The impact of developmental timing for stress and recovery

“Substantial regional variation exists, with maturation of low-level sensory and motor cortices occurring prior to prefrontal and temporal cortices involved in higher-level cognition and regulation of behavior (Yakovlev and Lecours, 1967; Benes et al., 1994; Sowell et al., 1999, 2001; Gogtay et al., 2004).”

“Human neuroimaging studies show corresponding patterns, in which gray matter volumes typically peak around 10e12 years of age (Giedd et al., 1999), with significant gray matter loss throughout adolescence and adulthood (Sowell et al., 2001, 2003).”

“…studies show that typical brain development is marked by an initial period of overproduction of synapses, followed by selective stabilization and elimination of a substantial proportion of synapses (Huttenlocher, 1979; Huttenlocher et al., 1982; Bourgeois and Rakic, 1993; LaMantia and Rakic, 1994).”

“, 2005), and early childhood adversity accounts for over 30% of all mental illnesses (Green et al., 2010).”

“There is a growing body of evidence to suggest that the hippocampus and PFC may have greater capacity for change or plasticity following stress with many of the effects being reversible following the termination of stress (McEwen, 1999; Vyas et al., 2004; Liston et al., 2009).”

“Approximately 10% of youth have anxiety and stressrelated disorders (Newman et al., 1996; Kim-Cohen et al., 2003; Kessler et al., 2005), and early childhood adversity accounts for over 30% of all mental illnesses (Green et al., 2010).”

“Approximately 10% of youth have anxiety and stressrelated disorders (Newman et al., 1996; Kim-Cohen et al., 2003; Kessler et al., 2005), and early childhood adversity accounts for over 30% of all mental illnesses (Green et al., 2010).”

“…unexplored in human development, the notion of too much or too little stress yielding suboptimal effects on brain and behavior, but moderate stress yielding benefits in an inverted-U pattern, has been around for some time (Arnsten and Goldman-Rakic, 1990, 1998; McEwen and Sapolsky, 1995).”

“During these periods, environmental input can lead to a series of developmental cascades (Masten and Cicchetti, 2010) that ultimately have significant influences on behavior, of a positive or negative nature.”

“…in response to threat and stress (Dunn and Whitener, 1986; Feldman et al., 1995; Redgate and Fahringer, 1973), and levels of glucocorticoids are regulated via negative feedback loops at several levels of the axis including the hippocampus and PFC (Diorio et al., 1993; Jacobson and Sapolsky, 1991).”

“Specifically, studies of rodents show that stress increases dendritic arborization and spine density of the amygdala, with concomitant increases in anxiety-like behaviors (Vyas et al., 2002; Vyas et al., 2003; Mitra et al., 2005).”

“…regional variation exists, with maturation of low-level sensory and motor cortices occurring prior to prefrontal and temporal cortices involved in higher-level cognition and regulation of behavior (Yakovlev and Lecours, 1967; Benes et al., 1994; Sowell et al., 1999, 2001; Gogtay et al., 2004).”

“, 2013) and alter the expression of neurotrophic factors essential for neuroplasticity (Smith et al., 1995).”

“The timing of stress and its interactions with dynamic developmental processes are critical to subsequent outcomes (e.g., Lupien et al., 2009; Monk, 2008; Monk et al., 2002; Pechtel and Pizzagalli, 2011; Eiland and Romeo, 2013).”

“…availability of neurochemicals and patterns of cortical cell firing, are posited to lead to transient imbalances that underlie behavioral changes nder the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). during adolescence (Galvan et al., 2006; Casey, Galvan, Getz, 2008).”

“Stress can arise through any number of environments that challenge an individual cognitively, emotionally, or physically, such as uncontrollable or unpredictable settings (e.g., Lupien et al., 2000; McEwen, 2012; Pollak, 2008; Sheridan et al., 2013; Teicher et al., 2006).”

“This mature pattern of inverse amygdala-mPFC functional connectivity is consistent with the inverse connectivity observed in the literature of emotion regulation in healthy adults (Banks et al., 2007; Hare et al., 2008; Hariri et al., 2003; Kim et al., 2003).”

“In contrast, chronic stress downregulates the hippocampus and prefrontal cortex (PFC), which regulate the stress response.”

“Caregiving provides a host of regulatory functions in humans, such as buffering against emotion dysregulation and stress reactivity in youth (Campos et al., 1975; Hofer, 1994; McCoy and Masters, 1985; Gunnar and Donzella, 2002).”

