Structure-function coupling in highly sampled individual brains.

Structural connectivity (SC) between distant regions of the brain support synchronized function known as functional connectivity (FC) and give rise to the large-scale brain networks that enable cognition and behavior. Understanding how SC enables FC is important to understand how injuries to SC may alter brain function and cognition. Previous work evaluating whole-brain SC-FC relationships showed that SC explained FC well in unimodal visual and motor areas, but only weakly in association areas, suggesting a unimodal-heteromodal gradient organization of SC-FC coupling. However, this work was conducted in group-averaged SC/FC data. Thus, it could not account for inter-individual variability in the locations of cortical areas and white matter tracts. We evaluated the correspondence of SC and FC within three highly sampled healthy participants. For each participant, we collected 78 min of diffusion-weighted MRI for SC and 360 min of resting state fMRI for FC. We found that FC was best explained by SC in visual and motor systems, as well as in anterior and posterior cingulate regions. A unimodal-to-heteromodal gradient could not fully explain SC-FC coupling. We conclude that the SC-FC coupling of the anterior-posterior cingulate circuit is more similar to unimodal areas than to heteromodal areas.

Early Life Neuroimaging: The Generalizability of Cortical Area Parcellations Across Development.

The cerebral cortex comprises discrete cortical areas that form during development. Accurate area parcellation in neuroimaging studies enhances statistical power and comparability across studies. The formation of cortical areas is influenced by intrinsic embryonic patterning as well as extrinsic inputs, particularly through postnatal exposure. Given the substantial changes in brain volume, microstructure, and functional connectivity during the first years of life, we hypothesized that cortical areas in 1-to-3-year-olds would exhibit major differences from those in neonates and progressively resemble adults as development progresses. Here, we parcellated the cerebral cortex into putative areas using local functional connectivity gradients in 92 toddlers at 2 years old. We demonstrated high reproducibility of these cortical regions across 1-to-3-year-olds in two independent datasets. The area boundaries in 1-to-3-year-olds were more similar to adults than neonates. While the age-specific group parcellation fitted better to the underlying functional connectivity in individuals during the first 3 years, adult area parcellations might still have some utility in developmental studies, especially in children older than 6 years. Additionally, we provided connectivity-based community assignments of the parcels, showing fragmented anterior and posterior components based on the strongest connectivity, yet alignment with adult systems when weaker connectivity was included.

Precision Functional Mapping to Advance Developmental Psychiatry Research.

Many psychiatric conditions have their roots in early development. Individual differences in prenatal brain function (which is influenced by a combination of genetic risk and the prenatal environment) likely interact with individual differences in postnatal experience, resulting in substantial variation in brain functional organization and development in infancy. Neuroimaging has been a powerful tool for understanding typical and atypical brain function and holds promise for uncovering the neurodevelopmental basis of psychiatric illness; however, its clinical utility has been relatively limited thus far. A substantial challenge in this endeavor is the traditional approach of averaging brain data across groups despite individuals varying in their brain organization, which likely obscures important clinically relevant individual variation. Precision functional mapping (PFM) is a neuroimaging technique that allows the capture of individual-specific and highly reliable functional brain properties. Here, we discuss how PFM, through its focus on individuals, has provided novel insights for understanding brain organization across the life span and its promise in elucidating the neural basis of psychiatric disorders. We first summarize the extant literature on PFM in normative populations, followed by its limited utilization in studying psychiatric conditions in adults. We conclude by discussing the potential for infant PFM in advancing developmental precision psychiatry applications, given that many psychiatric disorders start during early infancy and are associated with changes in individual-specific functional neuroanatomy. By exploring the intersection of PFM, development, and psychiatric research, this article underscores the importance of individualized approaches in unraveling the complexities of brain function and improving clinical outcomes across development.

Precision functional mapping (PFM) is a neuroimaging technique that allows researchers to capture properties of brain function and organization that are specific to individuals. Here, we discuss how PFM, through its focus on individual patterns of brain activity, has provided novel insights for understanding brain organization across the life span and its promise in helping to uncover relationships between brain function and psychiatric illness beginning at birth. By exploring the intersection of PFM, development, and psychiatric research, this article underscores the importance of individualized approaches in uncovering the complexities of brain function and improving clinical outcomes across development.

Psychiatric neuroimaging designs for individualised, cohort, and population studies.

