Salience Network Regions Research Articles

Spontaneous pupil dilations during the resting state are associated with activation of the salience network

Resting state functional magnetic resonance imaging (rs-fMRI) is increasingly applied for the development of functional biomarkers in brain disorders. Recent studies have revealed spontaneous vigilance drifts during the resting state, involving changes in brain activity and connectivity that challenge the validity of uncontrolled rs-fMRI findings. In a combined rs-fMRI/eye tracking study, the pupil size of 32 healthy subjects after 2h of sleep restriction was recorded as an indirect index for activity of the locus coeruleus, the brainstem's noradrenergic arousal center. The spontaneous occurrence of pupil dilations, but not pupil size per se, was associated with increased activity of the salience network, thalamus and frontoparietal regions. In turn, spontaneous constrictions of the pupil were associated with increased activity in visual and sensorimotor regions. These results were largely replicated in a sample of 36 healthy subjects who did not undergo sleep restriction, although in this sample the correlation between thalamus and pupil dilation fell below whole-brain significance. Our data show that spontaneous pupil fluctuations during rest are indeed associated with brain circuitry involved in tonic alertness and vigilance. Pupillometry is an effective method to control for changes in tonic alertness during rs-fMRI.

Dynamic Brain Network Correlates of Spontaneous Fluctuations in Attention.

Human attention is intrinsically dynamic, with focus continuously shifting between elements of the external world and internal, self-generated thoughts. Communication within and between large-scale brain networks also fluctuates spontaneously from moment to moment. However, the behavioral relevance of dynamic functional connectivity and possible link with attentional state shifts is unknown. We used a unique approach to examine whether brain network dynamics reflect spontaneous fluctuations in moment-to-moment behavioral variability, a sensitive marker of attentional state. Nineteen healthy adults were instructed to tap their finger every 600 ms while undergoing fMRI. This novel, but simple, approach allowed us to isolate moment-to-moment fluctuations in behavioral variability related to attention, independent of common confounds in cognitive tasks (e.g., stimulus changes, response inhibition). Spontaneously increasing tap variance ("out-of-the-zone" attention) was associated with increasing activation in dorsal-attention and salience network regions, whereas decreasing tap variance ("in-the-zone" attention) was marked by increasing activation of default mode network (DMN) regions. Independent of activation, tap variance representing out-of-the-zone attention was also time-locked to connectivity both within DMN and between DMN and salience network regions. These results provide novel mechanistic data on the understudied neural dynamics of everyday, moment-to-moment attentional fluctuations, elucidating the behavioral importance of spontaneous, transient coupling within and between attention-relevant networks.

Decoupling of the amygdala to other salience network regions in adolescent-onset recurrent major depressive disorder.

Recent meta-analyses of resting-state networks in major depressive disorder (MDD) implicate network disruptions underlying cognitive and affective features of illness. Heterogeneity of findings to date may stem from the relative lack of data parsing clinical features of MDD such as phase of illness and the burden of multiple episodes. Resting-state functional magnetic resonance imaging data were collected from 17 active MDD and 34 remitted MDD patients, and 26 healthy controls (HCs) across two sites. Participants were medication-free and further subdivided into those with single v. multiple episodes to examine disease burden. Seed-based connectivity using the posterior cingulate cortex (PCC) seed to probe the default mode network as well as the amygdala and subgenual anterior cingulate cortex (sgACC) seeds to probe the salience network (SN) were conducted. Young adults with remitted MDD demonstrated hyperconnectivity of the left PCC to the left inferior frontal gyrus and of the left sgACC to the right ventromedial prefrontal cortex (PFC) and left hippocampus compared with HCs. Episode-independent effects were observed between the left PCC and the right dorsolateral PFC, as well as between the left amygdala and right insula and caudate, whereas the burden of multiple episodes was associated with hypoconnectivity of the left PCC to multiple cognitive control regions as well as hypoconnectivity of the amygdala to large portions of the SN. This is the first study of a homogeneous sample of unmedicated young adults with a history of adolescent-onset MDD illustrating brain-based episodic features of illness.