“Human neuroimaging studies show corresponding patterns, in which gray matter volumes typically peak around 10e12 years of age (Giedd et al., 1999), with significant gray matter loss throughout adolescence and adulthood (Sowell et al., 2001, 2003).”

“This mature pattern of inverse amygdala-mPFC functional connectivity is consistent with the inverse connectivity observed in the literature of emotion regulation in healthy adults (Banks et al., 2007; Hare et al., 2008; Hariri et al., 2003; Kim et al., 2003).”

“In addition to environmental interventions, novel studies of brain plasticity are beginning to shed light on ways in which it may be possible to alter plasticity by re-opening sensitive periods (reviewed in Davidson and McEwen, 2012).”

“In contrast to the immature positive functional connectivity displayed in comparison children, the children who experienced early-life stress showed the adult-like pattern of inverse amygdala-mPFC functional connectivity (Gee et al., 2013a,b) (Fig.”

“In these studies, we (Liston et al., 2009) have shown enhanced focus of attention and rewiring of prefrontal circuitry during stress that was reversible when the stressor was of moderate intensity and short-lived (a few weeks).”

“This mature pattern of inverse amygdala-mPFC functional connectivity is consistent with the inverse connectivity observed in the literature of emotion regulation in healthy adults (Banks et al., 2007; Hare et al., 2008; Hariri et al., 2003; Kim et al., 2003).”

“6) consistent with prior work showing similar effects following chronic stress (Cook and Wellman, 2004; Radley et al., 2004, 2006), with some evidence that effects on mPFC were reversible (Radley et al., 2005).”

“prior work showing similar effects following chronic stress (Cook and Wellman, 2004; Radley et al., 2004, 2006), with some evi-”

“Substantial regional variation exists, with maturation of low-level sensory and motor cortices occurring prior to prefrontal and temporal cortices involved in higher-level cognition and regulation of behavior (Yakovlev and Lecours, 1967; Benes et al., 1994; Sowell et al., 1999, 2001; Gogtay et al., 2004).”

“In addition, maternal presence has been shown to reduce cortisol levels in childhood (Hostinar et al., 2014).”

“In contrast to the immature positive functional connectivity displayed in comparison children, the children who experienced early-life stress showed the adult-like pattern of inverse amygdala-mPFC functional connectivity (Gee et al., 2013a,b) (Fig.”

“Simultaneously, increases in white matter occur through myelination of axons (Brody et al., 1987; Benes et al., 1994).”

“Approximately 10% of youth have anxiety and stressrelated disorders (Newman et al., 1996; Kim-Cohen et al., 2003; Kessler et al., 2005), and early childhood adversity accounts for over 30% of all mental illnesses (Green et al., 2010).”

“Specifically, studies of rodents show that stress increases dendritic arborization and spine density of the amygdala, with concomitant increases in anxiety-like behaviors (Vyas et al., 2002; Vyas et al., 2003; Mitra et al., 2005).”

“…the developing brain most vulnerable to AAAS). might be particularly sensitive to stress (Plotsky et al., 2005; Sabatini et al., 2007; reviewed in Tottenham and Sheridan, 2009) and therefore more resistant to recovery following chronic stress (Ganzel et al., 2007; Lupien et al., 2011; Malter…”

“Stress can arise through any number of environments that challenge an individual cognitively, emotionally, or physically, such as uncontrollable or unpredictable settings (e.g., Lupien et al., 2000; McEwen, 2012; Pollak, 2008; Sheridan et al., 2013; Teicher et al., 2006).”

“Evidence from a promising line of studies suggests that shifting the excitatoryinhibitory balance in relevant neural circuits may increase plasticity (Thompson et al., 2008; Bavelier et al., 2010).”

“…studies show that typical brain development is marked by an initial period of overproduction of synapses, followed by selective stabilization and elimination of a substantial proportion of synapses (Huttenlocher, 1979; Huttenlocher et al., 1982; Bourgeois and Rakic, 1993; LaMantia and Rakic, 1994).”

“Stress can arise through any number of environments that challenge an individual cognitively, emotionally, or physically, such as uncontrollable or unpredictable settings (e.g., Lupien et al., 2000; McEwen, 2012; Pollak, 2008; Sheridan et al., 2013; Teicher et al., 2006).”

