Measuring neuroplasticity in human development: the potential to inform the type and timing of mental health interventions.

Neuroplasticity during sensitive periods, the molecular and cellular process of enduring neural change in response to external stimuli during windows of high environmental sensitivity, is crucial for adaptation to expected environments and has implications for psychiatry. Animal research has characterized the developmental sequence and neurobiological mechanisms that govern neuroplasticity, yet gaps in our ability to measure neuroplasticity in humans limit the clinical translation of these principles. Here, we present a roadmap for the development and validation of neuroimaging and electrophysiology measures that index neuroplasticity to begin to address these gaps. We argue that validation of measures to track neuroplasticity in humans will elucidate the etiology of mental illness and inform the type and timing of mental health interventions to optimize effectiveness. We outline criteria for evaluating putative neuroimaging measures of plasticity in humans including links to neurobiological mechanisms shown to govern plasticity in animal models, developmental change that reflects heightened early life plasticity, and prediction of neural and/or behavior change. These criteria are applied to three putative measures of neuroplasticity using electroencephalography (gamma oscillations, aperiodic exponent of power/frequency) or functional magnetic resonance imaging (amplitude of low frequency fluctuations). We discuss the use of these markers in psychiatry, envision future uses for clinical and developmental translation, and suggest steps to address the limitations of the current putative neuroimaging measures of plasticity. With additional work, we expect these markers will significantly impact mental health and be used to characterize mechanisms, devise new interventions, and optimize developmental trajectories to reduce psychopathology risk.

Two common and distinct forms of variation in human functional brain networks.

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.

In the face of ambiguity: intrinsic brain organization in development predicts one's bias toward positivity or negativity.

Exacerbated negativity bias, including in responses to ambiguity, represents a common phenotype of internalizing disorders. Individuals differ in their propensity toward positive or negative appraisals of ambiguity. This variability constitutes one's valence bias, a stable construct linked to mental health. Evidence suggests an initial negativity in response to ambiguity that updates via regulatory processes to support a more positive bias. Previous work implicates the amygdala and prefrontal cortex, and regions of the cingulo-opercular system, in this regulatory process. Nonetheless, the neurodevelopmental origins of valence bias remain unclear. The current study tests whether intrinsic brain organization predicts valence bias among 119 children and adolescents (6 to 17 years). Using whole-brain resting-state functional connectivity, a machine-learning model predicted valence bias (r = 0.20, P = 0.03), as did a model restricted to amygdala and cingulo-opercular system features (r = 0.19, P = 0.04). Disrupting connectivity revealed additional intra-system (e.g. fronto-parietal) and inter-system (e.g. amygdala to cingulo-opercular) connectivity important for prediction. The results highlight top-down control systems and bottom-up perceptual processes that influence valence bias in development. Thus, intrinsic brain organization informs the neurodevelopmental origins of valence bias, and directs future work aimed at explicating related internalizing symptomology.

Maternal prenatal social disadvantage and neonatal functional connectivity: Associations with psychopathology symptoms at age 12 months.

Recent research has reported effects of socioeconomic status on neurobehavioral development as early as infancy, including positive associations between income and brain structure, functional connectivity, and behavior later in childhood (Ramphal, Whalen, et al., 2020; Triplett et al., 2022). This study extends this literature by investigating the relation of maternal prenatal social disadvantage (PSD) to neonatal amygdala and hippocampus functional connectivity and whether socioeconomic-related alterations in functional connectivity subsequently predict behavior at age 12 months in a large, socioeconomically diverse sample (N = 261 mother-infant dyads). PSD was assessed across gestation; neonatal magnetic resonance imaging was completed within the first weeks of life; and infant internalizing and externalizing symptoms were evaluated using the Infant-Toddler Social and Emotional Assessment at age 12 months. The results showed that PSD was significantly related to neonatal right amygdala and left hippocampus functional connectivity with prefrontal and motor-related regions. Social disadvantage-related right amygdala and left hippocampus functional connectivity with these regions was subsequently related to infant externalizing and internalizing symptoms at age 12 months. Building off an emerging literature exploring prenatal impacts on neonatal functional connectivity, this study further emphasizes the important role of the maternal environment during gestation on infant brain function and its relationship with externalizing and internalizing behavior in the first years of life. The results suggest that the prenatal socioeconomic environment may be a promising target for interventions aimed at improving infant neurobehavioral outcomes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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.