Spontaneous neuronal activity in insula predicts symptom severity of unmedicated obsessive compulsive disorder adults.

Emerging evidence has suggested that the pathophysiology of obsessive compulsive disorder (OCD) might involve widely distributed large-scale brain systems. The dysfunction within salience network, which is comprised of dorsal anterior cingulated cortex (dACC) and bilateral insular areas, has been proposed to contribute to OCD onset. The mechanism underlying salience network abnormality remains unclear and it is worthwhile to investigate its clinical relevance using functional neuroimaging approaches. In this study, we performed the spontaneous brain activity measurement using resting-state functional magnetic resonance imaging (fMRI) on unmedicated OCD patients (n=23). Specifically, the amplitude of low frequency (0.01-0.08 Hz) fluctuations (ALFF) was calculated for regions in salience network. The voxel-based Pearson's correlative analysis was conducted to explore the relationship beween ALFF measures and symptom severity for OCD patients. The results showed that the spontaneous neuronal activity in insula was significantly correlated to OCD clinical symptoms, especially compulsive behaviors. Our findings consolidated that the salience network played an important role in the pathogenesis of OCD and the intensity of intrinsic brain activity in insula provided a predictive biomarker for OCD symptom severity.

Neural networks supporting switching, hypothesis testing, and rule application

We identified dynamic changes in recruitment of neural connectivity networks across three phases of a flexible rule learning and set-shifting task similar to the Wisconsin Card Sort Task: switching, rule learning via hypothesis testing, and rule application. During fMRI scanning, subjects viewed pairs of stimuli that differed across four dimensions (letter, color, size, screen location), chose one stimulus, and received feedback. Subjects were informed that the correct choice was determined by a simple unidimensional rule, for example “choose the blue letter”. Once each rule had been learned and correctly applied for 4–7 trials, subjects were cued via either negative feedback or visual cues to switch to learning a new rule. Task performance was divided into three phases: Switching (first trial after receiving the switch cue), hypothesis testing (subsequent trials through the last error trial), and rule application (correct responding after the rule was learned). We used both univariate analysis to characterize activity occurring within specific regions of the brain, and a multivariate method, constrained principal component analysis for fMRI (fMRI-CPCA), to investigate how distributed regions coordinate to subserve different processes. As hypothesized, switching was subserved by a limbic network including the ventral striatum, thalamus, and parahippocampal gyrus, in conjunction with cortical salience network regions including the anterior cingulate and frontoinsular cortex. Activity in the ventral striatum was associated with switching regardless of how switching was cued; visually cued shifts were associated with additional visual cortical activity. After switching, as subjects moved into the hypothesis testing phase, a broad fronto-parietal–striatal network (associated with the cognitive control, dorsal attention, and salience networks) increased in activity. This network was sensitive to rule learning speed, with greater extended activity for the slowest learning speed late in the time course of learning. As subjects shifted from hypothesis testing to rule application, activity in this network decreased and activity in the somatomotor and default mode networks increased.

Default and Executive Network Coupling Supports Creative Idea Production.

The role of attention in creative cognition remains controversial. Neuroimaging studies have reported activation of brain regions linked to both cognitive control and spontaneous imaginative processes, raising questions about how these regions interact to support creative thought. Using functional magnetic resonance imaging (fMRI), we explored this question by examining dynamic interactions between brain regions during a divergent thinking task. Multivariate pattern analysis revealed a distributed network associated with divergent thinking, including several core hubs of the default (posterior cingulate) and executive (dorsolateral prefrontal cortex) networks. The resting-state network affiliation of these regions was confirmed using data from an independent sample of participants. Graph theory analysis assessed global efficiency of the divergent thinking network, and network efficiency was found to increase as a function of individual differences in divergent thinking ability. Moreover, temporal connectivity analysis revealed increased coupling between default and salience network regions (bilateral insula) at the beginning of the task, followed by increased coupling between default and executive network regions at later stages. Such dynamic coupling suggests that divergent thinking involves cooperation between brain networks linked to cognitive control and spontaneous thought, which may reflect focused internal attention and the top-down control of spontaneous cognition during creative idea production.