“The extent to which neuroplasticity and brain function change throughout childhood and adolescence suggests that interventions based on the adult brain cannot be simply applied to youth who experience stress-related mental health disorders (Lee et al., 2014).”

“…(shaded eriods of neural development may also render the developing brain most vulnerable to AAAS). might be particularly sensitive to stress (Plotsky et al., 2005; Sabatini et al., 2007; reviewed in Tottenham and Sheridan, 2009) and therefore more resistant to recovery following chronic…”

“The early-life stress manipulation involved limiting the nesting material provided to the dams, which disrupted maternal care of the pups (Gilles et al., 1996; Ivy et al., 2008; Rice et al., 2008).”

“For example, reductions of inhibitory neural activity in adulthood have increased visual plasticity in rodents (He et al., 2007; Sugiyama et al., 2008; Harauzov et al., 2010) and even restored visual function in ambly-”

“The timing of stress and its interactions with dynamic developmental processes are critical to subsequent outcomes (e.g., Lupien et al., 2009; Monk, 2008; Monk et al., 2002; Pechtel and Pizzagalli, 2011; Eiland and Romeo, 2013).”

“6) consistent with prior work showing similar effects following chronic stress (Cook and Wellman, 2004; Radley et al., 2004, 2006), with some evidence that effects on mPFC were reversible (Radley et al., 2005).”

“This process is critical to the etiology and treatment of anxiety disorders such as phobias and posttraumatic stress disorder (PTSD), which are characterized by an inappropriate fear response to a cue that is no longer dangerous (Rothbaum and Davis, 2003).”

“Parallel findings of increased amygdala volume and functional reactivity, smaller hippocampal volume, and altered prefrontal function and connectivity have been observed in humans following stress (Ganzel et al., 2007, 2008; Liston et al., 2006; Liston et al., 2009; Sheridan et al., 2012a,b).”

“The early-life stress manipulation involved limiting the nesting material provided to the dams, which disrupted maternal care of the pups (Gilles et al., 1996; Ivy et al., 2008; Rice et al., 2008).”

“Although all groups showed similar acquisition of cued fear, the adolescents showed attenuated fear extinction learning relative to children and adults (Pattwell et al., 2012).”

“Caregiving provides a host of regulatory functions in humans, such as buffering against emotion dysregulation and stress reactivity in youth (Campos et al., 1975; Hofer, 1994; McCoy and Masters, 1985; Gunnar and Donzella, 2002).”

“In rodents, a sensitive period for the effects of maternal presence on amygdala development has been identified (Moriceau and Sullivan, 2006; Callaghan and Richardson, 2011).”

“…most vulnerable to AAAS). might be particularly sensitive to stress (Plotsky et al., 2005; Sabatini et al., 2007; reviewed in Tottenham and Sheridan, 2009) and therefore more resistant to recovery following chronic stress (Ganzel et al., 2007; Lupien et al., 2011; Malter Cohen et al., 2013a,b).”

“Consistent with this idea, findings from the Bucharest Early Intervention Project show that children who were removed from institutionalized care and placed in foster families had lower rates of internalizing disorders than those who continued in institutional care (Zeanah et al., 2009).”

“Based on the identification of a sensitive period for maternal influence in rodents, we tested whether caregiver presence differentially affected frontoamygdala circuitry in children versus adolescents (Gee et al., 2014).”

“Partial evidence for this notion in humans has been shownwith moderate stress early in life being associated with reduced cortisol reactivity to subsequent stressors, compared with mild or severe stress early in life (Gunnar et al., 2009; Hagan et al., 2014).”

“This mature pattern of inverse amygdala-mPFC functional connectivity is consistent with the inverse connectivity observed in the literature of emotion regulation in healthy adults (Banks et al., 2007; Hare et al., 2008; Hariri et al., 2003; Kim et al., 2003).”

“…impact of psychological stressors on neuroplasticity, although glucocorticoids, and their directmanipulation, canmodify the brain in anatomically selective ways (Sapolsky, 1986; Liston et al., 2013) and alter the expression of neurotrophic factors essential for neuroplasticity (Smith et al., 1995).”

“As adolescents transition from dependence on their caregivers to a more independent state, they face many new challenges to which they must adapt (Romeo, 2010; Spear, 2010; Malter Cohen et al., 2013b).”

