THE EFFECTS OF EARLY-LIFE
STRESS ON THE HUMAN BRAIN
A literature review with main focus on the hippocampus, corpus callosum, prefrontal cortex and amygdalaBachelor Degree Project in Cognitive Neuroscience Basic level 22.5 ECTS
Spring term 2020 Inez Wojtasik
Abstract
Early-life stress, consisting of several stressors appears to be associated with several impacts on the brain. The impacts of stress seem to be more vulnerable to the developing brain as it undergoes important changes during childhood. This thesis aims to present the association between childhood maltreatment, which is a form of early-life stress, and affected brain regions such as the hippocampus, prefrontal cortex, corpus callosum, and the amygdala. The findings in this thesis demonstrated the left hippocampus to be more vulnerable to the effects of maltreatment, corpus callosum appeared to be gender and maltreatment specific, indicating that the corpus callosum were more vulnerable to neglect in boys whereas in females the structure was more vulnerable to sexual abuse. The prefrontal cortex demonstrated a marked reduction in gray matter, and the amygdala showed increased activation in response to emotional facial expressions. Cognitive deficits as a result of early-life stress were also discussed, showing that worse intellectual ability and the academic performance had been noted in children with exposure to early-life stress.
Keywords: early-life stress, childhood maltreatment, brain development,
Table of Contents
1. Introduction 4
2. Stress 6
2.1 The Stress Response 6
2.2 The Limbic Structures and Prefrontal Cortex 7
3. Early-Life Stress and the Brain 8
3.1 Childhood Maltreatment 10
3.2 Childhood Maltreatment and the Hippocampus 11
3.3 Childhood Maltreatment and the Corpus Callosum 13
3.4 Childhood Maltreatment and the Prefrontal Cortex 14
3.5 Childhood Maltreatment and the Amygdala 16
4. Cognitive Deficits 18
1. Introduction
Childhood is a sensitive period of time. The environment affects the process of early brain development (Glaser, 2000). Child abuse and neglect are two examples that present the maturing child’s brain with experiences that may affect the child’s future development and functioning (Glaser, 2000).
Early life stress (ELS) leads to extended phases of stress and affects coping resources due to single- or numerous stressful events in childhood (Brown et al., 2009). It may lead to deficits in cognitive functions during adult life, including deficits in memory, attention, language, and in executive functioning (Chugani et al., 2001; De Bellis, Hooper, Spratt, & Woolley, 2009). Commonly studied stressors in early childhood include physical, sexual, emotional and verbal abuse, neglect, disaster, social deprivation, and challenging home environment that involves alcohol/drug abuse, witnessing parental violence, parental separation or parental death/illness, criminality, and poverty (Brown et al., 2009).
The assumed association between ELS and later cognitive functions is strengthened by the observation of brain regions involved in cognitive functions - showing abnormalities after exposure to ELS (Bremner et al., 1999). For example, stress exposure during childhood appears to be associated with volume- and functional deficits in the hippocampus in adulthood, a brain region associated with memory and learning (Squire, Stark, & Clark, 2004). The long-term effects of exposure to stress in early life may impair cognitive functions later in life (Hedges & Woon, 2011).
In contrast to the number of studies linking stress and trauma exposure in childhood to later neuropsychiatric illness, relatively few studies have investigated the association between childhood exposure to stress and later cognitive functions. However, numerous lines of evidence suggest that exposure to early-life stress may consequently influence cognitive functions. (Hedges & Woon, 2011).
This field is of special interest because what an individual has been through during his/her childhood may have significant effects on the later quality of life. It is thus a difficult and complex field that includes several variables, such as what a person has been exposed to, at what time, in which context, etc. The field of ELS is markedly understudied,
more research would be needed to investigate the impact of early stress exposure on cognitive functions in adulthood.
the hippocampus, corpus callosum, prefrontal cortex, and amygdala. Including a brief overview of possible cognitive deficits followed by early-life stress. The research has been done through a literature review on the brain impairments caused by early-life stress, by collecting relevant literature in the field of early-life stress. Databases that have been used are Google Scholar, Scopus, and Web of Science, using keywords like ‘early-life stress’,
‘childhood maltreatment’, ‘brain development’, ‘hippocampus’, ‘limbic system’, ‘corpus callosum’ ‘cognitive deficits’, ‘prefrontal cortex’ and ‘amygdala’. The most relevant papers with particular focus on how early-life stress affects the brain were selected, as well as articles concerning childhood maltreatment and cognitive deficits followed by early exposure to stress, and review articles.
One form of early-life stress, childhood maltreatment, is related to several brain impairments, including abnormalities in the prefrontal cortex, a structure that manages emotional and cognitive functioning (Wilson et al., 2011), the hippocampus, as mentioned earlier is involved in cognitive- and crucial for memory function (Hedges & Woon, 2011), the corpus callosum, a structure that links the left and right hemispheres (Wilson et al., 2011) and the amygdala that plays a central role in emotional processing (McCrory, De Brito, & Viding, 2011). These brain regions present the main focus within the childhood maltreatment section.
2. Stress
The biological stress response is a normal system that activates behavioral and physiological change within the body to allow a survival response to different stressors. This activation of the stress response system allows emotional and intellectual growth and
development (Delima & Vimpani, 2011).
Stress is defined as ’’a stimulus or experience that produces a negative emotional reaction or affect, including fear and a sense of loss of control’’ (Glaser, 2000, p. 103). During both early childhood and old age the brain is particularly sensitive to stress, probably because it undergoes such important changes during these periods (Gazzaniga, Ivry & Mangun, 2014). Chronic or repeated exposure to stress has lasting effects on the brain, through activation of the hypothalamic-pituitary-adrenal (HPA) axis and the release of cortisol, with the greatest impact in young individuals as brain structures are under
development, and in adults and older individuals as the structures are undergoing age-related changes (Lupien, McEwen, Gunnar, & Heim, 2009). However, in small quantities, cortisol can aid learning and increase attentiveness (Gazzaniga et al., 2014). Although the term "stress" has a negative indication, evidence suggests that under certain circumstances, exposure to stress may have the potential to increase an organism's resilience and performance (Aschbacher et al., 2013). Stress has been connected to support-seeking behavior, enhanced motivation, as well as working harder (Kaiseler, Polman, & Nicholls, 2009). It has also been found to improve mental function, enhance memory (Cahill, Gorski, & Le, 2003) and speed up brain processing (Hancock, 1989). The term ’’eustress’’ is defined as ’’a beneficial or healthy response to stress, associated with positive feelings” and also
described as “an optimal amount of stress” (Rudland et al., 2020, p. 41).
2.1 The Stress Response
demands caused by various challenges. Further, it regulates several physiological systems, like the immune system, the cardiovascular system, the sympathetic-adrenal-medullary (SAM) axis, as well as affective and cognitive processes (Kudielka & Kirschbaum, 2005). During stress, the corticotropin-releasing hormone (CRH) is secreted from the hypothalamus which in turn causes the release of adrenocorticotropic hormone (ACTH) from the pituitary gland. ACTH triggers the secretion of glucocorticoids from the adrenal cortex, namely cortisol (Kudielka & Kirschbaum, 2005).