Psychiatric neuroimaging faces challenges to rigour and reproducibility that prompt reconsideration of the relative strengths and limitations of study designs. Owing to high resource demands and varying inferential goals, current designs differentially emphasise sample size, measurement breadth, and longitudinal assessments. In this overview and perspective, we provide a guide to the current landscape of psychiatric neuroimaging study designs with respect to this balance of scientific goals and resource constraints. Through a heuristic data cube contrasting key design features, we discuss a resulting trade-off among small sample, precision longitudinal studies (e.g., individualised studies and cohorts) and large sample, minimally longitudinal, population studies. Precision studies support tests of within-person mechanisms, via intervention and tracking of longitudinal course. Population studies support tests of generalisation across multifaceted individual differences. A proposed reciprocal validation model (RVM) aims to recursively leverage these complementary designs in sequence to accumulate evidence, optimise relative strengths, and build towards improved long-term clinical utility.

A subset of brain regions within adult functional connectivity networks demonstrate high reliability across early development.

The human cerebral cortex contains groups of areas that support sensory, motor, cognitive, and affective functions, often categorized as functional networks. These areas show stronger internal and weaker external functional connectivity (FC) and exhibit similar FC profiles within rather than between networks. Previous studies have demonstrated the development of these networks from nascent forms present before birth to their mature, adult-like topography in childhood. However, analyses often still use definitions based on adult functional networks. We aim to assess how this might lead to the misidentification of functional networks and explore potential consequences and solutions. Our findings suggest that even though adult networks provide only a marginally better than-chance description of the infant FC organization, misidentification was largely driven by specific areas. By restricting functional networks to areas showing adult-like network clustering, we observed consistent within-network FC both within and across scans and throughout development. Additionally, these areas were spatially closer to locations with low variability in network identity among adults. Our analysis aids in understanding the potential consequences of using adult networks "as is" and provides guidance for future research on selecting and utilizing functional network models based on the research question and scenario.

Replicability and generalizability in population psychiatric neuroimaging.

Studies linking mental health with brain function in cross-sectional population-based association studies have historically relied on small, underpowered samples. Given the small effect sizes typical of such brain-wide associations, studies require samples into the thousands to achieve the statistical power necessary for replicability. Here, we detail how small sample sizes have hampered replicability and provide sample size targets given established association strength benchmarks. Critically, while replicability will improve with larger samples, it is not guaranteed that observed effects will meaningfully apply to target populations of interest (i.e., be generalizable). We discuss important considerations related to generalizability in psychiatric neuroimaging and provide an example of generalizability failure due to "shortcut learning" in brain-based predictions of mental health phenotypes. Shortcut learning is a phenomenon whereby machine learning models learn an association between the brain and an unmeasured construct (the shortcut), rather than the intended target of mental health. Given the complex nature of brain-behavior interactions, the future of epidemiological approaches to brain-based studies of mental health will require large, diverse samples with comprehensive assessment.

Psilocybin desynchronizes the human brain.

A single dose of psilocybin, a psychedelic that acutely causes distortions of space-time perception and ego dissolution, produces rapid and persistent therapeutic effects in human clinical trials1-4. In animal models, psilocybin induces neuroplasticity in cortex and hippocampus5-8. It remains unclear how human brain network changes relate to subjective and lasting effects of psychedelics. Here we tracked individual-specific brain changes with longitudinal precision functional mapping (roughly 18 magnetic resonance imaging visits per participant). Healthy adults were tracked before, during and for 3 weeks after high-dose psilocybin (25 mg) and methylphenidate (40 mg), and brought back for an additional psilocybin dose 6-12 months later. Psilocybin massively disrupted functional connectivity (FC) in cortex and subcortex, acutely causing more than threefold greater change than methylphenidate. These FC changes were driven by brain desynchronization across spatial scales (areal, global), which dissolved network distinctions by reducing correlations within and anticorrelations between networks. Psilocybin-driven FC changes were strongest in the default mode network, which is connected to the anterior hippocampus and is thought to create our sense of space, time and self. Individual differences in FC changes were strongly linked to the subjective psychedelic experience. Performing a perceptual task reduced psilocybin-driven FC changes. Psilocybin caused persistent decrease in FC between the anterior hippocampus and default mode network, lasting for weeks. Persistent reduction of hippocampal-default mode network connectivity may represent a neuroanatomical and mechanistic correlate of the proplasticity and therapeutic effects of psychedelics.

Functional parcellation of the neonatal cortical surface.

The cerebral cortex is organized into distinct but interconnected cortical areas, which can be defined by abrupt differences in patterns of resting state functional connectivity (FC) across the cortical surface. Such parcellations of the cortex have been derived in adults and older infants, but there is no widely used surface parcellation available for the neonatal brain. Here, we first demonstrate that existing parcellations, including surface-based parcels derived from older samples as well as volume-based neonatal parcels, are a poor fit for neonatal surface data. We next derive a set of 283 cortical surface parcels from a sample of n = 261 neonates. These parcels have highly homogenous FC patterns and are validated using three external neonatal datasets. The Infomap algorithm is used to assign functional network identities to each parcel, and derived networks are consistent with prior work in neonates. The proposed parcellation may represent neonatal cortical areas and provides a powerful tool for neonatal neuroimaging studies.

