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Toward actionable neural markers of depression risk?
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Decades of neuroimaging studies have shown modest differences in brain structure and connectivity in depression, hindering mechanistic insights or the identification of risk factors for disease onset¹. Furthermore, whereas depression is episodic, few longitudinal neuroimaging studies exist, limiting understanding of mechanisms that drive mood-state transitions. The emerging field of precision functional mapping has used densely sampled longitudinal neuroimaging data to show behaviourally meaningful differences in brain network topography and connectivity between and in healthy individuals2–4, but this approach has not been applied in depression. Here, using precision functional mapping and several samples of deeply sampled individuals, we found that the frontostriatal salience network is expanded nearly twofold in the cortex of most individuals with depression. This effect was replicable in several samples and caused primarily by network border shifts, with three distinct modes of encroachment occurring in different individuals. Salience network expansion was stable over time, unaffected by mood state and detectable in children before the onset of depression later in adolescence. Longitudinal analyses of individuals scanned up to 62 times over 1.5 years identified connectivity changes in frontostriatal circuits that tracked fluctuations in specific symptoms and predicted future anhedonia symptoms. Together, these findings identify a trait-like brain network topology that may confer risk for depression and mood-state-dependent connectivity changes in frontostriatal circuits that predict the emergence and remission of depressive symptoms over time.
The cortex has a characteristic layout with specialized functional areas forming distributed large-scale networks. However, substantial work shows striking variation in this organization across people, which relates to differences in behavior. While most previous work treats individual differences as linked to boundary shifts between the borders of regions, here we show that cortical ‘variants’ also occur at a distance from their typical position, forming ectopic intrusions. Both ‘border’ and ‘ectopic’ variants are common across individuals, but differ in their location, network associations, properties of subgroups of individuals, activations during tasks, and prediction of behavioral phenotypes. Border variants also track significantly more with shared genetics than ectopic variants, suggesting a closer link between ectopic variants and environmental influences. This work argues that these two dissociable forms of variation—border shifts and ectopic intrusions—must be separately accounted for in the analysis of individual differences in cortical systems across people.
Analysis and interpretation of studies on cognitive and affective dysregulation often draw upon the network paradigm, especially the Triple Network Model, which consists of the default mode network (DMN), the frontoparietal network (FPN), and the salience network (SN). DMN activity is primarily dominant during cognitive leisure and self-monitoring processes. The FPN peaks during task involvement and cognitive exertion. Meanwhile, the SN serves as a dynamic “switch” between the DMN and FPN, in line with salience and cognitive demand. In the cognitive and affective domains, dysfunctions involving SN activity are connected to a broad spectrum of deficits and maladaptive behavioral patterns in a variety of clinical disorders, such as depression, insomnia, narcissism, PTSD (in the case of SN hyperactivity), chronic pain, and anxiety, high degrees of neuroticism, schizophrenia, epilepsy, autism, and neurodegenerative illnesses, bipolar disorder (in the case of SN hypoactivity). We discuss behavioral and neurological data from various research domains and present an integrated perspective indicating that these conditions can be associated with a widespread disruption in predictive coding at multiple hierarchical levels. We delineate the fundamental ideas of the brain network paradigm and contrast them with the conventional modular method in the first section of this article. Following this, we outline the interaction model of the key functional brain networks and highlight recent studies coupling SN-related dysfunctions with cognitive and affective impairments.
Human cortex is patterned by a complex and interdigitated web of large-scale functional networks. Recent methodological breakthroughs reveal variation in the size, shape, and spatial topography of cortical networks across individuals. While spatial network organization emerges across development, is stable over time, and is predictive of behavior, it is not yet clear to what extent genetic factors underlie interindividual differences in network topography. Here, leveraging a nonlinear multidimensional estimation of heritability, we provide evidence that individual variability in the size and topographic organization of cortical networks are under genetic control. Using twin and family data from the Human Connectome Project (n = 1,023), we find increased variability and reduced heritability in the size of heteromodal association networks (h
2
: M = 0.34, SD = 0.070), relative to unimodal sensory/motor cortex (h
2
: M = 0.40, SD = 0.097). We then demonstrate that the spatial layout of cortical networks is influenced by genetics, using our multidimensional estimation of heritability (h
2
-multi; M = 0.14, SD = 0.015). However, topographic heritability did not differ between heteromodal and unimodal networks. Genetic factors had a regionally variable influence on brain organization, such that the heritability of network topography was greatest in prefrontal, precuneus, and posterior parietal cortex. Taken together, these data are consistent with relaxed genetic control of association cortices relative to primary sensory/motor regions and have implications for understanding population-level variability in brain functioning, guiding both individualized prediction and the interpretation of analyses that integrate genetics and neuroimaging.
