Sensitive periods and other timing hypotheses in developmental psychopathology: A tutorial.

Researchers often aim to assess whether repeated measures of an exposure are associated with repeated measures of an outcome. A question of particular interest is how associations between exposures and outcomes may differ over time. In other words, researchers may seek the best form of a temporal model. While several models are possible, researchers often consider a few key models. For example, researchers may hypothesize that an exposure measured during a sensitive period may be associated with repeated measures of the outcome over time. Alternatively, they may hypothesize that the exposure measured immediately before the current time period may be most strongly associated with the outcome at the current time. Finally, they may hypothesize that all prior exposures are important. Many analytic methods cannot compare and evaluate these alternative temporal models, perhaps because they make the restrictive assumption that the associations between exposures and outcomes remains constant over time. Instead, we provide a tutorial describing four temporal models that allow the associations between repeated measures of exposures and outcomes to vary, and showing how to test which temporal model is best supported by the data. By finding the best temporal model, developmental psychopathology researchers can find optimal windows for intervention.

Child maltreatment in a high adversity context: Associations of age, type and timing of exposure with psychopathology in middle childhood.

BACKGROUND: While cumulative childhood maltreatment (CM) has been linked to psychopathological outcomes, recent studies point to the relevance of the type and timing of exposure. The aim of the current study was to better understand their importance beyond the cumulative burden of CM for psychopathological symptoms in middle childhood. METHODS: A total of N = 341 children (M = 9.92, SD = 1.51) were interviewed to assess trauma load (UCLA - University of California at Los Angeles Event List), exposure to CM (pediMACE - Maltreatment and Abuse Chronology of Exposure - Pediatric Interview) and different outcomes of psychopathology (UCLA Posttraumatic Stress Disorder Reaction Index, Children's Depression Inventory (CDI), Strengths and Difficulties Questionnaire (SDQ). We employed conditioned random forest regression, incorporating type, timing, and cumulative indicators of CM, to assess the importance of each predictor simultaneously. RESULTS: Exposure to CM (abuse, neglect and cumulative indicators) exhibited a robust association with psychopathological outcomes. Recent abuse and recent neglect showed most robust associations with outcomes, neglect was stronger related to internalizing problems and timing of exposure showed clear associations with diverse pathological outcomes. CONCLUSION: Beyond the cumulative burden, type and timing of CM show direct and diverse associations to pathological outcomes in middle childhood. Our results highlight the critical importance of early and detailed identification of CM, particularly recent exposure. This finding is valuable for researchers and clinicians, as it can refine diagnostic assessments and pave the way for effective early intervention strategies for affected children.

Sensitive periods in language development: Do children outperform adults on auditory word-form segmentation?

Children are more successful language learners than adults, yet the nature and cause of this phenomenon are still not well understood. Auditory statistical learning from speech has been a prominent focus of research in the field of language development because it is regarded as a fundamental learning mechanism underlying word segmentation in early language acquisition. However, a handful of studies that investigated developmental trajectories for auditory statistical learning found no clear child advantages. The degree to which the learning task measures explicit rather than implicit mechanisms might obscure a potential advantage for younger learners, as suggested by recent findings. In the present study, we compared children aged 7-12 years and young adults on an adapted version of the task that disentangles explicit and implicit contributions to learning. They were exposed to a continuous stream of speech sounds comprising four repeating trisyllabic pseudowords. Learning of the hidden words was tested (a) online through a target-detection task and (b) offline via a forced-choice word recognition test that included a memory judgement procedure. Both measures revealed comparable learning abilities. However, children's performance on the recognition task showed evidence for both explicit and implicit word knowledge while adults appeared primarily sensitive to explicit memory. Since implicit memory is more stable in time than explicit memory, we suggest that future work should focus more on developmental differences in the nature of the memory that is formed, rather than the strength of learning, when trying to understand child advantages in language acquisition.

Revisiting adolescence as a sensitive period for sociocultural processing.