2.2 The Limbic Structures and Prefrontal Cortex
According to Wilson, Hansen, and Li (2011), ’’the limbic system is often considered the emotional control center of the brain’’ (p. 90). Noradrenaline is the main stimulatory neurotransmitter of the limbic system, produced in the locus coeruleus (Vermetten &
Bremner, 2002). The limbic system is directly affected when a person experiences a traumatic and stressful situation, such as child abuse (Wilson et al., 2011).
The hippocampus and amygdala which are parts of the limbic system are implicated in the HPA axis regulation (Herman, Ostrander, Mueller, & Figueiredo, 2005). The
hippocampus and prefrontal cortex have an inhibitory role on the HPA axis whereas the amygdala is involved in the activation of glucocorticoid secretion (Herman et al., 2005). The hippocampus continues to develop after birth, it might therefore be the brain region that is most vulnerable to the effects of chronic stress (Lupien et al., 2009). The hippocampus has a high concentration of receptors for glucocorticoids, especially in the dentate gyrus and CA1 region, where the latter is the origin of connections from the hippocampus to the neocortex that are important in the consolidation of episodic memory (memories of personal
experiences) (Gazzaniga et al., 2014). Animal studies have shown that exposure to prolonged stress and the resulting increase in cortisol can cause atrophy in the hippocampus (Sapolsky, Uno, Rebert, & Finch, 1990). The frontal cortex undergoes major development in adolescence and is perhaps the most sensitive area to the effects of stress, leading to a long-lasting
glucocorticoid response to stress that persists into adulthood (Lupien et al., 2009). In
adulthood and when you grow old, the brain regions that undergo the most rapid decline as a result of aging are highly sensitive to the effects of stress hormones (Lupien et al., 2009). Like the hippocampus, the medial prefrontal cortex expresses large numbers of glucocorticoid receptors (Ahima & Harlan, 1990; Fuxe et al., 1985).
amygdala neurons to basal forebrain, hypothalamic, and brainstem structures (Herman et al., 2005). The association of HPA-regulatory areas of the limbic system with mood disorders - indicates that functional changes in areas such as the amygdala, hippocampus, and prefrontal cortex may be responsible for hyper- or hyposecretion of glucocorticoids seen in these emotional states (Herman et al., 2005). The involvement of the limbic system in HPA
regulation is very complex, with stimulus attributes and topographical organization playing an important role in how a particular region will impact stress responses (Herman et al., 2005).
3. Early-life Stress and the Brain
Experience determines an individual's reaction to future events in life. A developing brain is especially sensitive to the effects of early exposure to stressors, mainly due to the reprogramming of several stress-sensitive pathways (Chen & Baram, 2016). Stress in early life can induce behavioral changes and changes in neuronal plasticity that persist into
adulthood. It is widely acknowledged that ELS is a risk factor for several psychiatric illnesses (Khan et al., 2015; Teicher & Samson, 2013; Teicher & Samson, 2016). Various brain regions undergo different maturation patterns, the developmental stage when stress occurs is decisive for the resulting neural consequences (Teicher et al., 2003). In contrast to adulthood, stress may have a greater impact on childhood and adolescence as the brain undergoes important changes (Pechtel & Pizzagalli, 2011).
Complex cognitive functions (e.g., executive skills) mature later than do more basic ones (e.g., sensorimotor skills) (Pechtel & Pizzagalli, 2011). Frontal lobe structures (e.g., dorsolateral PFC) are among the last areas to develop - involved in executive functioning, motor coordination, and attention (Pechtel & Pizzagalli, 2011). The long developmental trajectories supporting higher-order functions makes the PFC particularly vulnerable to the effects of stress (Gogtay et al., 2004). In addition to large numbers of glucocorticoid receptors, as mentioned earlier, the PFC contains also a large number of stress-sensitive dopaminergic projections (Brake, Sullivan, & Gratton, 2000). It can thus be hypothesized that complex functions in structures like the PFC are more vulnerable to the effects of ELS, due to its protracted development into early adulthood (Pechtel & Pizzagalli, 2011).
immature hippocampus contains a particular cell population that can release the corticotropin-releasing hormone in response to stress, possibly explaining the heightened sensitivity of the hippocampus to abuse during early childhood (Chen et al., 2004). Early effects of abuse on the hippocampus are consistent with evidence from humans and primates that the
hippocampus matures rapidly and is functional very early in childhood (Teicher et al., 2012). As soon as by 4 years of age the hippocampus has obtained about 85% of adult volume (Giedd et al., 1996). Permanent impairments of learning and memory have been confirmed through animal studies showing an association between ELS (e.g., maternal separation) and hippocampal volume reduction (Karten, Olariu, & Cameron, 2005). Further, the hippocampus and the PFC are highly sensitive to disruptions due to their large amount of glucocorticoid receptors (Teicher et al., 2003). It is because glucocorticoids acting via glucocorticoid
receptors impairs neural plasticity (Gunnar & Quevedo, 2007). However, according to Pechtel and Pizzagalli (2011), ''exactly how ELS affects cognitive functioning and emotional well-being via specific neurobiological pathways remains poorly understood'' (p. 59).
The amygdala is in its fundamental cytoarchitecture and function at birth. As soon as at the age of 4, it has reached its peak volume in women (Shaw et al., 2008). The amygdala is very functional and reactive in childhood compared to adulthood, indicating a very early sensitive period that can be affected by ELS (Tottenham et al., 2010). According to Pechtel and Pizzagalli (2011), the amygdala is described as ''pivotal in learning and responding to social and emotional stimuli in the child’s environment'' (p. 65). Further, adults with ELS history may be at higher risk of developing anxiety and mood disorders due to the amygdala's resilience to recovery after removal from a stressful environment (Pechtel & Pizzagalli, 2011).
corpus callosum because of the structure's long development period (Pechtel & Pizzagalli, 2011).
3.1 Childhood Maltreatment
Child maltreatment represents a toxic relational environment that carries a risk for maladaptation across various biological and psychological development areas (Cicchetti, 2002). According to Delima and Vimpani (2011), the previous definition of childhood maltreatment includes only ’’acts of commission’’ to the child. This contains physical acts of abuse, where ’’the child is subject to disciplinary action by his/her caregiver(s), with resultant bruising, severe pain, temporary loss of mobility, scars, burns, shaking, etc’’ (p. 43). Sexual acts of abuse ’’involves the sexual abuse or exploitation of the child and/or exposing them to sexual acts’’ (p. 43). And also emotional acts of abuse, ’’the child is subject to repeated verbal abuse, being sworn at or receiving hurtful and demeaning comments about his/herself’’ (Delima & Vimpani, 2011, p. 43). This includes also the child hearing about violent acts committed upon someone important for the child. However, studies of children over the last decade have demonstrated the importance to also include ’’acts of omission’’ in the definition of maltreatment. This includes witnessing family violence where ’’the child hears or watches aggressive verbal altercations and/or physical violence’’ (p. 43), and neglect, which is a ’’type of maltreatment that ranges from failing to provide basic food, shelter, clothing, and care to exposure to harmful substances’’ (p. 43). Although neglect is often labeled as ’’environmental circumstance’’, studies have shown that the resulting brain damage patterns are similar to those seen in children exposed to trauma and maltreatment (Delima & Vimpani, 2011). The common factors in maltreatment that negatively affect early brain development are long-term and uncontrolled events as well as circumstances that are perceived as life-threatening
(Delima & Vimpani, 2011).Studies have shown differences in neuroanatomy and cognitive function in children who have been exposed to maltreatment and those who do not, indicating that the effects of maltreatment cause impairment of brain structure and function (De Bellis, 1999).