“6) consistent with prior work showing similar effects following chronic stress (Cook and Wellman, 2004; Radley et al., 2004, 2006), with some evidence that effects on mPFC were reversible (Radley et al., 2005).”

“…most vulnerable to AAAS). might be particularly sensitive to stress (Plotsky et al., 2005; Sabatini et al., 2007; reviewed in Tottenham and Sheridan, 2009) and therefore more resistant to recovery following chronic stress (Ganzel et al., 2007; Lupien et al., 2011; Malter Cohen et al., 2013a,b).”

“These findings parallel findings of increased hormonal stress reactivity during puberty and adolescence (Romeo et al., 2006; Folib et al., 2011).”

“However, environments that result in a mismatch between the expected and actual environment may prove particularly stressful (Finlay, 2007; Casey et al., 2010).”

“, 2008), increased anxiety-like behaviors (Romeo et al., 2003), and more social instability in adulthood (Kikusui and Mori, 2009).”

“the brain in anatomically selective ways (Sapolsky, 1986; Liston et al., 2013) and alter the expression of neurotrophic factors”

“In studies of children reared in orphanages abroad and later adopted into stable families, the findings consistently suggest that earlier adoption is better (Rutter, 1998; Gunnar et al., 2000; Tottenham et al., 2010).”

“Stress can arise through any number of environments that challenge an individual cognitively, emotionally, or physically, such as uncontrollable or unpredictable settings (e.g., Lupien et al., 2000; McEwen, 2012; Pollak, 2008; Sheridan et al., 2013; Teicher et al., 2006).”

“For example, reductions of inhibitory neural activity in adulthood have increased visual plasticity in rodents (He et al., 2007; Sugiyama et al., 2008; Harauzov et al., 2010) and even restored visual function in amblyopic adult rats (Vetencourt et al., 2008).”

“Parallel findings of increased amygdala volume and functional reactivity, smaller hippocampal volume, and altered prefrontal function and connectivity have been observed in humans following stress (Ganzel et al., 2007, 2008; Liston et al., 2006; Liston et al., 2009; Sheridan et al., 2012a,b).”

“The early-life stress manipulation involved limiting the nesting material provided to the dams, which disrupted maternal care of the pups (Gilles et al., 1996; Ivy et al., 2008; Rice et al., 2008).”

“Consistent with work in rats (McCallum et al., 2010; Kim et al., 2011) we showed differential effects of fear extinction in adolescent mice and humans, relative to younger and older ages.”

“As adolescents transition from dependence on their caregivers to a more independent state, they face many new challenges to which they must adapt (Romeo, 2010; Spear, 2010; Malter Cohen et al., 2013b).”

“Research on nonhuman primates has shown that moderate stress exposure is associated with lower cortisol following stress and decreased anxiety (Parker et al., 2004), as well as increased prefrontal volume and enhanced prefrontal function (Parker et al., 2005; Katz et al., 2009).”

“The amygdala is critical in activating the LHPA axis in response to threat and stress (Dunn and Whitener, 1986; Feldman et al., 1995; Redgate and Fahringer, 1973), and levels of glucocorticoids are regulated via negative feedback loops at several levels of the axis including the hippocampus and PFC…”

“In rodents, a sensitive period for the effects of maternal presence on amygdala development has been identified (Moriceau and Sullivan, 2006; Callaghan and Richardson, 2011).”

“, 2003), and more social instability in adulthood (Kikusui and Mori, 2009).”

“These findings parallel findings of increased hormonal stress reactivity during puberty and adolescence (Romeo et al., 2006; Folib et al., 2011).”

“The amygdala is critical in activating the LHPA axis in response to threat and stress (Dunn and Whitener, 1986; Feldman et al., 1995; Redgate and Fahringer, 1973), and levels of glucocorticoids are regulated via negative feedback loops at several levels of the axis including the hippocampus and PFC…”

“Consistent with work in rats (McCallum et al., 2010; Kim et al., 2011) we showed differential effects of fear extinction in adolescent mice and humans, relative to younger and older ages.”

“…in rodent pups is associated with greater LHPA axis reactivity (Moriceau et al., 2010), accelerated amygdala development (Moriceau and Sullivan, 2006; Ono et al., 2008), increased anxiety-like behaviors (Romeo et al., 2003), and more social instability in adulthood (Kikusui and Mori, 2009).”

“Moreover, evidence from rodent models suggests that early-life stress may affect different phenotypes in childhood than adolescence (Raineki et al., 2012; Rinc on-Cort es and Sullivan, 2014).”