Waves of research and public discourse have characterized adolescence as periods of developmental risk and opportunity. Underlying this discussion is the recognition that adolescence is a period of major biological and social transition when experience may have an outsized effect on development. This article updates and expands upon prior work suggesting that adolescence may be a sensitive period for sociocultural processing specifically. By integrating evidence from developmental psychology and neuroscience, we identify how trajectories of social and neurobiological development may relate to adolescents' ability to adapt to and learn from their social environments. However, we also highlight gaps in the literature, including challenges in attributing developmental change to adolescent experiences. We discuss the importance of better understanding variability in biology (e.g., pubertal development) and cultural environments, as well as distinguishing between sensitive periods and periods of heightened sensitivity. Finally, we look toward future directions and translational implications of this research.

Effects of parental job loss on psychotropic drug use in children: Long-term effects, timing, and cumulative exposure.

Intra-family crossover effects triggered by job losses have received growing attention across scientific disciplines, but existing research has reached discrepant conclusions concerning if, and if so how, parental job losses affect child mental health. Drawing on sociological models of stress and life course epidemiology, we ask if parental job losses have long-term effects on child mental health, and if these effects are conditional on the timing of, or the cumulative exposure to, job losses. We use intergenerationally linked Swedish register data combined with entropy balance and structural nested mean models for the analyses. The data allow us to track 400,000 children over 14 years and thereby test different life-course models of cross-over effects. We identify involuntary job losses using information on workplace closures, thus reducing the risk of confounding. Results show that paternal but not maternal job loss significantly increases the risk of psychotropic drug use among children, that the average effects are modest in size (less than 4% in relative terms), that they may persist for up to five years, and that they are driven by children aged 6-10 years. Moreover, cumulative exposure to multiple job losses are more harmful than zero or one job loss.

Early and accumulated experience shape migration and flight in Egyptian vultures.

Two types of experience affect animals' behavioral proficiencies and, accordingly, their fitness: early-life experience, an animal's environment during its early development, and acquired experience, the repeated practice of a specific task.1,2,3,4,5,6,7,8 Yet, how these two experience types and their interactions affect different proficiencies is still an open question. Here, we study the interactions between these two types of experience during migration, a critical and challenging period.9,10 We do so by comparing migratory proficiencies between birds with different early-life experiences and explain these differences by testing fine-scale flight mechanisms. We used data collected by GPS transmitters during 127 autumn migrations of 65 individuals to study the flight proficiencies of two groups of Egyptian vultures (Neophron percnopterus), a long-distance, soaring raptor.11,12 The two groups differed greatly in their early-life experience, one group being captive bred and the other wild hatched.13 Both groups improved their migratory performance with acquired experience, exhibiting shorter migration times, longer daily progress, and improved flight skills, specifically more efficient soaring-gliding behavior. The observed improvements were mostly apparent for captive-bred vultures, which were the least efficient during their first migration but were able to catch up in their migratory performance already in the second migration. Thus, we show how the strong negative effects of early-life experience were offset by acquired experience. Our findings uncover how the interaction between early-life and acquired experiences may shape animals' proficiencies and shed new light on the ontogeny of animal migration, suggesting possible effects of sensitive periods of learning on the acquisition of migratory skills.

Sensitive Periods for the Effect of Child Maltreatment on Psychopathology Symptoms in Adolescence.

Introduction: Child maltreatment is among the strongest risk factors for mental disorders. However, little is known about whether there are ages when children may be especially vulnerable to its effects. We sought to identify potential sensitive periods when exposure to the 2 most common types of maltreatment (neglect and harsh physical discipline) had a particularly detrimental effect on youth mental health. Methods: Data came from the Future of Families and Child Wellbeing Study (FFCWS), a birth cohort oversampled from "fragile families" (n = 3,474). Maltreatment was assessed at 3, 5, and 9 years of age using an adapted version of the Parent-Child Conflict Tactics Scales (CTS-PC). Using least angle regression, we examined the relationship between repeated measures of exposure to maltreatment on psychopathology symptoms at age 15 years (Child Behavior Checklist; CBCL/6-18). For comparison, we evaluated the strength of evidence to support the existence of sensitive periods in relation to an accumulation of risk model. Results: We identified sensitive periods for harsh physical discipline, whereby psychopathology symptom scores were highest among girls exposed at age 9 years (r2 = 0.67 internalizing symptoms; r2 = 1% externalizing symptoms) and among boys exposed at age 5 years (r2 = 0.41%). However, for neglect, the accumulation of risk model explained more variability in psychopathology symptoms for both boys and girls. Conclusion: Child maltreatment may have differential effects based on the child's sex, type of exposure, and the age at which it occurs. These findings provide additional evidence for clinicians assessing the benefits and drawbacks of screening efforts and point toward possible mechanisms driving increased vulnerability to psychopathology.