Maltreatment that includes harsh, extended and uncontrolled life stressors activate a prolonged biological stress response (Chrousos & Gold, 1992). The developing brain, as mentioned earlier, is particularly vulnerable to stress, especially the prefrontal cortex,
emotional responses, such as high levels of perceived anxiety, aggression, and suicidal tendencies, in some cases learned helplessness due to impaired self-regulation (De Bellis, 2001).
3.2 Childhood Maltreatment and the Hippocampus
The hippocampus is a highly stress-sensitive structure, abnormalities in the hippocampus have been reported in a multitude of psychiatric disorders including major depression and post-traumatic stress disorder (PTSD). The hippocampus seems to be
especially sensitive to early-life stress based on the number of types (multiplicity) or severity of maltreatment (Teicher et al., 2018).
Studies have found that adults with a history of childhood maltreatment have decreased volumes in the hippocampus (e.g., Teicher, Anderson, & Polcari, 2012; Dannlowski et al., 2012). However, there are studies with mixed results, some of them
presenting a decrease in hippocampal volume, others report no effects in hippocampal volume or increased hippocampal volume, Whittle et al. (2013) indicate that ’’this discrepancy
between studies of adults versus children and adolescents suggests that the effects of childhood adversity on the hippocampus may not be static but rather changes across the lifespan’’ (p. 940). The effects of early adversity on the hippocampus may not appear until many years after exposure to stressful events (Lupien et al., 2009).
A study by Teicher, Anderson, and Polcari (2012) was conducted to test the hypothesis that childhood maltreatment was associated with volume reductions in the hippocampus. A total of 193 subjects took part in the study. The history of exposure was recorded by Adverse Childhood Experience (ACE) and Childhood Trauma Questionnaire (CTQ) scores. Information from a semistructured Traumatic Antecedents Interview (TAI) that evaluates reports of different maltreatment forms and Conflict-Tactic Scales (CTS) were used to determine subjects ACE scores, which indicate the number of different types of
maltreatment-related adverse experiences. The CTQ, on the other hand, is a self-report inventory that inquires about five types of maltreatment: emotional, physical, and sexual abuse and emotional and physical neglect.
It was found that volumes of the left hippocampus were most affected by exposure to childhood maltreatment. Reductions in volume between subjects with high vs. low
maltreatment and hippocampal volume in adults have also reported greater left-sided than right-sided effects (e.g. Bremner et al., 1997; Stein, Koverola, Hanna, Torchia, & McClarty, 1997; Vythilingam et al., 2002). In contrast, no studies have reported particularly right-sided hippocampal deficits in maltreated subjects (Teicher et al., 2012). A limitation of the present study by Teicher et al. 2012 and of all studies reporting the possible consequences of
childhood maltreatment on the adult hippocampus, is the retrospective assessment of maltreatment (Teicher et al., 2012). As a result of false or ’’restored’’ memories, there is a risk that people in emotional distress will describe their childhood as more stressful or offensive (Pope & Hudson, 1995).
Another study by Riem, Alink, Out, Van Ijzendoorn, and Bakermans-Kranenburg, (2015) examined the effects of maltreatment experiences on hippocampal volume in female twin pairs. The sample consisted of 34 participants. Attachment representations and
experiences of maltreatment were coded using the Adult Attachment Interview (AAI), a semi-structured interview in which participants were required to reflect upon their attachment-related experiences, they were asked to describe their relationships with attachment figures (Riem et al., 2015). Also, questions regarding experiences of childhood abuse were included. In addition, the Posttraumatic Diagnostic Scale (PDS), a self-report measure of PTSD
symptoms, was administered in order to measure experiences of traumatic events, that is, serious accidents, natural disasters, sexual assaults, etc (Riem et al., 2015).
Evidence for a reduction of the hippocampal volume was found both in individuals with experiences of childhood maltreatment and in individuals with other traumatic events. This is in line with previous studies showing that individuals with a maltreatment-related history have smaller hippocampal volumes (Woon & Hedges, 2008). Interestingly, childhood experiences reported during the AAI were associated with a decrease in the left hippocampal volume, while exposure to traumatic events measured with the PDS was associated with a decrease in the right hippocampal volume (Riem et al., 2015). Previous studies have also found higher left-sided effects on the hippocampus in relation to childhood maltreatment (Riem et al., 2015). These results show that stress may cause laterality changes in the hippocampus, possibly because of neuroanatomical and neurochemical asymmetries in the hippocampus (Zach, Mrzilkova, Rezacova, Stuchlik, & Vales, 2010). Different types of stressful events may thus have clear effects on neural structures, which might explain why traumatic events and experiences of maltreatment were related to each side of the
maltreatment during early childhood (Riem et al., 2015). A limitation of the current study was also the use of retrospective assessment of maltreatment. The effects of maltreatment can be underestimated in this study because previous research has shown that maltreated individuals may provide false negative reports (Fergusson, Horwood, & Woodward, 2000).
In line with the empirical study, as described above, a meta-analysis was also done by Riem et al. 2015 who confirmed that the maltreatment experiences are more pronounced when occurring in middle childhood than in early or late childhood and adolescence. This is in disagreement with the suggestion that the hippocampus has increased sensitivity to early experiences of abuse (Teicher & Samson, 2013). However, two possible explanations for the stronger association between hippocampal volume reduction and maltreatment during middle childhood were presented. The first one, childhood amnesia, indicates that there is little recall of events that occur before the age of 3-4 years (Rubin, 2000). Young children can recall events correctly, but this recall is weak and children tend to forget early experiences as they grow older (Peterson, Warren, & Short, 2011). Memories may get lost or changed in the long term, which would be an explanation for childhood amnesia (Bauer, Burch, Scholin, & Guler, 2007). As a result, early childhood may not get covered up in the self-reported maltreatment experiences, which might explain nonsignificant findings in this age group (Riem et al., 2015). Persistence of maltreatment is another explanation. Physical or emotional maltreatment is usually not limited to a single incident, the neurobiological effects of
maltreatment are therefore stronger when maltreatment occurs at ages 0-12 years, rather than at ages 0-5 years, as individuals may have been exposed to violent experiences for a longer period of time. Deeper neurobiological changes may take place as a result of persistent and chronic abuse (Riem et al., 2015).