“Parallel findings of increased amygdala volume and functional reactivity, smaller hippocampal volume, and altered prefrontal function and connectivity have been observed in humans following stress (Ganzel et al., 2007, 2008; Liston et al., 2006; Liston et al., 2009; Sheridan et al., 2012a,b).”

“…neural development may also render the developing brain most vulnerable to AAAS). might be particularly sensitive to stress (Plotsky et al., 2005; Sabatini et al., 2007; reviewed in Tottenham and Sheridan, 2009) and therefore more resistant to recovery following chronic stress (Ganzel et al.,…”

“The timing of stress and its interactions with dynamic developmental processes are critical to subsequent outcomes (e.g., Lupien et al., 2009; Monk, 2008; Monk et al., 2002; Pechtel and Pizzagalli, 2011; Eiland and Romeo, 2013).”

“In contrast, stress-induced amygdala morphology and volume changes seem to persist (Vyas et al., 2002; Adamec et al., 2005; Tottenham et al., 2010).”

“Maternal separation in rodent pups is associated with greater LHPA axis reactivity (Moriceau et al., 2010), accelerated amygdala development (Moriceau and Sullivan, 2006; Ono et al., 2008), increased anxiety-like behaviors (Romeo et al., 2003), and more social instability in adulthood (Kikusui and…”

“Evidence from a promising line of studies suggests that shifting the excitatoryinhibitory balance in relevant neural circuits may increase plasticity (Thompson et al., 2008; Bavelier et al., 2010).”

“Research on nonhuman primates has shown that moderate stress exposure is associated with lower cortisol following stress and decreased anxiety (Parker et al., 2004), as well as increased prefrontal volume and enhanced prefrontal function (Parker et al., 2005; Katz et al., 2009).”

“Caregiving provides a host of regulatory functions in humans, such as buffering against emotion dysregulation and stress reactivity in youth (Campos et al., 1975; Hofer, 1994; McCoy and Masters, 1985; Gunnar and Donzella, 2002).”

“The amygdala is critical in activating the LHPA axis in response to threat and stress (Dunn and Whitener, 1986; Feldman et al., 1995; Redgate and Fahringer, 1973), and levels of glucocorticoids are regulated via negative feedback loops at several levels of the axis including the hippocampus and PFC…”

“Research on nonhuman primates has shown that moderate stress exposure is associated with lower cortisol following stress and decreased anxiety (Parker et al., 2004), as well as increased prefrontal volume and enhanced prefrontal function (Parker et al., 2005; Katz et al., 2009).”

“…unexplored in human development, the notion of too much or too little stress yielding suboptimal effects on brain and behavior, but moderate stress yielding benefits in an inverted-U pattern, has been around for some time (Arnsten and Goldman-Rakic, 1990, 1998; McEwen and Sapolsky, 1995).”

“Caregiving provides a host of regulatory functions in humans, such as buffering against emotion dysregulation and stress reactivity in youth (Campos et al., 1975; Hofer, 1994; McCoy and Masters, 1985; Gunnar and Donzella, 2002).”

“A study of the impact of the 9/11 terrorist attacks on healthy adults provides further evidence of the importance of timing of stress on its neural and behavioral effects (Ganzel et al., 2007).”

“Stress can arise through any number of environments that challenge an individual cognitively, emotionally, or physically, such as uncontrollable or unpredictable settings (e.g., Lupien et al., 2000; McEwen, 2012; Pollak, 2008; Sheridan et al., 2013; Teicher et al., 2006).”

“However, environments that result in a mismatch between the expected and actual environment may prove particularly stressful (Finlay, 2007; Casey et al., 2010).”

“Partial evidence for this notion in humans has been shownwith moderate stress early in life being associated with reduced cortisol reactivity to subsequent stressors, compared with mild or severe stress early in life (Gunnar et al., 2009; Hagan et al., 2014).”

“…unexplored in human development, the notion of too much or too little stress yielding suboptimal effects on brain and behavior, but moderate stress yielding benefits in an inverted-U pattern, has been around for some time (Arnsten and Goldman-Rakic, 1990, 1998; McEwen and Sapolsky, 1995).”

“The timing of stress and its interactions with dynamic developmental processes are critical to subsequent outcomes (e.g., Lupien et al., 2009; Monk, 2008; Monk et al., 2002; Pechtel and Pizzagalli, 2011; Eiland and Romeo, 2013).”

