and thalamic dynamics may account for the default‐mode network

The default‐mode network (DMN) has been reported to comprise a set of inter‐connected transmodal cortical areas, including the posterior cingulate cortex (PCC), medial prefrontal cortex, posterior inferior parietal lobule, lateral temporal region and others. However, the subcortical constituents of the DMN are still not clear. This study aimed to examine whether the correlation maps derived from subcortical structures may also account for neural pattern of the DMN. Structural magnetic resonance imaging (MRI) and resting‐state functional MRI scans of 36 subjects were selected from the Rockland sample (Nathan Kline Institute). The hippocampus and thalamus were chosen as subcortical regions of interest (ROIs). Each ROI was partitioned into composite modules which in turn provided simplified and representative dynamics of blood‐oxygen‐level‐dependent (BOLD) signals. PCC‐seeded and ROI‐based correlation maps were compared by conjunction analyses and paired t‐tests (corrected P < 0.05). Our results unveiled that the hippocampus‐, thalamus‐ and PCC‐centred correlation patterns actually overlapped to a substantial degree. Integrating the signals in the thalamus and hippocampus altogether fully explained the PCC‐seeded DMN. Supplementary analyses based on the BOLD dynamics in several subcortical nuclei (caudate, putamen and globus pallidus) were dissimilar to the DMN. The DMN derived from the ROI/seed‐based approach may represent combined limbic and region‐specific informatics (and their closely interacting neural substrates). The possible causes for previous methods of task‐induced deactivation and seed‐based correlation that failed to depict the holistic limbic picture are discussed. The neocortical manifestation of DMN may reflect the limbic information in the transmodal brain regions.     

Dynamic functional network connectivity in idiopathic generalized epilepsy with generalized tonic–clonic seizure

Idiopathic generalized epilepsy (IGE) has been linked with disrupted intra‐network connectivity of multiple resting‐state networks (RSNs); however, whether impairment is present in inter‐network interactions between RSNs, remains largely unclear. Here, 50 patients with IGE characterized by generalized tonic–clonic seizures (GTCS) and 50 demographically matched healthy controls underwent resting‐state fMRI scans. A dynamic method was implemented to investigate functional network connectivity (FNC) in patients with IGE‐GTCS. Specifically, independent component analysis was first carried out to extract RSNs, and then sliding window correlation approach was employed to obtain dynamic FNC patterns. Finally, k‐mean clustering was performed to characterize six discrete functional connectivity states, and state analysis was conducted to explore the potential alterations in FNC and other dynamic metrics. Our results revealed that state‐specific FNC disruptions were observed in IGE‐GTCS and the majority of aberrant functional connectivity manifested itself in default mode network. In addition, temporal metrics derived from state transition vectors were altered in patients including the total number of transitions across states and the mean dwell time, the fraction of time spent and the number of subjects in specific FNC state. Furthermore, the alterations were significantly correlated with disease duration and seizure frequency. It was also found that dynamic FNC could distinguish patients with IGE‐GTCS from controls with an accuracy of 77.91% (P < 0.001). Taken together, this study not only provided novel insights into the pathophysiological mechanisms of IGE‐GTCS but also suggested that the dynamic FNC analysis was a promising avenue to deepen our understanding of this disease. Hum Brain Mapp 38:957–973, 2017. © 2016 Wiley Periodicals, Inc.     

Recreational use of GHB is associated with alterations of resting state functional connectivity of the central executive and default mode networks

Gamma‐hydroxybutyrate acid (GHB) is a recreational drug with a high addictive potential. Severe side effects such as GHB‐induced coma are common and linked to increased emergency room attendances. Task‐based functional‐imaging studies have revealed an association between the regular use of GHB and multiple GHB‐induced comas, and altered neurocognitive function. However the effects of multiple GHB‐induced comas and regular GHB‐use on intrinsic brain connectivity during rest remain unknown. The study population consisted of 23 GHB‐users with ≥4 GHB‐induced comas (GHB‐Coma), 22 GHB‐users who never experienced a GHB‐induced coma (GHB‐NoComa) and 24 polydrug users who never used GHB (No‐GHB). Resting‐state scans were collected to assess resting‐state functional‐connectivity within and between the default mode network (DMN), the bilateral central executive network (CEN) and the salience network (SN). The GHB‐NoComa group showed decreased rsFC of the right CEN with a region in the anterior cingulate cortex (p_FWE = 0.048) and decreased rsFC between the right CEN and the DMN (p_FWE = 0.048) when compared with the No‐GHB group. These results suggest that regular GHB‐use is associated with decreased rsFC within the right CEN and between the right CEN and the DMN. The presence of multiple GHB‐induced comas is not associated with (additional) alterations in rsFC.     

Altered resting‐state network connectivity in congenital blind

The brain of congenital blind (CB) has experienced a series of structural and functional alterations, either undesirable outcomes such as atrophy of the visual pathway due to sight loss from birth, or compensatory plasticity to interact efficiently with the environment. However, little is known, so far, about alterations in the functional architecture of resting‐state networks (RSNs) in CB. This study aimed to investigate intra‐ and internetwork connectivity differences between CB and sighted controls (SC), using independent component analysis (ICA) on resting state functional MRI data. Compared with SC, CB showed significantly increased network connectivity within the salience network (SN) and the occipital cortex. Moreover, CB exhibited enhanced internetwork connectivity between the SN and the frontoparietal network (FPN) and between the FPN and the occipital cortex; however, they showed decreased internetwork connectivity between the occipital cortex and the sensorimotor network. These findings suggest that CB experience large scale reorganization at the level of the functional network. More importantly, the enhanced intra‐ and internetwork connectivity of the SN, FPN, and occipital cortex in CB may improve their abilities to identify salient stimuli, to initiate the executive function, and to top‐down control of attention, which are critical for the CB to guide appropriate behavior and to better adaption to the environment. Hum Brain Mapp 35:2573–2581, 2014. © 2013 Wiley Periodicals, Inc .     

Altered functional connectivity in default mode network in absence epilepsy: a resting-state fMRI study

Dysfunctional default mode network (DMN) has been observed in various mental disorders, including epilepsy (see review Broyd et al. [2009]: Neurosci Biobehav Rev 33:279–296). Because interictal epileptic discharges may affect DMN, resting-state fMRI was used in this study to determine DMN functional connectivity in 14 healthy controls and 12 absence epilepsy patients. To avoid interictal epileptic discharge effects, testing was performed within interictal durations when there were no interictal epileptic discharges. Cross-correlation functional connectivity analysis with seed at posterior cingulate cortex, as well as region-wise calculation in DMN, revealed decreased integration within DMN in the absence epilepsy patients. Region-wise functional connectivity among the frontal, parietal, and temporal lobe was significantly decreased in the patient group. Moreover, functional connectivity between the frontal and parietal lobe revealed a significant negative correlation with epilepsy duration. These findings indicated DMN abnormalities in patients with absence epilepsy, even during resting interictal durations without interictal epileptic discharges. Abnormal functional connectivity in absence epilepsy may reflect abnormal anatomo-functional architectural integration in DMN, as a result of cognitive mental impairment and unconsciousness during absence seizure.