3.3 Childhood Maltreatment and the Corpus Callosum
A smaller corpus callosum area has been reported in children with conflicting results in adults. This indicates that in contrast to the hippocampus - structural differences seen in the corpus callosum are present already at an early stage and may persist throughout life
(Jackowski et al., 2011).
integration have been described in adults maltreated as children (Navalta, Polcari, Webster, Boghossian, & Teicher, 2006).
In another study by Teicher et al. (2004), the size differences of the corpus callosum were found to be gender and maltreatment specific. Boys were most vulnerable to the effects of neglect on the corpus callosum, while girls for the effects of sexual abuse.
When the size of the corpus callosum is reduced, it may lead to lateralization where one side of the brain may be unusually taxed during a task (Weber & Reynolds, 2004). For example, in a study by Schiffer, Teicher, and Papanicolaou (1995), probe auditory evoked potentials were used to study laterality and hemispheric integration. Subjects were asked to first recall a neutral or work-related memory and then a disturbing memory from childhood. As a result, both hemispheres appeared to be equally active in healthy individuals while there was a marked difference in adults with childhood trauma. During recall of the neutral
memory, there was an increased processing of the left hemisphere, while during recall of the disturbing memory, there was an increased activation in the right hemisphere. These findings suggest that childhood trauma is associated with increased hemispheric laterality and
decreased hemispheric integration (Schiffer et al., 1995).
3.4 Childhood Maltreatment and the Prefrontal Cortex
The prefrontal cortex (PFC) plays an important role in several functions, including higher motor control, inhibitory control, working memory, emotion and motivation
regulation, attention, personality expression, and moderating learned social behavior (Miller & Cohen, 2001; Ochsner & Gross, 2005). As mentioned earlier, the PFC is most susceptible to damage in childhood and adolescents due to its long-term development. This can lead to abnormal development of the structure in maltreated individuals (Hart & Rubia, 2012).
A study by Tomoda et al. (2009) examined the association between exposure to harsh corporal punishment, a type of child maltreatment, and brain structure. Harsh corporal punishment (HCP) was defined as a severe form of corporal punishment, in which an object (e.g., belt) was used for the purpose of disciplining a child (Tomoda et al., 2009). The sample consisted of 45 individuals. History of exposure to corporal punishment (CP) was collected using the Life Experiences Questionnaire (LEQ) and through the face-to-face interview. The LEQ consisted of 34 items that reflect exposure to traumatic events in general and include questions about parental CP. Additionally, a detailed semi-structured interview was conducted to evaluate the degree of exposure which examined the ways in which subjects were
the right medial frontal gyrus (medial prefrontal cortex) in individuals exposed to HCP. Possible associations between HCP and reduced gray matter volume in the left medial frontal gyrus (dorsolateral prefrontal cortex) and the right anterior cingulate gyrus were also found. The brain regions identified with diminished gray matter volume, as described above, are part of the medial rostral prefrontal cortex (MRPFC), which plays a key role in social cognition and in functional organization (Amodio & Frith, 2006; Gilbert et al., 2007). The medial prefrontal cortex and dorsal anterior cingulate gyrus seem to be especially involved with self-knowledge, person perception, and mentalizing (Amodio & Frith, 2006). If children have an inadequate ability to internally control their actions, it may increase their risk of exposure to CP or HCP, or if they have deficits in self-perception, person perception, or mentalizing. Thus, it is likely that differences observed in regional gray matter volume were pre-existing abnormalities that increased their risk of exposure to HCP, or that exposure to HCP may have impaired the development of these regions. In brief, HCP may create an incompatible
perception of one’s actions or one’s beliefs about others. In this way, it may impair the essential element of social cognition. A limitation within this study was notable variations between groups in gender ratio, perceived financial stress, and parental education level which can influence brain development (Tomoda et al., 2009).
In another study by van Harmelen et al. (2010), they sought to examine the effect of childhood emotional maltreatment on the adult brain. The study examined also whether these brain alterations were related to the development of psychopathology. The sample consisted of 181 subjects. Childhood maltreatment was assessed with the NEMESIS trauma interview (De, Bijl, Smit, Vollebergh, & Spijker, 2002). Subjects were asked whether they had
may additionally contribute to the development of depression and/or anxiety. As in other studies, the limitation of this study was the use of retrospective assessment.
3.5 Childhood Maltreatment and the Amygdala
The amygdala is essential in emotional processing and memory, evaluating threatening information and fear conditioning (McCrory, De Brito, & Viding, 2012).
Dannlowski et al. (2013) sought to investigate the influence of childhood maltreatment on automatic amygdala responsiveness to negative and positive facial cues. The authors used a subliminal priming paradigm to target the automatic stages of emotion processing. The sample consisted of 150 subjects, free from any lifetime history of psychiatric disorders. The Childhood Trauma Questionnaire (CTQ) was used to evaluate maltreatment during childhood. Also, the perceived stress scale (PSS) and the List of Threatening Experiences Questionnaire (LTE-Q) were applied as measures of more recent stressful life situations. In line with the authors hypothesis, the results indicated a strong effect of childhood maltreatment on amygdala excitability to negative facial expressions.
Neglected and abused children have an increased sensitivity to threatening facial expressions, it might help to protect them from further aversion by quickly identifying
negative signals and preparing defensive responses. According to Masten et al. (2008), youths with a history of neglect or abuse are faster than comparison youths in identifying threatening facial expressions. One of the limitations within this study is the probability that subjects whose amygdala is more sensitive to negative faces were able to recall negative events better from their childhood. Another limitation is that the current sample consisted of healthy subjects without any current psychopathology, which limits the conclusions.
Another study conducted by van Harmelen et al. (2013) investigated whether patients and healthy subjects reporting childhood emotional maltreatment (CEM) displayed increased amygdala reactivity to emotional faces, in comparison to patients and healthy subjects
Events Questionnaire (Brugha, Bebbington, Tennant, Hurry, 1985) was used to assess recent life events. The face task used in this study was based on the event-related emotional
paradigm used by Wolfensberger, Veltman, Hoogendijk, Boomsma, and de Geus. (2008) that has been found to activate the amygdala. Photos of fearful, angry, sad, happy, neutral faces, and a control condition were shown to all participants. In line with the researchers
expectations, it was shown subjects reporting CEM had increased amygdala activation in response to emotional facial expressions, independent of depression severity, neuroticism, psychiatric status and history of concurrent physical or sexual abuse. Contrary to the
expectations, hyperactivation of the amygdala in subjects reporting CEM was found in both negative facial expressions and in response to happy and neutral faces. This might indicate that individuals with a history of CEM perceive all facial expressions as highly prominent. Further, this study found that the results of increased amygdala reactivity in subjects reporting CEM were observed independent of psychiatric status. Other studies found the opposite, where amygdala hyperreactivity was shown in depressed (Sheline et al., 2001; Anand et al., 2005; Fales et al., 2008) and anxious patients (Straube, Kolassa, Glauer, Mentzel, & Miltner, 2004; Bishop, 2007). During social-emotional circumstances, individuals with enhanced amygdala activation might develop strong memory traces and increased fear conditioning in response to emotional stimuli. This may be noteworthy when trying to understand difficulties in interpersonal relationships and increased emotional sensitivity (Spertus, Yehuda, Wong, Halligan, & Seremetis, 2003; Gilbert et al., 2009; van Harmelen et al., 2010b) that has been reported in these individuals.