Cortical Structural Connectivity Alterations in Primary Insomnia: Insights from MRI-Based Morphometric Correlation Analysis.

The etiology and maintenance of insomnia are proposed to be associated with increased cognitive and physiological arousal caused by acute stressors and associated cognitive rumination. A core feature of such hyperarousal theory of insomnia involves increased sensory processing that interferes with the onset and maintenance of sleep. In this work, we collected structural magnetic resonance imaging data from 35 patients with primary insomnia and 35 normal sleepers and applied structural covariance analysis to investigate whether insomnia is associated with disruptions in structural brain networks centered at the sensory regions (primary visual, primary auditory, and olfactory cortex). As expected, insomnia patients showed increased structural covariance in cortical thickness between sensory and motor regions. We also observed trends of increased covariance between sensory regions and the default-mode network, and the salience network regions, and trends of decreased covariance between sensory regions and the frontoparietal working memory network regions, in insomnia patients. The observed changes in structural covariance tended to correlated with poor sleep quality. Our findings support previous functional neuroimaging studies and provide novel insights into variations in brain network configuration that may be involved in the pathophysiology of insomnia.

Bridging psychiatry and neurology through social neuroscience.

Social neuroscience launched a novel multilevel (neural, hormonal, molecular and genetic) explanation of social cognition in psychiatry. In particular, the use of different levels of scientific inquiry assessing a) behavioral social cognition sensitivity to psychiatric impairment, b) neural networks engaged in social behaviors, c) the genetic underpinning of social phenomena, and d) the influence of the social environment on biological processes, have been outstandingly addressed by Cacioppo et al's paper 1. Neuroscientific progress suggests that the separation between psychiatry and neurology is counterproductive. Classical neurological conditions present a range of social cognition impairments that are often underrecognized and frequently undertreated. Social neuroscience has made important progress in elucidating the neurobiology of the social brain, but has not focused sufficiently on neurological disorders. Here we consider the implications of social neuroscience research for a specific neuropsychiatric condition, the behavioral variant of frontotemporal dementia (bvFTD). Moreover, we highlight the importance of social neuroscience for the cross-talk among psychiatry and neurology. BvFTD is a neurodegenerative disease whose initial symptoms are often confused with several psychiatric conditions. It is characterized by early decline in social interpersonal behavior, personality changes, and progressive deterioration in social functioning 2. Conventional neuropsychological assessment as well as clinical routine neuroimaging have been not been very useful for early diagnosis 2. The social neuroscience approach has raised new opportunities for research and translational applications in bvFTD. First, social cognition assessment in bvFTD has allowed the detection of early and subtle behavioral impairments, appearing even before imaging signatures of brain atrophy, or a clear decline in formal cognitive status 3. In particular, social cognition tasks that resemble everyday behavior seem to be a far more adequate assessment for this purpose 4. Social cognition assessment may soon become part of the clinical screening for bvFTD. Second, it has been proposed that models of social cognition associated with a degeneration of the fronto-insulo-temporal (social context network model) or fronto-insular (salience network) regions may explain the myriad of bvFTD social cognition impairments 2. For instance, Von Economo neurons are large spindle-shaped cells, abundant in the insular and anterior cingulate cortex. Among primates, these neurons have evolved only in hominids, and seem to be particularly vulnerable in neuropsychiatric conditions resulting in social cognition impairments. In bvFTD, a specific loss of these neurons within fronto-temporo-insular atrophy, at early stages, has been associated clinically with changes in empathy, social awareness, and other social cognition domains 5. Third, an important genetic component of bvFTD has been related with social cognition impairment. There are three main genes for bvFTD: MAPT, GRN, and C9ORF72. Patients with C9ORF72 mutations exhibit widespread frontotemporal atrophy, associated with psychiatric presentations as well as with social neglect 6. In a similar way, animal models and clinical studies of GRN have shown early social and emotional changes, without gross impairment in overall health 6. Fourth, the potential role of the social world, and its interaction with brain changes in bvFTD, deserves consideration. For instance, feeling lonely is associated with increased risk for dementia 7 and with a wish to hasten death in FTD 8. An inter-level social neuroscience approach combining the study of social behavior, neural networks, genetic influences, and the interactions between social behaviors and social cognition would help to provide a more in-depth understanding of bvFTD, as well as of the overlaps of this disorder with the symptomatology and social cognition impairments of several psychiatric conditions 9. A new form of cross-talk between psychiatry and neurology may thus be developed in the social neuroscience arena, spearheaded by work on bvFTD as perhaps the clearest example of the bridges between the two disciplines. Stimulating this cross-talk between neurological and psychiatric research seems to be one of the most promising roles for social neuroscience. Several neurological conditions with mental health manifestations (e.g., neurodegenerative conditions, prosopagnosia, tuberous sclerosis, and Angelman, Heller, Prader-Willi, Williams, Turner and Klinefelter syndromes) present impaired social functioning 10. Here, we have highlighted the multilevel social neuroscience approach to bvFTD, but the understanding of several other neurological conditions could benefit from this approach. Many social cognition domains (social emotions, decision making, theory of mind, empathy, moral cognition, and social norms) may be impacted differentially in various psychiatric and neurological conditions, and the differences in such parameters could be built into technologies for diagnosis and measurement of treatment efficacy. Psychiatrists and neurologists within this novel social neuroscience approach may be able to contribute a powerful multidisciplinary and transdisciplinary approach 11, that would be both clinically and theoretically relevant to major advances in contemporary neuropsychiatry.