The brainstem's red nucleus was evolutionarily upgraded to support goal-directed action.

The red nucleus is a large brainstem structure that coordinates limb movement for locomotion in quadrupedal animals (Basile et al., 2021). The humans red nucleus has a different pattern of anatomical connectivity compared to quadrupeds, suggesting a unique purpose (Hatschek, 1907). Previously the function of the human red nucleus remained unclear at least partly due to methodological limitations with brainstem functional neuroimaging (Sclocco et al., 2018). Here, we used our most advanced resting-state functional connectivity (RSFC) based precision functional mapping (PFM) in highly sampled individuals (n = 5) and large group-averaged datasets (combined N ~ 45,000), to precisely examine red nucleus functional connectivity. Notably, red nucleus functional connectivity to motor-effector networks (somatomotor hand, foot, and mouth) was minimal. Instead, red nucleus functional connectivity along the central sulcus was specific to regions of the recently discovered somato-cognitive action network (SCAN; (Gordon et al., 2023)). Outside of primary motor cortex, red nucleus connectivity was strongest to the cingulo-opercular (CON) and salience networks, involved in action/cognitive control (Dosenbach et al., 2007; Newbold et al., 2021) and reward/motivated behavior (Seeley, 2019), respectively. Functional connectivity to these two networks was organized into discrete dorsal-medial and ventral-lateral zones. Red nucleus functional connectivity to the thalamus recapitulated known structural connectivity of the dento-rubral thalamic tract (DRTT) and could prove clinically useful in functionally targeting the ventral intermediate (VIM) nucleus. In total, our results indicate that far from being a 'motor' structure, the red nucleus is better understood as a brainstem nucleus for implementing goal-directed behavior, integrating behavioral valence and action plans.

Disuse-driven plasticity in the human thalamus and putamen.

Motor adaptation in cortico-striato-thalamo-cortical loops has been studied mainly in animals using invasive electrophysiology. Here, we leverage functional neuroimaging in humans to study motor circuit plasticity in the human subcortex. We employed an experimental paradigm that combined two weeks of upper-extremity immobilization with daily resting-state and motor task fMRI before, during, and after the casting period. We previously showed that limb disuse leads to decreased functional connectivity (FC) of the contralateral somatomotor cortex (SM1) with the ipsilateral somatomotor cortex, increased FC with the cingulo-opercular network (CON) as well as the emergence of high amplitude, fMRI signal pulses localized in the contralateral SM1, supplementary motor area and the cerebellum. From our prior observations, it remains unclear whether the disuse plasticity affects the thalamus and striatum. We extended our analysis to include these subcortical regions and found that both exhibit strengthened cortical FC and spontaneous fMRI signal pulses induced by limb disuse. The dorsal posterior putamen and the central thalamus, mainly CM, VLP and VIM nuclei, showed disuse pulses and FC changes that lined up with fmri task activations from the Human connectome project motor system localizer, acquired before casting for each participant. Our findings provide a novel understanding of the role of the cortico-striato-thalamo-cortical loops in human motor plasticity and a potential link with the physiology of sleep regulation. Additionally, similarities with FC observation from Parkinson Disease (PD) questions a pathophysiological link with limb disuse.

Framewise multi-echo distortion correction for superior functional MRI.

Functional MRI (fMRI) data are severely distorted by magnetic field (B0) inhomogeneities which currently must be corrected using separately acquired field map data. However, changes in the head position of a scanning participant across fMRI frames can cause changes in the B0 field, preventing accurate correction of geometric distortions. Additionally, field maps can be corrupted by movement during their acquisition, preventing distortion correction altogether. In this study, we use phase information from multi-echo (ME) fMRI data to dynamically sample distortion due to fluctuating B0 field inhomogeneity across frames by acquiring multiple echoes during a single EPI readout. Our distortion correction approach, MEDIC (Multi-Echo DIstortion Correction), accurately estimates B0 related distortions for each frame of multi-echo fMRI data. Here, we demonstrate that MEDIC's framewise distortion correction produces improved alignment to anatomy and decreases the impact of head motion on resting-state functional connectivity (RSFC) maps, in higher motion data, when compared to the prior gold standard approach (i.e., TOPUP). Enhanced framewise distortion correction with MEDIC, without the requirement for field map collection, furthers the advantage of multi-echo over single-echo fMRI.