The organization of human brain networks can be measured by capturing correlated brain activity with fMRI. There is considerable interest in understanding how brain networks vary across individuals or neuropsychiatric populations or are altered during the performance of specific behaviors. However, the plausibility and validity of such measurements is dependent on the extent to which functional networks are stable over time or are state dependent. We analyzed data from nine high-quality, highly sampled individuals to parse the magnitude and anatomical distribution of network variability across subjects, sessions, and tasks. Critically, we find that functional networks are dominated by common organizational principles and stable individual features, with substantially more modest contributions from task-state and day-to-day variability. Sources of variation were differentially distributed across the brain and differentially linked to intrinsic and task-evoked sources. We conclude that functional networks are suited to measuring stable individual characteristics, suggesting utility in personalized medicine.
Major depressive disorder (MDD) has been linked to imbalanced communication among large-scale brain networks, as reflected by abnormal resting-state functional connectivity (rsFC). However, given variable methods and results across studies, identifying consistent patterns of network dysfunction in MDD has been elusive.
To investigate network dysfunction in MDD through a meta-analysis of rsFC studies.
Seed-based voxelwise rsFC studies comparing individuals with MDD with healthy controls (published before June 30, 2014) were retrieved from electronic databases (PubMed, Web of Science, and EMBASE) and authors contacted for additional data.
Twenty-seven seed-based voxel-wise rsFC data sets from 25 publications (556 individuals with MDD and 518 healthy controls) were included in the meta-analysis.
Coordinates of seed regions of interest and between-group effects were extracted. Seeds were categorized into seed-networks by their location within a priori functional networks. Multilevel kernel density analysis of between-group effects identified brain systems in which MDD was associated with hyperconnectivity (increased positive or reduced negative connectivity) or hypoconnectivity (increased negative or reduced positive connectivity) with each seed-network.
Major depressive disorder was characterized by hypoconnectivity within the frontoparietal network, a set of regions involved in cognitive control of attention and emotion regulation, and hypoconnectivity between frontoparietal systems and parietal regions of the dorsal attention network involved in attending to the external environment. Major depressive disorder was also associated with hyperconnectivity within the default network, a network believed to support internally oriented and self-referential thought, and hyperconnectivity between frontoparietal control systems and regions of the default network. Finally, the MDD groups exhibited hypoconnectivity between neural systems involved in processing emotion or salience and midline cortical regions that may mediate top-down regulation of such functions.
Reduced connectivity within frontoparietal control systems and imbalanced connectivity between control systems and networks involved in internal or external attention may reflect depressive biases toward internal thoughts at the cost of engaging with the external world. Meanwhile, altered connectivity between neural systems involved in cognitive control and those that support salience or emotion processing may relate to deficits regulating mood. These findings provide an empirical foundation for a neurocognitive model in which network dysfunction underlies core cognitive and affective abnormalities in depression.
A main goal in translational neuroscience is to identify neural correlates of psychopathology (“biomarkers”) that can be used to facilitate diagnosis, prognosis, and treatment. This goal has led to substantial research into how psychopathology symptoms relate to large-scale brain systems. However, these efforts have not yet resulted in practical biomarkers used in clinical practice. One reason for this underwhelming progress may be that many study designs focus on increasing sample size instead of collecting additional data within each individual. This focus limits the reliability and predictive validity of brain and behavioral measures in any one person. As biomarkers exist at the level of individuals, an increased focus on validating them within individuals is warranted. We argue that personalized models, estimated from extensive data collection within individuals, can address these concerns. We review evidence from two, thus far separate, lines of research on personalized models of (1) psychopathology symptoms and (2) fMRI measures of brain networks. We close by proposing approaches uniting personalized models across both domains to improve biomarker research.
Human functional MRI (fMRI) research primarily focuses on analyzing data averaged across groups,
which limits the detail, specificity, and clinical utility of fMRI resting-state functional connectivity
(RSFC) and task-activation maps. To push our understanding of functional brain organization to the
level of individual humans, we assembled a novel MRI dataset containing 5 hr of RSFC data, 6 hr
of task fMRI, multiple structural MRIs, and neuropsychological tests from each of ten adults.
Using these data, we generated ten high-fidelity, individual-specific functional connectomes. This
individual-connectome approach revealed several new types of spatial and organizational variability
in brain networks, including unique network features and topologies that corresponded with
structural and task-derived brain features. We are releasing this highly sampled, individualfocused
dataset as a resource for neuroscientists, and we propose precision individual connectomics
as a model for future work examining the organization of healthy and diseased individual human
brains.
Neuroimaging and circuit mechanisms of depression
- Romer