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.

Large-scale encoding of emotion concepts becomes increasingly similar between individuals from childhood to adolescence.

Humans require a shared conceptualization of others' emotions for adaptive social functioning. A concept is a mental blueprint that gives our brains parameters for predicting what will happen next. Emotion concepts undergo refinement with development, but it is not known whether their neural representations change in parallel. Here, in a sample of 5-15-year-old children (n = 823), we show that the brain represents different emotion concepts distinctly throughout the cortex, cerebellum and caudate. Patterns of activation to each emotion changed little across development. Using a model-free approach, we show that activation patterns were more similar between older children than between younger children. Moreover, scenes that required inferring negative emotional states elicited higher default mode network activation similarity in older children than younger children. These results suggest that representations of emotion concepts are relatively stable by mid to late childhood and synchronize between individuals during adolescence.

Baby Brains at Work: How Task-Based Functional Magnetic Resonance Imaging Can Illuminate the Early Emergence of Psychiatric Risk.

Psychiatric disorders are complex, often emerging from multiple atypical processes within specified domains over the course of development. Characterizing the development of the neural circuits supporting these domains may help break down the components of complex disorders and reveal variations in functioning associated with psychiatric risk. This review highlights the current and potential role of infant task-based functional magnetic resonance imaging (fMRI) in elucidating the developmental neurobiology of psychiatric disorders. Task-fMRI measures evoked brain activity in response to specific stimuli through changes in the blood oxygen level-dependent signal. First, we review extant studies using task fMRI from birth through the first few years of life and synthesize current evidence for when, where, and how different neural computations are performed across the infant brain. Neural circuits for sensory perception, the perception of abstract categories, and the detection of statistical regularities have been characterized with task fMRI in infants, providing developmental context for identifying and interpreting variation in the functioning of neural circuits related to psychiatric risk. Next, we discuss studies that specifically examine variation in the functioning of these neural circuits during infancy in relation to risk for psychiatric disorders. These studies reveal when maturation of specific neural circuits diverges, the influence of environmental risk factors, and the potential utility for task fMRI to facilitate early treatment or prevention of later psychiatric problems. Finally, we provide considerations for future infant task-fMRI studies with the potential to advance understanding of both functioning of neural circuits during infancy and subsequent risk for psychiatric disorders.

Maturation of large-scale brain systems over the first month of life.

The period immediately after birth is a critical developmental window, capturing rapid maturation of brain structure and a child's earliest experiences. Large-scale brain systems are present at delivery, but how these brain systems mature during this narrow window (i.e. first weeks of life) marked by heightened neuroplasticity remains uncharted. Using multivariate pattern classification techniques and functional connectivity magnetic resonance imaging, we detected robust differences in brain systems related to age in newborns (n = 262; R2 = 0.51). Development over the first month of life occurred brain-wide, but differed and was more pronounced in brain systems previously characterized as developing early (i.e. sensorimotor networks) than in those characterized as developing late (i.e. association networks). The cingulo-opercular network was the only exception to this organizing principle, illuminating its early role in brain development. This study represents a step towards a normative brain "growth curve" that could be used to identify atypical brain maturation in infancy.

Network-specific selectivity of functional connections in the neonatal brain.

The adult human brain is organized into functional brain networks, groups of functionally connected segregated brain regions. A key feature of adult functional networks is long-range selectivity, the property that spatially distant regions from the same network have higher functional connectivity than spatially distant regions from different networks. Although it is critical to establish the status of functional networks and long-range selectivity during the neonatal period as a foundation for typical and atypical brain development, prior work in this area has been mixed. Although some studies report distributed adult-like networks, other studies suggest that neonatal networks are immature and consist primarily of spatially isolated regions. Using a large sample of neonates (n = 262), we demonstrate that neonates have long-range selective functional connections for the default mode, fronto-parietal, and dorsal attention networks. An adult-like pattern of functional brain networks is evident in neonates when network-detection algorithms are tuned to these long-range connections, when using surface-based registration (versus volume-based registration), and as per-subject data quantity increases. These results help clarify factors that have led to prior mixed results, establish that key adult-like functional network features are evident in neonates, and provide a foundation for studies of typical and atypical brain development.