4. Cognitive Deficits
Children that have been exposed to ELS have demonstrated worse academic performance, impaired intellectual ability, and a greater need for individualized education programs (De Bellis, Hooper, Spratt, & Woolley, 2009). Cognitive deficits including verbal declarative memory (Bremner et al. 2004) memory and response inhibition (Navalta et al., 2006), working memory (Entringer et al., 2009) and short-term verbal memory (Bremner et al., 1995) have also been found in young adults. Additionally, exposure to ELS may lead to deficits in language, attention, memory, and executive functioning in humans (Chugani et al., 2001; De Bellis et al., 2009) and to impaired spatial learning and memory in animal models (Aisa, Tordera, Lasheras, Del Río, & Ramírez, 2007; Aisa et al., 2009). Reduced hemispheric integration, smaller corpus callosum, and smaller intracranial volume are some of the neural correlates that impair the overall cognitive functioning followed by ELS (Teicher et al., 2004; Noble, Tottenham, & Casey, 2005; Schiffer et al., 1995). ELS in humans is also associated with different neuropsychiatric outcomes, including posttraumatic stress disorder (PTSD), schizophrenia, panic disorder, substance abuse, attention-deficit disorder (Heim & Nemeroff, 2001), depression (Heim & Nemeroff, 2001; Kaufman, Plotsky, Nemeroff, & Charney, 2000), borderline personality disorder (Zanarini et al., 2000), and abnormal stress response (Kajantie, & Räikkönen, 2010); Kaufman et al., 2000).
As discussed in the previous parts, when stress occurs during a certain time it may have differential effects on cognitive outcome, in a study by Andersen et al. (2008) it was found that sexual abuse occurring between ages 3 and 5 years and between 11 and 13 was associated with hippocampal abnormalities during adulthood. Sexual abuse occurring between 9 and 10 years showed to be associated with volume deficits in the corpus callosum in
adulthood and sexual abuse between ages 14 and 16 years was associated with deficits in the frontal cortex (Andersen et al., 2008).
Disruptions in development of the amygdala are likely to contribute to
The field of long-term cognitive function following childhood maltreatment is markedly understudied (Hedges & Woon, 2011) and in addition, as mentioned before, the association between ELS and cognitive deficits is complicated because complex cognitive functions mature later than do more basic ones (Pechtel and Pizzagalli 2010). However, in one of the few studies investigating the long-term cognitive consequences of exposure to childhood trauma, Bremner et al. (1995) found that adults with PTSD who had been severely abused during childhood showed deficits in verbal memory compared with healthy adults. Further, in a study by Navalta et al., (2006), women with a history of repeated childhood sexual abuse showed reduced memory and response inhibition in comparison to healthy subjects.
In the case of a dysfunctional prefrontal cortex, it can contribute to depression as a result of impaired emotional regulation and rumination (Gotlib & Joormann, 2010).
Animal models of early-life stress have consistently shown long-term cognitive deficits. Using a maternal-separation paradigm, it was found that rats exposed to stress in early-life performed worse than control rats on a learning and memory task (Aisa et al., 2007; Aisa et al., 2009). Further, progressive learning and memory decline was associated with ELS in a rodent model, with the decrease in learning and memory most saliently during middle age (Brunson et al., 2005).
A study of squirrel monkeys is an example that not all types of ELS in non-human primates may have harmful effects, squirrel monkeys had been exposed to soft early stress and demonstrated better prefrontal dependent cognitive ability than non stressed animals (Parker, Buckmaster, Justus, Schatzberg, & Lyons, 2005), this provides us with the
importance to understand both type and severity of the stress exposure and the developmental timing of the exposure. Taken together, exposure to ELS in rodents presents harmful, long-term effects on memory, and learning (Hedges & Woon, 2011).
Although relatively few studies have investigated the association between the
5. Discussion and Conclusion
The aim of this thesis, as previously mentioned, was to present the consequences of ELS on human brain regions like the hippocampus, corpus callosum, prefrontal cortex, and the amygdala. Since the field of ELS appears to be highly complex, where several aspects seem to interact, showing that the neurobiological effects of maltreatment may be dependent on the time after exposure, the timing of the maltreatment, and the type and severity of maltreatment (Riem et al., 2015). It is remarkable that more studies have been done on animals than humans, it is therefore difficult to determine the causal link between ELS and the human brain. ELS was defined as exposure to single/multiple stressful events during childhood that leads to prolonged phases of stress, some of the commonly studied stressors in early childhood include physical, sexual, emotional and verbal abuse. Further, studies have shown an association between exposure to early stress during childhood and deficits in different brain areas. One of those areas is the hippocampus, in order of high concentration of receptors for glucocorticoids, the hippocampus is particularly vulnerable to the effects of stress. Studies by Riem et al., (2015) and Teicher et al. (2012) demonstrated the left
hippocampus to be especially affected by childhood maltreatment. Furthermore, Riem et al., (2015) showed that the effects of traumatic experiences affected the opposite part, also the right hippocampus (Riem et al., 2015). Suggesting that laterality changes can occur in the hippocampus where different types of stressful experiences may have different effects on neural structures. In contrast to previous studies showing hippocampal vulnerability to stress during early childhood, Riem et al., (2015) presented that maltreatment experienced at older ages had larger reductions in the hippocampus in comparison to early childhood. This was explained by childhood amnesia which indicates that the recall of events in young children is weak and as they grow older, they tend to forget early experiences (Peterson et al., 2011). Also by the persistence of maltreatment, indicating that a longer period of maltreatment might explain why neurobiological effects are stronger when a person is exposed to maltreatment during middle childhood (Riem et al., 2015).
changes may become apparent years after exposure to early stress, the differences in corpus callosum size seem to be present already at the early stage and probably persist through life (Jackowski et al., 2011).
The prefrontal cortex, especially the medial prefrontal cortex, dorsolateral prefrontal cortex, and the right anterior cingulate gyrus presents abnormalities related to harsh corporal punishment. Those areas in the PFC are part of the medial rostral prefrontal cortex which plays an important role in social cognition and functional organization (Amodio & Frith, 2006; Gilbert et al., 2007). Emotional maltreatment during childhood was especially
associated with gray matter reduction in the left dorsal medial PFC. The prefrontal cortex has an extended sensitive period because it continues to develop into early adulthood, together with the hippocampus the prefrontal cortex has a high density of glucocorticoids that are sensitive to stress exposure.