Early adversity and the development of explore-exploit tradeoffs.

Childhood adversity can have wide-ranging and long-lasting effects on later life. But what are the mechanisms that are responsible for these effects? This article brings together the cognitive science literature on explore-exploit tradeoffs, the empirical literature on early adversity, and the literature in evolutionary biology on 'life history' to explain how early experience influences later life. We propose one potential mechanism: early experiences influence 'hyperparameters' that determine the balance between exploration and exploitation. Adversity might accelerate a shift from exploration to exploitation, with broad and enduring effects on the adult brain and mind. These effects may be produced by life-history adaptations that use early experience to tailor development and learning to the likely future states of an organism and its environment.

Development and experience-dependence of multisensory spatial processing.

Multisensory spatial processes are fundamental for efficient interaction with the world. They include not only the integration of spatial cues across sensory modalities, but also the adjustment or recalibration of spatial representations to changing cue reliabilities, crossmodal correspondences, and causal structures. Yet how multisensory spatial functions emerge during ontogeny is poorly understood. New results suggest that temporal synchrony and enhanced multisensory associative learning capabilities first guide causal inference and initiate early coarse multisensory integration capabilities. These multisensory percepts are crucial for the alignment of spatial maps across sensory systems, and are used to derive more stable biases for adult crossmodal recalibration. The refinement of multisensory spatial integration with increasing age is further promoted by the inclusion of higher-order knowledge.

Prefrontal microglia deficiency during adolescence disrupts adult cognitive functions and synaptic structures: A follow-up study in female mice.

The prefrontal cortex (PFC) provides executive top-down control of a variety of cognitive processes. A distinctive feature of the PFC is its protracted structural and functional maturation throughout adolescence to early adulthood, which is necessary for acquiring mature cognitive abilities. Using a mouse model of cell-specific, transient and local depletion of microglia, which is based on intracerebral injection of clodronate disodium salt (CDS) into the PFC of adolescent male mice, we recently demonstrated that microglia contribute to the functional and structural maturation of the PFC in males. Because microglia biology and cortical maturation are partly sexually dimorphic, the main objective of the present study was to examine whether microglia similarly regulate this maturational process in female mice as well. Here, we show that a single, bilateral intra-PFC injection of CDS in adolescent (6-week-old) female mice induces a local and transient depletion (70 to 80% decrease from controls) of prefrontal microglia during a restricted window of adolescence without affecting neuronal or astrocytic cell populations. This transient microglia deficiency was sufficient to disrupt PFC-associated cognitive functions and synaptic structures at adult age. Inducing transient prefrontal microglia depletion in adult female mice did not cause these deficits, demonstrating that the adult PFC, unlike the adolescent PFC, is resilient to transient microglia deficiency in terms of lasting cognitive and synaptic maladaptations. Together with our previous findings in males, the present findings suggest that microglia contribute to the maturation of the female PFC in a similar way as to the prefrontal maturation occurring in males.

Vulnerability of facial attractiveness perception to early and multi-year visual deprivation.

Judgments of facial attractiveness invariably accompany our perception of faces. Even neonates appear to be capable of making such judgments in a manner consistent with adults. This suggests that the processes supporting facial attractiveness require little, if any, visual experience to manifest. Here we investigate the resilience of these processes to several years of early-onset visual deprivation. Specifically, we study whether congenitally blind children treated several years after birth possess the ability to rate facial attractiveness in a manner congruent to normally sighted individuals. The data reveal significant individual variability in the way each newly sighted child perceives attractiveness. This is in marked contrast to data from normally sighted controls who exhibit strong across-subject agreement in facial attractiveness ratings. This variability may be attributable, in part, to atypical facial encoding strategies used by the newly sighted children. Overall, our results suggest that the development of facial attractiveness perception is likely to be vulnerable to early visual deprivation, pointing to the existence of a possible sensitive period early in the developmental trajectory.