“These time-dependent findings are in accordance with studies highlighting the role of stressor timing on neuroplasticity and risk for psychopathology (Gee and Casey, 2015).”

“Moreover, dynamic changes in this circuitry may help to explain the influence of environmental and genetic factors on the onset of certain disorders at specific developmental windows (e.g., Burghy et al., 2012; reviewed in Gee & Casey, 2015; Gee et al., 2016).”

“Leveraging such theoretical advances in conjunction with examining timing-specific effects [66,69,70] may yield a richer understanding of associations between dimensions of stress exposure in adolescence and the emergence of psychopathology.”

“…both a time when sensitivity to new environmental exposures (Casey et al., 2010; Somerville & Casey, 2010), particularly non-familial social stimuli, is high and when large individual differences in affective behaviors can be first observed (Casey, Pattwell, Glatt, & Lee, 2013; Gee & Casey, 2015).”

“Stress events may increase vulnerability to psychiatric illness by altering the developmental processes of brain regions related to affective and cognitive processing [20].”

“This novel gene by development interaction observed across species provides insight into how risk for anxiety and consequences of stress vary across development (Gee and Casey, 2015) and may contribute to efforts to tailor treatments for anxiety based on genetic variation and developmental stage.”

“…during specific phases of development is important to later neurobiological functioning (Andersen et al., 2008; Cowell et al., 2015; Gee and Casey, 2015; Kuhlman et al., 2015a,b), and is critical to our understanding of how biological systems develop under conditions of threat and…”

“velopmental periods that are especially sensitive to both trauma exposure and positive interventions.(31) Of note, exposure to manageable, nontraumatic stressful”

“Connections between these regions may be especially affected by adversity because of their dense expression of glucocorticoid receptors (14, 24–27) and the developmental timing of circuit maturation (14, 15, 28).”

“However, exposure to stress—even to the same type of stress—does not have a uniform effect on all individuals or on the same individual at different stages of development (Gabbay, Oatis, Silva, & Hirsch, 2004; Gee & Casey, 2015; Lupien et al., 2009).”

“During adolescence, stressors increase stress reactivity, decrease hippocampal volumes, and alter neural plasticity [3, 4].”

“Just as there are critical periods during which stress can have a particularly deleterious effect, timing is likely to play an important role in the effectiveness of treatment (Gee & Casey 2015).”

“36,46 The reduction in excitatory synapse number 5 , the augmented binding of NRSF and the recruitment of MeCP2 as a result of enhanced maternal care were all transient.”

“Given dynamic changes in neuroplasticity across development, caregiving experiences are likely to interact with the typical course of brain development such that parents influence offspring emotional functioning in unique ways at different developmental stages (Gee & Casey, 2015).”

“…childhood experiences display marked sexual dimorphism in its occurrence, but also in the ensuing neurological and behavioral consequences which depend on the type, timing and duration of stress exposure (Fox et al., 2010; Gee and Casey, 2015; McLaughlin et al., 2019; White and Kaffman, 2019).”

“…see Humphreys & Zeanah, 2014; McLaughlin, 2016; Teicher & Samson, 2013; on early-life stress and brain development, see Fareri & Tottenham, 2016; Gee & Casey, 2015; McLaughlin, Sheridan, & Lambert, 2014; on early-life stress and later physical health, see Danese & McEwen, 2012; Ehrlich, Miller,…”

“The nature of stress exposure (e.g., Sheridan and McLaughlin, 2014) and its timing relative to specific sensitive periods of neuroplasticity (e.g., Tottenham and Sheridan, 2009; Gee and Casey, 2015) may be critical determinants of long-term effects.”

“Studies examining the neural mechanisms of development and maintenance of trauma-related psychopathology have focused mainly on circuits implicated in fear processing [17 – 19], emotional regulation [20, 21], and stress response [22, 23], including cortical, limbic, and salience regions.”

“Effects of trauma—including maltreatment—on neuromaturation are often wide-ranging across neural systems and far-reaching across development (Gee & Casey, 2015).”

“…significant consequences of exposure to ELS, combined with the growing recognition that many of these effects are not observed until adolescence (Gee & Casey, 2015; Kessler et al., 2005; Lee et al., 2014), researchers have begun to focus on elucidating the psychological and neurobiological…”

“In this context, accumulating evidence indicates that lasting phenotypic changes induced by ELS involve modifications to cellular programs in the brain [57, 71].”