Increased amygdala activation was shown in individuals reporting childhood maltreatment. However, there was a contrast between current findings, Dannlowski et al., (2013) presented automatic amygdala responsiveness to negative but not to positive facial representations whereas Van Harmelen et al. (2013) presented hyperactivation of the amygdala in both negative, happy and neutral facial expressions. Because of increased sensitivity to threatening facial expressions in neglected and abused children, this
vulnerability may help them to quickly identify negative signals and prepare for defensive actions (Dannlowski et al., 2013). As a result of amygdala reactivity observed in individuals independent of psychiatric status (Van Harmelen et al., 2013) as well as amygdala
hyperreactivity in depressed (Sheline et al., 2001; Anand et al., 2005; Fales et al., 2008) and anxious patients (Straube et al., 2004; Bishop, 2007) it is difficult to make a conclusion if there is a link between increased amygdala activation and psychiatric disorders. Additionally, a pattern regarding the amygdala and hippocampus emerged presenting that these structures may be particularly sensitive to stress at 4 years of age as they are mostly fully developed (Andersen et al., 2008; Pechtel & Pizzagalli, 2011). The early development of these regions may indicate an early vulnerable period in which exposure to early stress may disrupt maturation. This, in turn, is in contrast to the earlier mentioned study by Riem et al. (2015), presenting larger hippocampal reductions when individuals were exposed to maltreatment during middle childhood than early childhood.
humans and to impaired spatial learning and memory in animals. Moreover, there is an association between ELS and neuropsychiatric outcomes such as PTSD, schizophrenia, panic disorder, substance abuse, attention-deficit disorder, depression and abnormal stress
response.
With regard to the future directions, studies examining neurobiological changes after maltreatment should measure age at exposure to maltreatment, to get a better insight into the sensitive periods in brain development (Riem et al., 2015). Longitudinal studies should be done to better recognize the pathway from trauma to abnormalities of brain structure and function (Watts‐English et al., 2006). Future studies need also to investigate continued trajectories of brain development during late adolescence and adulthood in individuals with a history of maltreatment, and whether these trajectories interact with or predict later
development of psychopathology (Whittle et al., 2013). Future animal studies might focus more on vulnerable periods in the development and functioning of the hippocampus, by investigating the effects of stress at different phases of development (Riem et al., 2015). In line with future studies on the hippocampus, an important question is whether the
hippocampus is vulnerable to maltreatment at particular ages, or to severity of exposure throughout childhood. This may lead to a distinct evaluation of the time when maltreated children are at the most prominent risk for alterations in hippocampal volume and different underlying mechanisms. The presence of sensitive periods indicates that vulnerability occurs during particular developmental stages and is likely attached to processes occurring exactly at that time (Teicher et al., 2018). Also, future studies should evaluate the influences of multiple variables, including genetic, biological, individual, environmental and situational factors (Watts‐English et al., 2006). Neuroendocrine evaluations and functional neuroimaging techniques when stress is induced in the laboratory would add to the understanding of brain structure and function (Watts‐English et al., 2006). Neuroimaging research is also needed to see if treatment affects brain structure and function, also to gain a better understanding of the effect of psychotherapy and medications in children reporting maltreatment (Watts‐English et al., 2006).
In conclusion, the evidence from this study suggests a heightened vulnerability of the brain in exposure to stressful events during early periods of life. As the brain develops, the release of cortisol as an effect of stress has detrimental effects on brain structures like the hippocampus, the prefrontal cortex, corpus callosum, and amygdala. Damage to brain
References
Aisa, B., Elizalde, N., Tordera, R., Lasheras, B., Del Río, J., & Ramírez, M. J. (2009). Effects of neonatal stress on markers of synaptic plasticity in the hippocampus:
implications for spatial memory. Hippocampus, 19(12), 1222-1231. doi:10.1002/hipo.20586
Aisa, B., Tordera, R., Lasheras, B., Del Río, J., & Ramírez, M. J. (2007). Cognitive
impairment associated to HPA axis hyperactivity after maternal separation in rats. Psychoneuroendocrinology, 32(3), 256-266. doi:
10.1016/j.psyneuen.2006.12.013
Amodio, D. M., & Frith, C. D. (2006). Meeting of minds: the medial frontal cortex and social cognition. Nature reviews neuroscience, 7(4), 268-277. doi: 10.1038/nrn1884
Anand, A., Li, Y., Wang, Y., Wu, J., Gao, S., Bukhari, L., ... & Lowe, M. J. (2005). Activity and connectivity of brain mood regulating circuit in depression: a functional magnetic resonance study. Biological psychiatry, 57(10), 1079-1088. doi: 10.1016/j.biopsych.2005.02.021
Anda, R. F., Dong, M., Brown, D. W., Felitti, V. J., Giles, W. H., Perry, G. S., ... & Dube, S.R. (2009). The relationship of adverse childhood experiences to a history of premature death of family members. BMC public health, 9(1),
106.doi:10.1186/1471-2458-9-106
Ahima, R. S., & Harlan, R. E. (1990). Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system. Neuroscience, 39(3), 579-604. doi: 10.1016/0306-4522(90)90244-X
Aschbacher, K., O’Donovan, A., Wolkowitz, O. M., Dhabhar, F. S., Su, Y., & Epel, E. (2013). Good stress, bad stress and oxidative stress: insights from anticipatory cortisol reactivity. Psychoneuroendocrinology, 38(9), 1698-1708. doi:
10.1016/j.psyneuen.2013.02.004
Bauer, P. J., Burch, M. M., Scholin, S. E., & Güler, O. E. (2007). Using cue words to investigate the distribution of autobiographical memories in childhood. Psychological Science, 18(10), 910-916. doi:
10.1111/j.1467-9280.2007.01999.x
Bishop, S. J. (2007). Neurocognitive mechanisms of anxiety: an integrative account. Trends in cognitive sciences, 11(7), 307-316. doi: 10.1016/j.tics.2007.05.008
Brake, W. G., Sullivan, R. M., & Gratton, A. (2000). Perinatal distress leads to lateralized medial prefrontal cortical dopamine hypofunction in adult rats. Journal of
Neuroscience, 20(14), 5538-5543. doi: 10.1523/JNEUROSCI.20-14-05538.2000
Bremner, J. D., Narayan, M., Staib, L. H., Southwick, S. M., McGlashan, T., & Charney, D. S. (1999). Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. American Journal of Psychiatry, 156(11),1787-1795.
Bremner, J. D., Randall, P., Scott, T. M., Capelli, S., Delaney, R., McCarthy, G., & Charney, D. S. (1995). Deficits in short-term memory in adult survivors of childhood abuse. Psychiatry research, 59(1-2), 97-107. doi: 10.1016/0165-1781(95)02800-5
Bremner, J. D., Vermetten, E., Afzal, N., & Vythilingam, M. (2004). Deficits in verbal declarative memory function in women with childhood sexual abuse-related posttraumatic stress disorder. The Journal of nervous and mental disease, 192(10), 643-649. doi: 10.1097/01.nmd.0000142027.52893.c8
Brown, D. W., Anda, R. F., Tiemeier, H., Felitti, V. J., Edwards, V. J., Croft, J. B., & Giles,W. H. (2009). Adverse childhood experiences and the risk of premature mortality. American journal of preventive medicine, 37(5), 389-396. doi: 10.1016/j.amepre.2009.06.021
Brugha, T. S., Bebbington, P. E., Tennant, C., & Hurry, J. (1985). The List of Threatening Experiences: a subset of 12 life event categories with considerable long-term contextual threat.