Testing lifecourse theories characterising associations between maternal depression and offspring depression in emerging adulthood: the Avon Longitudinal Study of Parents and Children.

BACKGROUND: Maternal depression is a major determinant of offspring mental health. Yet, little is understood about how the duration and timing of maternal depression shapes youth risk for depressive symptoms, which if understood could inform when best to intervene. This study aimed to determine how the timing and duration of maternal depression was related to offspring depression in emerging adulthood, and if these associations varied by sex. METHODS: We analysed data from the Avon Longitudinal Study of Parents and Children (a prenatal cohort in the Avon area of England, 1991-2003), n = 3,301. We applied the structured lifecourse modelling approach to maternal depression (assessed at 13 points from prenatal period to adolescence) and emerging adult depressive symptoms (age 21). Lifecourse models assessed were accumulation (sum of timepoints when maternal depression was reported), sensitive periods (each period assessed as one during which maternal depression has a stronger effect) and instability (frequent fluctuations in maternal depression). RESULTS: Female adolescents (n = 2,132) had higher SMFQ scores (mean = 6.15, SD = 5.90) than males (n = 1,169, mean = 4.87, SD = 4.82). Maternal depression was most common in the infancy period (21.2% males; 21.4% females). For males, accumulation was the most appropriate lifecourse model; for each additional period of maternal depression, depressive symptoms in emerging adulthood increased by 0.11 (95% CI: 0.07, 0.15, one-sided p value ≤ .001). For females, exposure to maternal depression was associated with increasing depressive symptoms in emerging adulthood, with the largest effect in mid-childhood (increase of 0.27 units, 95% CI 0.03-0.50, p = .015 for difference between mid-childhood and other time-periods) and a smaller, equal effect at all other time-periods (increase of 0.07 units per time-period, 95% CI: 0.03-0.12, p = .002). CONCLUSIONS: This study highlights the importance of ongoing maternal depression for the development of depression in offspring through to emerging adulthood. Because long-term exposure to maternal depression was particularly important, early interventions are warranted.

Associations Between Childhood Trauma Characteristics and Theory of Mind in Adults: Results From a Large, Diverse Sample.

Theory of mind (ToM) is an essential social cognitive process encompassing abilities to represent and understand others' mental states. Although previous reports linked childhood trauma to social cognitive deficits, how characteristics of trauma exposure, such as subtype or timing, affect ToM remains unaddressed. Using data from a diverse adult sample (n = 2200), we tested whether exposure type and first exposure timing of common childhood trauma associated with ToM. Neither interpersonal loss (ß = - 0.25, p = 0.170, [- 0.61, 0.10]) nor child maltreatment (ß = - 0.21, p = 0.369, [- 0.66, 0.25]) was associated with lower ToM. There was no effect of timing of age at which trauma was experienced (F = 2.19, p = 0.087). While we did not identify age-dependent effects, future studies should examine links between timing or chronicity of prospectively reported childhood trauma and social cognition. Understanding of how childhood experiences shape ToM could reveal mechanisms underlying social cognition development and inform prevention efforts.

Neuroplasticity following cochlear implants.

The auditory cortex of people with sensorineural hearing loss can be re-afferented using a cochlear implant (CI): a neural prosthesis that bypasses the damaged cells in the cochlea to directly stimulate the auditory nerve. Although CIs are the most successful neural prosthesis to date, some CI users still do not achieve satisfactory outcomes using these devices. To explain variability in outcomes, clinicians and researchers have increasingly focused their attention on neuroscientific investigations that examined how the auditory cortices respond to the electric signals that originate from the CI. This chapter provides an overview of the literature that examined how the auditory cortex changes its functional properties in response to inputs from the CI, in animal models and in humans. We focus first on the basic responses to sounds delivered through electrical hearing and, next, we examine the integrity of two fundamental aspects of the auditory system: tonotopy and processing of binaural cues. When addressing the effects of CIs in humans, we also consider speech-evoked responses. We conclude by discussing to what extent this neuroscientific literature can contribute to clinical practices and help to overcome variability in outcomes.