What have we really learned from functional connectivity in clinical populations?

Functional connectivity (FC), or the statistical interdependence of blood-oxygen dependent level (BOLD) signals between brain regions using fMRI, has emerged as a widely used tool for probing functional abnormalities in clinical populations due to the promise of the approach across conceptual, technical, and practical levels. With an already vast and steadily accumulating neuroimaging literature on neurodevelopmental, psychiatric, and neurological diseases and disorders in which FC is a primary measure, we aim here to provide a high-level synthesis of major concepts that have arisen from FC findings in a manner that cuts across different clinical conditions and sheds light on overarching principles. We highlight that FC has allowed us to discover the ubiquity of intrinsic functional networks across virtually all brains and clarify typical patterns of neurodevelopment over the lifespan. This understanding of typical FC maturation with age has provided important benchmarks against which to evaluate divergent maturation in early life and degeneration in late life. This in turn has led to the important insight that many clinical conditions are associated with complex, distributed, network-level changes in the brain, as opposed to solely focal abnormalities. We further emphasize the important role that FC studies have played in supporting a dimensional approach to studying transdiagnostic clinical symptoms and in enhancing the multimodal characterization and prediction of the trajectory of symptom progression across conditions. We highlight the unprecedented opportunity offered by FC to probe functional abnormalities in clinical conditions where brain function could not be easily studied otherwise, such as in disorders of consciousness. Lastly, we suggest high priority areas for future research and acknowledge critical barriers associated with the use of FC methods, particularly those related to artifact removal, data denoising and feasibility in clinical contexts.

Cingulo-opercular control network and disused motor circuits joined in standby mode.

Whole-brain resting-state functional MRI (rs-fMRI) during 2 wk of upper-limb casting revealed that disused motor regions became more strongly connected to the cingulo-opercular network (CON), an executive control network that includes regions of the dorsal anterior cingulate cortex (dACC) and insula. Disuse-driven increases in functional connectivity (FC) were specific to the CON and somatomotor networks and did not involve any other networks, such as the salience, frontoparietal, or default mode networks. Censoring and modeling analyses showed that FC increases during casting were mediated by large, spontaneous activity pulses that appeared in the disused motor regions and CON control regions. During limb constraint, disused motor circuits appear to enter a standby mode characterized by spontaneous activity pulses and strengthened connectivity to CON executive control regions.

Translating RDoC to Real-World Impact in Developmental Psychopathology: A Neurodevelopmental Framework for Application of Mental Health Risk Calculators.

The National Institute of Mental Health Research Domain Criteria's (RDoC) has prompted a paradigm shift from categorical psychiatric disorders to considering multiple levels of vulnerability for probabilistic risk of disorder. However, the lack of neurodevelopmentally-based tools for clinical decision-making has limited RDoC's real-world impact. Integration with developmental psychopathology principles and statistical methods actualize the clinical implementation of RDoC to inform neurodevelopmental risk. In this conceptual paper, we introduce the probabilistic mental health risk calculator as an innovation for such translation and lay out a research agenda for generating an RDoC- and developmentally-informed paradigm that could be applied to predict a range of developmental psychopathologies from early childhood to young adulthood. We discuss methods that weigh the incremental utility for prediction based on intensity and burden of assessment, the addition of developmental change patterns, considerations for assessing outcomes, and integrative data approaches. Throughout, we illustrate the risk calculator approach with different neurodevelopmental pathways and phenotypes. Finally, we discuss real-world implementation of these methods for improving early identification and prevention of developmental psychopathology. We propose that mental health risk calculators can build a needed bridge between RDoC's multiple units of analysis and developmental science.

Plasticity and Spontaneous Activity Pulses in Disused Human Brain Circuits.

To induce brain plasticity in humans, we casted the dominant upper extremity for 2 weeks and tracked changes in functional connectivity using daily 30-min scans of resting-state functional MRI (rs-fMRI). Casting caused cortical and cerebellar regions controlling the disused extremity to functionally disconnect from the rest of the somatomotor system, while internal connectivity within the disused sub-circuit was maintained. Functional disconnection was evident within 48 h, progressed throughout the cast period, and reversed after cast removal. During the cast period, large, spontaneous pulses of activity propagated through the disused somatomotor sub-circuit. The adult brain seems to rely on regular use to maintain its functional architecture. Disuse-driven spontaneous activity pulses may help preserve functionally disconnected sub-circuits.