Modulatory interactions between the default mode network and task positive networks in resting-state.

The two major brain networks, i.e., the default mode network (DMN) and the task positive network, typically reveal negative and variable connectivity in resting-state. In the present study, we examined whether the connectivity between the DMN and different components of the task positive network were modulated by other brain regions by using physiophysiological interaction (PPI) on resting-state functional magnetic resonance imaging data. Spatial independent component analysis was first conducted to identify components that represented networks of interest, including the anterior and posterior DMNs, salience, dorsal attention, left and right executive networks. PPI analysis was conducted between pairs of these networks to identify networks or regions that showed modulatory interactions with the two networks. Both network-wise and voxel-wise analyses revealed reciprocal positive modulatory interactions between the DMN, salience, and executive networks. Together with the anatomical properties of the salience network regions, the results suggest that the salience network may modulate the relationship between the DMN and executive networks. In addition, voxel-wise analysis demonstrated that the basal ganglia and thalamus positively interacted with the salience network and the dorsal attention network, and negatively interacted with the salience network and the DMN. The results demonstrated complex modulatory interactions among the DMNs and task positive networks in resting-state, and suggested that communications between these networks may be modulated by some critical brain structures such as the salience network, basal ganglia, and thalamus.

Salience network-midbrain dysconnectivity and blunted reward signals in schizophrenia

Theories of schizophrenia propose that abnormal functioning of the neural reward system is linked to negative and psychotic symptoms, by disruption of reward processing and promotion of context-independent false associations. Recently, it has been argued that an insula–anterior cingulate cortex (ACC) salience network system enables switching of brain states from the default mode to a task-related activity mode. Abnormal interaction between the insula–ACC system and reward processing regions may help explain abnormal reinforcer processing and symptoms. Here we use functional magnetic resonance imaging to assess the neural correlates of reward processing in schizophrenia. Furthermore, we investigated functional connectivity between the dopaminergic midbrain, a key region for the processing of reinforcers, and other brain regions. In response to rewards, controls activated task related regions (striatum, amygdala/hippocampus and midbrain) and the insula–ACC salience network. Patients similarly activated the insula–ACC salience network system but failed to activate task related regions. Reduced functional connectivity between the midbrain and the insula was found in schizophrenia, with the extent of this abnormality correlating with increased psychotic symptoms. The findings support the notion that reward processing is abnormal in schizophrenia and highlight the potential role of abnormal interactions between the insula–ACC salience network and reward regions.