“, 2014) along with ongoing maturation in stress-sensitive regions of the brain (Casey et al., 2016; Gee and Casey, 2015; Tottenham and Sheridan, 2010).”

“…a series of major changes between birth and early adulthood, and disruption in the form of exposure to extreme stress during “sensitive periods” of heightened plasticity may have a disproportionate impact on the brain (Gee, 2020; Gee & Cohodes, 2021; Gee & Casey, 2015; Hensch, 2005; Knudsen, 2004).”

“cence, although the process begins in the prenatal developmental phase.(67,70) The importance of white matter in the brain is not specific to”

“a(87, 88); b(44, 89); c(33, 90); d(91); e(78); f(92).”

“Interestingly, while exposure to stress during the early life period clearly has immediate effects on the activation of stress responsive systems in the brain and body, many of these detrimental effects do not emerge until later in life, such as during adolescence or even adulthood (Andersen, 2015; Gee and Casey, 2015…”

“And interventions can mitigate the effects of early-life experiences (Gee & Casey, 2015).”

“Consistent with principle 2, there may be periods in development when specific risk factors influence SITBs most strongly, and salient risk factors may change across development (Gee & Casey, 2015; Niederkrotenthaler et al., 2012).”

“Across species, there are consistent and robust findings demonstrating a relationship between caregiving-related adversity and the developing brain (Gee, 2016; Gee & Casey, 2015; Green et al., 2010; McLaughlin et al., 2010, 2015; Tottenham, 2014, 2018; Tottenham & GabardDurnam, 2017).”

“Lastly, we were unable to investigate the possible impact of childhood trauma duration and onset, which could contribute to the results as there may be sensitive periods when specific brain areas are most sensitive to stressful events (Dannlowski et al., 2012; Gee and Casey, 2015).”

“Other work on sensitive periods in emotional development has focused on the role of children’s neural development [10,11], particularly how the development of prefrontal and amygdala circuitry [12,13] may be influenced by extreme adversity [14].”

“Moreover, childhood victimization has been the focus of the majority of these studies with very few investigating the association between victimization in adolescence, a potentially key sensitive window for long-term physiological and behavior changes [23,24] in which victimization exposures peak [25] and altered epig…”

“observed until adolescence (Kessler et al., 2005; Lee et al., 2014; Gee and Casey, 2015), researchers focused bio-psycho-social consequences of trauma on adolescence (Tottenham and Galván, 2016; Colich et al.”

“…the likelihood that different environmental factors will influence the brain in unique ways depending on developmental stage (Cohodes et al., 2020; Gee & Casey, 2015; Lupien et al., 2009; Tottenham & Sheridan, 2010), conducting subtyping of brain-environment relationships across development is a…”

“Neural plasticity during adolescence is second only to infancy; this heightened plasticity may render the brain especially vulnerable to variation in environmental input during adolescence (Gee & Casey, 2015).”

“In addition, developmental timing of adversity, especially in infancy and adolescence, can impact differentially on lifelong trajectories of health and wellbeing (Gee and Casey, 2015).”

“As previously noted, caregiver involvement in external regulation of children’s emotions is a dynamic process that likely changes across development (see Callaghan & Tottenham, 2016 and Gee & Casey, 2015 for reviews).”

“Several studies have highlighted the effects of various stressors on brain functioning, thereby indicating that some brain areas are particularly affected by acute and chronic stress (e.g., Gee and Casey, 2015).”

“This was somewhat surprising, given that early life stress exposure often interacts with developing systems to influence behavior (Gee & Casey, 2015).”

“In addition to early childhood, adverse effects of stress appear to be particularly pronounced during adolescence (Gee & Casey, 2015), a period characterized by normative developmental increases in glucocorticoid secretion and receptors, heightened emotional sensitivity and reactivity, and a more…”

“…and cognitive functioning during a developmental period when cortical thickness and cognitive processes undergo rapid changes and may be most vulnerable to environmental insults (Ducharme et al., 2016; Gagnon & Wagner, 2016; Gee & Casey, 2015; Raver et al., 2013; Shields, Sazma, & Yonelinas, 2016).”