Multi-echo Acquisition and Thermal Denoising Advances Infant Precision Functional Imaging.

The characterization of individual functional brain organization with Precision Functional Mapping has provided important insights in recent years in adults. However, little is known about the ontogeny of inter-individual differences in brain functional organization during human development, but precise characterization of systems organization during periods of high plasticity might be most influential towards discoveries promoting lifelong health. Collecting and analyzing precision fMRI data during early development has unique challenges and emphasizes the importance of novel methods to improve data acquisition, processing, and analysis strategies in infant samples. Here, we investigate the applicability of two such methods from adult MRI research, multi-echo (ME) data acquisition and thermal noise removal with Noise reduction with distribution corrected principal component analysis (NORDIC), in precision fMRI data from three newborn infants. Compared to an adult example subject, T2* relaxation times calculated from ME data in infants were longer and more variable across the brain, pointing towards ME acquisition being a promising tool for optimizing developmental fMRI. The application of thermal denoising via NORDIC increased tSNR and the overall strength of functional connections as well as the split-half reliability of functional connectivity matrices in infant ME data. While our findings related to NORDIC denoising are coherent with the adult literature and ME data acquisition showed high promise, its application in developmental samples needs further investigation. The present work reveals gaps in our understanding of the best techniques for developmental brain imaging and highlights the need for further developmentally-specific methodological advances and optimizations, towards precision functional imaging in infants.

Functional parcellation of the neonatal brain.

The cerebral cortex is organized into distinct but interconnected cortical areas, which can be defined by abrupt differences in patterns of resting state functional connectivity (FC) across the cortical surface. Such parcellations of the cortex have been derived in adults and older infants, but there is no widely used surface parcellation available for the neonatal brain. Here, we first demonstrate that adult- and older infant-derived parcels are a poor fit with neonatal data, emphasizing the need for neonatal-specific parcels. We next derive a set of 283 cortical surface parcels from a sample of n=261 neonates. These parcels have highly homogenous FC patterns and are validated using three external neonatal datasets. The Infomap algorithm is used to assign functional network identities to each parcel, and derived networks are consistent with prior work in neonates. The proposed parcellation may represent neonatal cortical areas and provides a powerful tool for neonatal neuroimaging studies.

Substructure of the brain's Cingulo-Opercular network.

The Cingulo-Opercular network (CON) is an executive network of the human brain that regulates actions. CON is composed of many widely distributed cortical regions that are involved in top-down control over both lower-level (i.e., motor) and higher-level (i.e., cognitive) functions, as well as in processing of painful stimuli. Given the topographical and functional heterogeneity of the CON, we investigated whether subnetworks within the CON support separable aspects of action control. Using precision functional mapping (PFM) in 15 participants with > 5 hours of resting state functional connectivity (RSFC) and task data, we identified three anatomically and functionally distinct CON subnetworks within each individual. These three distinct subnetworks were linked to Decisions, Actions, and Feedback (including pain processing), respectively, in convergence with a meta-analytic task database. These Decision, Action and Feedback subnetworks represent pathways by which the brain establishes top-down goals, transforms those goals into actions, implemented as movements, and processes critical action feedback such as pain.

Structure-Function Coupling in Highly Sampled Individual Brains.

Structural connections (SC) between distant regions of the brain support synchronized function known as functional connectivity (FC) and give rise to the large-scale brain networks that enable cognition and behavior. Understanding how SC enables FC is important to understand how injuries to structural connections may alter brain function and cognition. Previous work evaluating whole-brain SC-FC relationships showed that SC explained FC well in unimodal visual and motor areas, but only weakly in association areas, suggesting a unimodal-heteromodal gradient organization of SC-FC coupling. However, this work was conducted in group-averaged SC/FC data. Thus, it could not account for inter-individual variability in the locations of cortical areas and white matter tracts. We evaluated the correspondence of SC and FC within three highly sampled healthy participants. For each participant, we collected 78 minutes of diffusion-weighted MRI for SC and 360 minutes of resting state fMRI for FC. We found that FC was best explained by SC in visual and motor systems, as well as in anterior and posterior cingulate regions. A unimodal-to-heteromodal gradient could not fully explain SC-FC coupling. We conclude that the SC-FC coupling of the anterior-posterior cingulate circuit is more similar to unimodal areas than to heteromodal areas. SIGNIFICANCE STATEMENT: Structural connections between distant regions of the human brain support networked function that enables cognition and behavior. Improving our understanding of how structure enables function could allow better insight into how brain disconnection injuries impair brain function.Previous work using neuroimaging suggested that structure-function relationships vary systematically across the brain, with structure better explaining function in basic visual/motor areas than in higher-order areas. However, this work was conducted in group-averaged data, which may obscure details of individual-specific structure-function relationships.Using individual-specific densely sampled neuroimaging data, we found that in addition to visual/motor regions, structure strongly predicts function in specific circuits of the higher-order cingulate gyrus. The cingulate's structure-function relationship suggests that its organization may be unique among higher-order cortical regions.