Neural Dysregulation in Posttraumatic Stress Disorder

Convergent research demonstrates disrupted attention and heightened threat sensitivity in posttraumatic stress disorder (PTSD). This might be linked to aberrations in large-scale networks subserving the detection of salient stimuli (i.e., the salience network [SN]) and stimulus-independent, internally focused thought (i.e., the default mode network [DMN]). Resting-state brain activity was measured in returning veterans with and without PTSD (n = 15 in each group) and in healthy community controls (n = 15). Correlation coefficients were calculated between the time course of seed regions in key SN and DMN regions and all other voxels of the brain. Compared with control groups, participants with PTSD showed reduced functional connectivity within the DMN (between DMN seeds and other DMN regions) including the rostral anterior cingulate cortex/ventromedial prefrontal cortex (z = 3.31; p = .005, corrected) and increased connectivity within the SN (between insula seeds and other SN regions) including the amygdala (z = 3.03; p = .01, corrected). Participants with PTSD also demonstrated increased cross-network connectivity. DMN seeds exhibited elevated connectivity with SN regions including the insula (z = 3.06; p = .03, corrected), and SN seeds exhibited elevated connectivity with DMN regions including the hippocampus (z = 3.10; p = .048, corrected). During resting-state scanning, participants with PTSD showed reduced coupling within the DMN, greater coupling within the SN, and increased coupling between the DMN and the SN. Our findings suggest a relative dominance of threat-sensitive circuitry in PTSD, even in task-free conditions. Disequilibrium between large-scale networks subserving salience detection versus internally focused thought may be associated with PTSD pathophysiology.

Effects of Meditation Experience on Functional Connectivity of Distributed Brain Networks

This study sought to examine the effect of meditation experience on brain networks underlying cognitive actions employed during contemplative practice. In a previous study, we proposed a basic model of naturalistic cognitive fluctuations that occur during the practice of focused attention meditation. This model specifies four intervals in a cognitive cycle: mind wandering (MW), awareness of MW, shifting of attention, and sustained attention. Using subjective input from experienced practitioners during meditation, we identified activity in salience network regions during awareness of MW and executive network regions during shifting and sustained attention. Brain regions associated with the default mode were active during MW. In the present study, we reasoned that repeated activation of attentional brain networks over years of practice may induce lasting functional connectivity changes within relevant circuits. To investigate this possibility, we created seeds representing the networks that were active during the four phases of the earlier study, and examined functional connectivity during the resting state in the same participants. Connectivity maps were then contrasted between participants with high vs. low meditation experience. Participants with more meditation experience exhibited increased connectivity within attentional networks, as well as between attentional regions and medial frontal regions. These neural relationships may be involved in the development of cognitive skills, such as maintaining attention and disengaging from distraction, that are often reported with meditation practice. Furthermore, because altered connectivity of brain regions in experienced meditators was observed in a non-meditative (resting) state, this may represent a transference of cognitive abilities “off the cushion” into daily life.

Mind wandering and attention during focused meditation: A fine-grained temporal analysis of fluctuating cognitive states

Studies have suggested that the default mode network is active during mind wandering, which is often experienced intermittently during sustained attention tasks. Conversely, an anticorrelated task-positive network is thought to subserve various forms of attentional processing. Understanding how these two systems work together is central for understanding many forms of optimal and sub-optimal task performance. Here we present a basic model of naturalistic cognitive fluctuations between mind wandering and attentional states derived from the practice of focused attention meditation. This model proposes four intervals in a cognitive cycle: mind wandering, awareness of mind wandering, shifting of attention, and sustained attention. People who train in this style of meditation cultivate their abilities to monitor cognitive processes related to attention and distraction, making them well suited to report on these mental events. Fourteen meditation practitioners performed breath-focused meditation while undergoing fMRI scanning. When participants realized their mind had wandered, they pressed a button and returned their focus to the breath. The four intervals above were then constructed around these button presses. We hypothesized that periods of mind wandering would be associated with default mode activity, whereas cognitive processes engaged during awareness of mind wandering, shifting of attention and sustained attention would engage attentional subnetworks. Analyses revealed activity in brain regions associated with the default mode during mind wandering, and in salience network regions during awareness of mind wandering. Elements of the executive network were active during shifting and sustained attention. Furthermore, activations during these cognitive phases were modulated by lifetime meditation experience. These findings support and extend theories about cognitive correlates of distributed brain networks.