“…2007; Copeland, Shanahan, Costello, & Angold, 2009; Patton et al., 2014) An important factor in the initiation and chronification of mental disorders during this sensitive developmental period is stress (Gee & Casey, 2015; Grant, Compas, Thurm, McMahon, & Gipson, 2004; Holder & Blaustein, 2014).”

“As with brain morphology, cognition is also affected by the specific timing of the insult during brain development (Gee & Casey, 2015).”

“Slower white matter development may indicate altered brain plasticity in response to injury from PAE teratogenesis (Lebel, Mattson, et al., 2012) and possibly other prenatal and postnatal adverse exposures (Bick & Nelson, 2016; Callaghan & Tottenham, 2016; Gee & Casey, 2015).”

“…in adults and adolescents have consistently documented structural deficits in the stress regulatory regions of the amygdala, hippocampus, and PFC, as well as altered striatal and amygdala activation and frontoamygdala connectivity (for reviews, see (Gee and Casey, 2015; Teicher et al., 2016).”

“In humans, longitudinal studies have indicated that the first postnatal years of life constitute a sensitive period for the enduring effects of ELS experienced within the context of the caregiver such as parental absence, maltreatment, neglect, and physical abuse, among others [18,19].”

“Children exposed to early life adversity have poorer outcomes in terms of social, emotional, and behavioral development (Gee, 2016; Gee and Casey, 2015; Green et al., 2010; McLaughlin et al., 2010, 2015; Tottenham, 2013).”

“…involved in children ’ s experiences of adversity — whether through connection to the adversity itself or through supporting children ’ s coping in its aftermath — is likely to be especially impactful during developmental periods of heightened sensitivity (Cohodes et al., 2021; Gee & Casey, 2015).”

“For example, the amygdala, hippocampus, and striatum, which are all sensitive to stress, increase in volume across adolescence [156].”

“The implications of stress exposure vary as a result of developmental time period during which the stress was incurred (Gee and Casey, 2015; Lupien et al., 2009).”

“Animal and human work has shown greater sensitivity to emotional cues during adolescence and accompanying dynamic changes in a neural circuit involving the prefrontal cortex (PFC) and connections with the amygdala and hippocampus (Casey, 2015; Cracco et al., 2017; Gee and Casey, 2015; Silvers et al., 2015; Tottenham a…”

“Although plenty of evidences indicate that ELS exposure leads to behavioral changes in adulthood (Bale et al., 2011; Gee and Casey, 2015; Lai and Huang, 2011; Loi et al., 2014; Lupien et al., 2009; Walker et al., 2017), there are some reports proposing that there is a period during early life in…”

“Researchers have emphasized the importance of taking a developmental perspective when examining CM/ETV (Margolin & Gordis, 2000) as the timing of exposure may impact how the individual experiences it and the relationship to correlates (Gee & Casey, 2015).”

“Moreover, the PFC, which is primarily responsible for inhibitory control, is highly susceptible to the adverse effects of ACEs (Gee & Casey, 2015; McEwen, 2007).”

“…between exposure to adversity and both clinical and neurodevelopmental outcomes (Cohodes et al., 2021; Ellis et al., 2022; Fox et al., 2010; Gee & Casey, 2015; Glynn & Baram, 2019; Hambrick et al., 2019; Luby et al., 2019; Manly et al., 2001; McLaughlin & Sheridan, 2016; McLaughlin et…”

“Importantly, exact effects may vary depending on precise time of exposure and nature of the stress (Gee and Casey, 2015).”

“…to the timing of stressor exposure, in turn, there is a wealth of research on sensitive or critical periods, which highlights how the impact of stress exposure on later behavior is especially strong during certain developmental periods (Eiland & Romeo, 2013; Epel et al., 2018; Gee & Casey, 2015).”

“…plasticity can be associated with heightened vulnerability, they also present enhanced opportunities for positive change through intervention (D. G. Gee & Casey, 2015) and potential to reshape neurobiological systems that were disrupted by stress earlier in development (Sisk & Gee, 2022).”

“The timing and types of early stressors may differently alter neurodevelopmental trajectories, affecting features such as the age and types of fi rst symptoms [201] and other clinical course features in BD AYA [202].”

“…– including experiential, environmental, and timing attributes – can yield a richer understanding of processes of risk and resilience (Belsky et al., 2012; Cohodes et al., 2021; Ellis et al., 2009, 2022; Gee & Casey, 2015; Kuhlman et al., 2017; Manly et al., 2001; Sheridan & McLaughlin, 2014).”