Machine Learning With Neuroimaging: Evaluating Its Applications in Psychiatry.

Psychiatric disorders are complex, involving heterogeneous symptomatology and neurobiology that rarely involves the disruption of single, isolated brain structures. In an attempt to better describe and understand the complexities of psychiatric disorders, investigators have increasingly applied multivariate pattern classification approaches to neuroimaging data and in particular supervised machine learning methods. However, supervised machine learning approaches also come with unique challenges and trade-offs, requiring additional study design and interpretation considerations. The goal of this review is to provide a set of best practices for evaluating machine learning applications to psychiatric disorders. We discuss how to evaluate two common efforts: 1) making predictions that have the potential to aid in diagnosis, prognosis, and treatment and 2) interrogating the complex neurophysiological mechanisms underlying psychopathology. We focus here on machine learning as applied to functional connectivity with magnetic resonance imaging, as an example to ground discussion. We argue that for machine learning classification to have translational utility for individual-level predictions, investigators must ensure that the classification is clinically informative, independent of confounding variables, and appropriately assessed for both performance and generalizability. We contend that shedding light on the complex mechanisms underlying psychiatric disorders will require consideration of the unique utility, interpretability, and reliability of the neuroimaging features (e.g., regions, networks, connections) identified from machine learning approaches. Finally, we discuss how the rise of large, multisite, publicly available datasets may contribute to the utility of machine learning approaches in psychiatry.

Integrative and Network-Specific Connectivity of the Basal Ganglia and Thalamus Defined in Individuals.

The basal ganglia, thalamus, and cerebral cortex form an interconnected network implicated in many neurological and psychiatric illnesses. A better understanding of cortico-subcortical circuits in individuals will aid in development of personalized treatments. Using precision functional mapping-individual-specific analysis of highly sampled human participants-we investigated individual-specific functional connectivity between subcortical structures and cortical functional networks. This approach revealed distinct subcortical zones of network specificity and multi-network integration. Integration zones were systematic, with convergence of cingulo-opercular control and somatomotor networks in the ventral intermediate thalamus (motor integration zones), dorsal attention and visual networks in the pulvinar, and default mode and multiple control networks in the caudate nucleus. The motor integration zones were present in every individual and correspond to consistently successful sites of deep brain stimulation (DBS; essential tremor). Individually variable subcortical zones correspond to DBS sites with less consistent treatment effects, highlighting the importance of PFM for neurosurgery, neurology, and psychiatry.

Atypical Functional Connectivity in Tourette Syndrome Differs Between Children and Adults.

BACKGROUND: Tourette syndrome (TS) is a neuropsychiatric disorder with symptomatology that typically changes over development. Whether and how brain function in TS also differs across development has been largely understudied. Here, we used functional connectivity magnetic resonance imaging to examine whole-brain functional networks in children and adults with TS. METHODS: Multivariate classification methods were used to find patterns among functional connections that distinguish individuals with TS from control subjects separately for children and adults (N = 202). We tested whether the patterns of connections that classify diagnosis in one age group (e.g., children) could classify diagnosis in another age group (e.g., adults). We also tested whether the developmental trajectory of these connections was altered in TS. RESULTS: Diagnostic classification was successful in children and adults separately but expressly did not generalize across age groups, suggesting that the patterns of functional connections that best distinguished individuals with TS from control subjects were age specific. Developmental patterns among these functional connections used for diagnostic classification deviated from typical development. Brain networks in childhood TS appeared "older" and brain networks in adulthood TS appeared "younger" in comparison with typically developing individuals. CONCLUSIONS: Our results demonstrate that brain networks are differentially altered in children and adults with TS. The observed developmental trajectory of affected connections is consistent with theories of accelerated and/or delayed maturation, but may also involve anomalous developmental pathways. These findings further our understanding of neurodevelopmental trajectories in TS and carry implications for future applications aimed at predicting the clinical course of TS in individuals over development.