Examining the epigenetic mechanisms of childhood adversity and sensitive periods: A gene set-based approach.

BACKGROUND: Sensitive periods are developmental stages of heightened plasticity when life experiences, including exposure to childhood adversity, have the potential to exert more lasting impacts. Epigenetic mechanisms, including DNA methylation (DNAm), may provide a pathway through which adversity induces long-term biological changes. DNAm shifts may be more likely to occur during sensitive periods, especially within genes that regulate the timing of sensitive periods. Here, we investigated the possibility that childhood adversity during specific life stages is associated with DNAm changes in genes known to regulate the timing and duration of sensitive periods. METHODS: Genome-wide DNAm profiles came from the Avon Longitudinal Study of Parents and Children (n = 785). We first used principal component analysis (PCA) to summarize DNAm variation across 530 CpG sites mapped to the promoters of 58 genes previously-identified as regulating sensitive periods. Gene-level DNAm summaries were calculated for genes regulating sensitive period opening (ngenes = 15), closing (ngenes = 36), and expression (ngenes = 8). We then performed linear discriminant analysis (LDA) to test associations between seven types of parent-reported, time-varying measures of exposure to childhood adversity and DNAm principal components. To our knowledge, this is the first time LDA has been applied to analyze functionally grouped DNAm data to characterize associations between an environmental exposure and epigenetic differences. RESULTS: Suggestive evidence emerged for associations between sexual or physical abuse as well as financial hardship during middle childhood, and DNAm of genetic pathways regulating sensitive period opening and expression. However, no statistically significant associations were identified after multiple testing correction. CONCLUSIONS: Our gene set-based method combining PCA and LDA complements epigenome-wide approaches. Although our results were largely null, these findings provide a proof-of-concept for studying time-varying exposures and gene- or pathway-level epigenetic modifications.

Typical resting-state activity of the brain requires visual input during an early sensitive period.

Sensory deprivation, following a total loss of one sensory modality e.g. vision, has been demonstrated to result in compensatory plasticity. It is yet not known to which extent neural changes, e.g. higher resting-state activity in visual areas (cross-modal plasticity) as a consequence of blindness, reverse, when sight is restored. Here, we used functional MRI to acquire blood oxygen level-dependent resting-state activity during an eyes open and an eyes closed state in congenital cataract-reversal individuals, developmental cataract-reversal individuals, congenitally permanently blind individuals and sighted controls. The amplitude of low frequency fluctuation of the blood oxygen level-dependent signal-a neural marker of spontaneous brain activity during rest-was analyzed. In accordance with previous reports, in normally sighted controls we observed an increase in amplitude of low-frequency fluctuation during rest with the eyes open compared with rest with eyes closed in visual association areas and in parietal cortex but a decrease in auditory and sensorimotor regions. In congenital cataract-reversal individuals, we found an increase of the amplitude of slow blood oxygen level-dependent fluctuations in visual cortex during rest with eyes open compared with rest with eyes closed too but this increase was larger in amplitude than in normally sighted controls. In contrast, congenital cataract-reversal individuals lagged a similar increase in parietal regions and did not show the typical decrease of amplitude of low-frequency fluctuation in auditory cortex. Congenitally blind individuals displayed an overall higher amplitude in slow blood oxygen level-dependent fluctuations in visual cortex compared with sighted individuals and compared with congenital cataract-reversal individuals in the eyes closed condition. Higher amplitude of low-frequency fluctuation in visual cortex of congenital cataract-reversal individuals than in normally sighted controls during eyes open might indicate an altered excitatory-inhibitory balance of visual neural circuits. By contrast, the lower parietal increase and the missing downregulation in auditory regions suggest a reduced influence of the visual system on multisensory and the other sensory systems after restoring sight in congenitally blind individuals. These results demonstrate a crucial dependence of visual and multisensory neural system functioning on visual experience during a sensitive phase in human brain development.