Brunson, K. L., Eghbal-Ahmadi, M., Bender, R., Chen, Y., & Baram, T. Z. (2001). Long-term, progressive hippocampal cell loss and dysfunction induced by early-life administration of corticotropin-releasing hormone reproduce the effects of early-life stress. Proceedings of the National Academy of Sciences, 98(15), 8856-8861. doi: 10.1073/pnas.151224898
Brunson, K. L., Kramár, E., Lin, B., Chen, Y., Colgin, L. L., Yanagihara, T. K., ... & Baram, T. Z. (2005). Mechanisms of late-onset cognitive decline after early-life stress. Journal of Neuroscience, 25(41), 9328-9338. doi:10.1523/JNEUROSCI.2281-05.2005
Chen, Y., & Baram, T. Z. (2016). Toward understanding how early-life stress reprograms cognitive and emotional brain networks. Neuropsychopharmacology, 41(1), 197-206. doi: 10.1038/npp.2015.181
Chen, Y., Bender, R. A., Brunson, K. L., Pomper, J. K., Grigoriadis, D. E., Wurst, W., & Baram, T. Z. (2004). Modulation of dendritic differentiation by corticotropin-releasing factor in the developing hippocampus. Proceedings of the National Academy of Sciences, 101(44), 15782-15787. doi: 10.1073/pnas.0403975101 Chrousos, G. P., & Gold, P. W. (1992). The concepts of stress and stress system disorders:
overview of physical and behavioral homeostasis. Jama, 267(9), 1244-1252. doi: 10.1001/jama.1992.03480090092034
Chugani, H. T., Behen, M. E., Muzik, O., Juhász, C., Nagy, F., & Chugani, D. C. (2001). Local brain functional activity following early deprivation: a study of postinstitutionalized Romanian orphans. Neuroimage, 14(6), 1290-1301. doi:10.1006/nimg.2001.0917
Cicchetti, D. (2002). The impact of social experience on neurobiological systems: Illustration from a constructivist view of child maltreatment. Cognitive development, 17(3-4), 1407-1428. doi: 10.1016/S0885-2014(02)00121-1
Dannlowski, U., Kugel, H., Huber, F., Stuhrmann, A., Redlich, R., Grotegerd, D., ... & Arolt, V. (2013). Childhood maltreatment is associated with an automatic negative emotion processing bias in the amygdala. Human brain mapping, 34(11), 2899-2909. doi: 10.1002/hbm.22112
De Bellis, M. D. (2001). Developmental traumatology: The psychobiological development of maltreated children and its implications for research, treatment, and policy. Development and psychopathology, 13(3), 539-564. doi:
10.1017/S0954579401003078
De Bellis, M. D., Hooper, S. R., Woolley, D. P., & Shenk, C. E. (2010). Demographic,
maltreatment, and neurobiological correlates of PTSD symptoms in children and adolescents. Journal of pediatric psychology, 35(5), 570-577.
doi:10.1093/jpepsy/jsp116
De Bellis, M. D., Keshavan, M. S., Shifflett, H., Iyengar, S., Beers, S. R., Hall, J., & Moritz, G. (2002). Brain structures in pediatric maltreatment-related posttraumatic stress disorder: a socio demographically matched study. Biological psychiatry, 52(11), 1066-1078. doi: 10.1016/S0006-3223(02)01459-2
De Bellis, M. D., Keshavan, M. S., Clark, D. B., Casey, B. J., Giedd, J. N., Boring, A. M., ... & Ryan, N. D. (1999). Developmental traumatology part II: brain development. Biological psychiatry, 45(10), 1271-1284. doi: 10.1016/S0006-3223(99)00045-1 De Bellis, M. D., Hooper, S. R., Spratt, E. G., & Woolley, D. P. (2009). Neuropsychological
findings in childhood neglect and their relationships to pediatric PTSD. Journal of the International Neuropsychological Society, 15(6), 868-878.
doi:10.1017/S1355617709990464
Delima, J., & Vimpani, G. (2011). The neurobiological effects of childhood maltreatment: An often overlooked narrative related to the long-term effects of early childhood trauma?. Family Matters, (89), 42.
Ekman, P., & Friesen, W. V. (1976). Measuring facial movement. Environmental psychology and nonverbal behavior, 1(1), 56-75. doi: 10.1007/BF01115465
Entringer, S., Buss, C., Kumsta, R., Hellhammer, D. H., Wadhwa, P. D., & Wüst, S. (2009). Prenatal psychosocial stress exposure is associated with subsequent working memory performance in young women. Behavioral neuroscience, 123(4), 886. doi: 10.1037/a0016265
Fales, C. L., Barch, D. M., Rundle, M. M., Mintun, M. A., Snyder, A. Z., Cohen, J. D., ... & Sheline, Y. I. (2008). Altered emotional interference processing in affective and cognitive-control brain circuitry in major depression. Biological psychiatry, 63(4), 377-384. doi: 10.1016/j.biopsych.2007.06.012
Fergusson, D. M., Horwood, L. J., & Woodward, L. J. (2000). The stability of child abuse reports: a longitudinal study of the reporting behaviour of young adults. Psychological medicine, 30(3), 529-544.
Fuxe, K., Wikström, A. C., Okret, S., Agnati, L. F., Härfstrand, A., Yu, Z. Y., ... &
Gustafsson, J. Å. (1985). Mapping of glucocorticoid receptor immunoreactive neurons in the rat tel-and diencephalon using a monoclonal antibody against rat liver glucocorticoid receptor. Endocrinology, 117(5), 1803-1812.
doi:10.1210/endo-117-5-1803
Gazzaniga, M. S., Ivry, R. B., & Mangun, G. R. (2014). Cognitive neuroscience: The biology of the mind (4th ed.). New York, NY: W. W. Norton.