Thalamo-cortical and cerebello-cortical functional connectivity in development.

The thalamus is a critical relay center for neural pathways involving sensory, motor, and cognitive functions, including cortico-striato-thalamo-cortical and cortico-ponto-cerebello-thalamo-cortical loops. Despite the importance of these circuits, their development has been understudied. One way to investigate these pathways in human development in vivo is with functional connectivity MRI, yet few studies have examined thalamo-cortical and cerebello-cortical functional connectivity in development. Here, we used resting-state functional connectivity to measure functional connectivity in the thalamus and cerebellum with previously defined cortical functional networks in 2 separate data sets of children (7-12 years old) and adults (19-40 years old). In both data sets, we found stronger functional connectivity between the ventral thalamus and the somatomotor face cortical functional network in children compared with adults, extending previous cortico-striatal functional connectivity findings. In addition, there was more cortical network integration (i.e. strongest functional connectivity with multiple networks) in the thalamus in children than in adults. We found no developmental differences in cerebello-cortical functional connectivity. Together, these results suggest different maturation patterns in cortico-striato-thalamo-cortical and cortico-ponto-cerebellar-thalamo-cortical pathways.

Precision Neuroimaging for Localization-Related Psychiatry.

This Viewpoint describes how precision functional mapping may be helpful for associating neuroanatomical regions with specific psychiatric disorders.

A somato-cognitive action network alternates with effector regions in motor cortex.

Motor cortex (M1) has been thought to form a continuous somatotopic homunculus extending down the precentral gyrus from foot to face representations1,2, despite evidence for concentric functional zones3 and maps of complex actions4. Here, using precision functional magnetic resonance imaging (fMRI) methods, we find that the classic homunculus is interrupted by regions with distinct connectivity, structure and function, alternating with effector-specific (foot, hand and mouth) areas. These inter-effector regions exhibit decreased cortical thickness and strong functional connectivity to each other, as well as to the cingulo-opercular network (CON), critical for action5 and physiological control6, arousal7, errors8 and pain9. This interdigitation of action control-linked and motor effector regions was verified in the three largest fMRI datasets. Macaque and pediatric (newborn, infant and child) precision fMRI suggested cross-species homologues and developmental precursors of the inter-effector system. A battery of motor and action fMRI tasks documented concentric effector somatotopies, separated by the CON-linked inter-effector regions. The inter-effectors lacked movement specificity and co-activated during action planning (coordination of hands and feet) and axial body movement (such as of the abdomen or eyebrows). These results, together with previous studies demonstrating stimulation-evoked complex actions4 and connectivity to internal organs10 such as the adrenal medulla, suggest that M1 is punctuated by a system for whole-body action planning, the somato-cognitive action network (SCAN). In M1, two parallel systems intertwine, forming an integrate-isolate pattern: effector-specific regions (foot, hand and mouth) for isolating fine motor control and the SCAN for integrating goals, physiology and body movement.

Using synthetic MR images for distortion correction.

Functional MRI (fMRI) data acquired using echo-planar imaging (EPI) are highly distorted by magnetic field inhomogeneities. Distortion and differences in image contrast between EPI and T1-weighted and T2-weighted (T1w/T2w) images makes their alignment a challenge. Typically, field map data are used to correct EPI distortions. Alignments achieved with field maps can vary greatly and depends on the quality of field map data. However, many public datasets lack field map data entirely. Additionally, reliable field map data is often difficult to acquire in high-motion pediatric or developmental cohorts. To address this, we developed Synth, a software package for distortion correction and cross-modal image registration that does not require field map data. Synth combines information from T1w and T2w anatomical images to construct an idealized undistorted synthetic image with similar contrast properties to EPI data. This synthetic image acts as an effective reference for individual-specific distortion correction. Using pediatric (ABCD: Adolescent Brain Cognitive Development) and adult (MSC: Midnight Scan Club; HCP: Human Connectome Project) data, we demonstrate that Synth performs comparably to field map distortion correction approaches, and often outperforms them. Field map-less distortion correction with Synth allows accurate and precise registration of fMRI data with missing or corrupted field map information.