Naturalistic stimuli reveal a sensitive period in cross modal responses of visual cortex: Evidence from adult-onset blindness.

How do life experiences impact cortical function? In people who are born blind, the "visual" cortices are recruited during nonvisual tasks, such as Braille reading and sound localization. Do visual cortices have a latent capacity to respond to nonvisual information throughout the lifespan? Alternatively, is there a sensitive period of heightened plasticity that makes visual cortex repurposing especially possible during childhood? To gain insight into these questions, we leveraged meaningful naturalistic auditory stimuli to simultaneously engage a broad range of cognitive domains and quantify cross-modal responses across congenitally blind (n = 22), adult-onset blind (vision loss >18 years-of-age, n = 14) and sighted (n = 22) individuals. During fMRI scanning, participants listened to two types of meaningful naturalistic auditory stimuli: excerpts from movies and a spoken narrative. As controls, participants heard the same narrative with the sentences shuffled and the narrative played backwards (i.e., meaningless sounds). We correlated the voxel-wise timecourses of different participants within condition and group. For all groups, all stimulus conditions induced synchrony in auditory cortex while only the narrative stimuli synchronized responses in higher-cognitive fronto-parietal and temporal regions. As previously reported, inter-subject synchrony in visual cortices was higher in congenitally blind than sighted blindfolded participants and this between-group difference was particularly pronounced for meaningful stimuli (movies and narrative). Critically, visual cortex synchrony was no higher in adult-onset blind than sighted blindfolded participants and did not increase with blindness duration. Sensitive period plasticity enables cross-modal repurposing in visual cortices.

Statistical Modeling of Sensitive Period Effects Using the Structured Life Course Modeling Approach (SLCMA).

Sensitive periods are times during development when life experiences can have a greater impact on outcomes than at other periods during the life course. However, a dearth of sophisticated methods for studying time-dependent exposure-outcome relationships means that sensitive periods are often overlooked in research studies in favor of more simplistic and easier-to-use hypotheses such as ever being exposed, or the effect of an exposure accumulated over time. The structured life course modeling approach (SLCMA; pronounced "slick-mah") allows researchers to model complex life course hypotheses, such as sensitive periods, to determine which hypothesis best explains the amount of variation between a repeated exposure and an outcome. The SLCMA makes use of the least angle regression (LARS) variable selection technique, a type of least absolute shrinkage and selection operator (LASSO) estimation procedure, to yield a parsimonious model for the exposure-outcome relationship of interest. The results of the LARS procedure are complemented with a post-selection inference method, called selective inference, which provides unbiased effect estimates, confidence intervals, and p-values for the final explanatory model. In this chapter, we provide a brief overview of the genesis of this sensitive period modeling approach and provide a didactic step-by-step user's guide to implement the SLCMA in sensitive- period research. R code to complete the SLCMA is available on our GitHub page at: https://github.com/thedunnlab/SLCMA-pipeline .

An evolutionary model of sensitive periods when the reliability of cues varies across ontogeny.

Sensitive periods are widespread in nature, but their evolution is not well understood. Recent mathematical modeling has illuminated the conditions favoring the evolution of sensitive periods early in ontogeny. However, sensitive periods also exist at later stages of ontogeny, such as adolescence. Here, we present a mathematical model that explores the conditions that favor sensitive periods at later developmental stages. In our model, organisms use environmental cues to incrementally construct a phenotype that matches their environment. Unlike in previous models, the reliability of cues varies across ontogeny. We use stochastic dynamic programming to compute optimal policies for a range of evolutionary ecologies and then simulate developmental trajectories to obtain mature phenotypes. We measure changes in plasticity across ontogeny using study paradigms inspired by empirical research: adoption and cross-fostering. Our results show that sensitive periods only evolve later in ontogeny if the reliability of cues increases across ontogeny. The onset, duration, and offset of sensitive periods-and the magnitude of plasticity-depend on the specific parameter settings. If the reliability of cues decreases across ontogeny, sensitive periods are favored only early in ontogeny. These results are robust across different paradigms suggesting that empirical findings might be comparable despite different experimental designs.