Comparative Neurology, 366(2), 223-230. doi: 10.1002/(SICI)1096-9861(19960304)366:2<223::AID-CNE3>3.0.CO;2-7
Gilbert, S. J., Williamson, I. D., Dumontheil, I., Simons, J. S., Frith, C. D., & Burgess, P. W. (2007). Distinct regions of medial rostral prefrontal cortex supporting social and nonsocial functions. Social Cognitive and Affective Neuroscience, 2(3), 217-226. doi: 10.1093/scan/nsm014
Gilbert, R., Widom, C. S., Browne, K., Fergusson, D., Webb, E., & Janson, S. (2009). Burden and consequences of child maltreatment in high-income countries. The lancet, 373(9657), 68-81. doi: 10.1016/S0140-6736(08)61706-7
Glaser, D. (2000). Child abuse and neglect and the brain—a review. The Journal of Child Psychology and Psychiatry and Allied Disciplines, 41(1), 97-116. doi: 10.1017/S0021963099004990
Gogtay, N., Giedd, J. N., Lusk, L., Hayashi, K. M., Greenstein, D., Vaituzis, A. C., ... & Rapoport, J. L. (2004). Dynamic mapping of human cortical development during childhood through early adulthood. Proceedings of the National Academy of Sciences, 101(21), 8174-8179. doi: 10.1073/pnas.0402680101 Gotlib, I. H., & Joormann, J. (2010). Cognition and depression: current status and future
directions. Annual review of clinical psychology, 6, 285-312. doi: 10.1146/annurev.clinpsy.121208.131305
Gunnar, M., & Quevedo, K. (2007). The neurobiology of stress and development. Annu. Rev. Psychol., 58, 145-173. doi: 10.1146/annurev.psych.58.110405.085605
Hancock, P. A. (1989). A dynamic model of stress and sustained attention. Human factors, 31(5), 519-537. doi: 10.1177/001872088903100503
Hedges, D. W., & Woon, F. L. (2011). Early-life stress and cognitive outcome.
Psychopharmacology, 214(1), 121-130. doi: 10.1007/s00213-010-2090-6 Heim, C., & Nemeroff, C. B. (2001). The role of childhood trauma in the neurobiology of
mood and anxiety disorders: preclinical and clinical studies. Biological psychiatry, 49(12), 1023-1039. doi: 10.1016/S0006-3223(01)01157-X Herman, J. P., Ostrander, M. M., Mueller, N. K., & Figueiredo, H. (2005). Limbic system
mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 29(8), 1201-1213. doi: 10.1016/j.pnpbp.2005.08.006
Jackowski, A., Perera, T. D., Abdallah, C. G., Garrido, G., Tang, C. Y., Martinez, J., ... & Dwork, A. J. (2011). Early-life stress, corpus callosum development,
hippocampal volumetrics, and anxious behavior in male nonhuman primates. Psychiatry Research: Neuroimaging, 192(1), 37-44. doi:
10.1016/j.pscychresns.2010.11.006
Kaiseler, M., Polman, R., & Nicholls, A. (2009). Mental toughness, stress, stress appraisal, coping and coping effectiveness in sport. Personality and individual differences, 47(7), 728-733. doi: 10.1016/j.paid.2009.06.012
Kajantie, E., & Räikkönen, K. (2010). Early life predictors of the physiological stress
response later in life. Neuroscience & Biobehavioral Reviews, 35(1), 23-32. doi: 10.1016/j.neubiorev.2009.11.013
Karten, Y. J., Olariu, A., & Cameron, H. A. (2005). Stress in early life inhibits neurogenesis in adulthood. Trends in neurosciences, 28(4), 171-172. doi:
10.1016/j.tins.2005.01.009
Khan, A., McCormack, H. C., Bolger, E. A., McGreenery, C. E., Vitaliano, G., Polcari, A., & Teicher, M. H. (2015). Childhood maltreatment, depression, and suicidal
ideation: critical importance of parental and peer emotional abuse during developmental sensitive periods in males and females. Frontiers in psychiatry, 6, 42. doi: 10.3389/fpsyt.2015.00042
Kudielka, B. M., & Kirschbaum, C. (2005). Sex differences in HPA axis responses to stress: a review. Biological psychology, 69(1), 113-132. doi:
10.1016/j.biopsycho.2004.11.009
Lupien, S. J., McEwen, B. S., Gunnar, M. R., & Heim, C. (2009). Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nature reviews neuroscience, 10(6), 434-445. doi: 10.1038/nrn2639
Masten, C. L., Guyer, A. E., Hodgdon, H. B., McClure, E. B., Charney, D. S., Ernst, M., ... & Monk, C. S. (2008). Recognition of facial emotions among maltreated children with high rates of post-traumatic stress disorder. Child abuse & neglect, 32(1), 139-153. doi: 10.1016/j.chiabu.2007.09.006
McCrory, E., De Brito, S. A., & Viding, E. (2011). The impact of childhood maltreatment: a review of neurobiological and genetic factors. Frontiers in psychiatry, 2, 48. doi: 10.3389/fpsyt.2011.00048
McCrory, E., De Brito, S. A., & Viding, E. (2012). The link between child abuse and
psychopathology: a review of neurobiological and genetic research. Journal of the Royal Society of Medicine, 105(4), 151-156. doi:10.1258/jrsm.2011.110222
Miller, E. K., & Cohen, J. D. (2001). An integrative theory of prefrontal cortex function. Annual review of neuroscience, 24(1), 167-202. doi:
10.1146/annurev.neuro.24.1.167
college women. The Journal of neuropsychiatry and clinical neurosciences, 18(1), 45-53.
Nelson, C. A., Zeanah, C. H., Fox, N. A., Marshall, P. J., Smyke, A. T., & Guthrie, D. (2007). Cognitive recovery in socially deprived young children: The Bucharest Early Intervention Project. Science, 318(5858), 1937-1940.
doi:10.1126/science.1143921
Noble, K. G., Tottenham, N., & Casey, B. J. (2005). Neuroscience perspectives on disparities in school readiness and cognitive achievement. The Future of Children, 71-89.
Ochsner, K. N., & Gross, J. J. (2005). The cognitive control of emotion. Trends in cognitive sciences, 9(5), 242-249. doi: 10.1016/j.tics.2005.03.010
Parker, K. J., Buckmaster, C. L., Justus, K. R., Schatzberg, A. F., & Lyons, D. M. (2005). Mild early life stress enhances prefrontal-dependent response inhibition in monkeys. Biological psychiatry, 57(8), 848-855. doi:
10.1016/j.biopsych.2004.12.024
Pechtel, P., & Pizzagalli, D. A. (2011). Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacology, 214(1), 55-70. doi: 10.1007/s00213-010-2009-2
Peterson, C., Warren, K. L., & Short, M. M. (2011). Infantile amnesia across the years: A 2‐year follow‐up of children’s earliest memories. Child development, 82(4), 1092-1105. https://doi: 10.1111/j.1467-8624.2011.01597.x
Pope Jr, H. G., & Hudson, J. I. (1995). Does childhood sexual abuse cause adult psychiatric disorders? Essentials of methodology. The Journal of Psychiatry & Law, 23(3), 363-381. doi:10.1177/009318539502300303
childhood and adolescence. Development and psychopathology, 27(2), 507-520. doi: 10.1017/S0954579415000127
Reshetnikov, V. V., Kovner, A. V., Lepeshko, A. A., Pavlov, K. S., Grinkevich, L. N., & Bondar, N. P. (2018). Stress early in life leads to cognitive impairments, reduced numbers of CA3 neurons and altered maternal behavior in adult female mice. Genes, Brain and Behavior, 19(3). doi: 10.1111/gbb.12541
Rubin, D. C. (2000). The distribution of early childhood memories. Memory, 8(4), 265-269. doi: 10.1080/096582100406810
Rudland, J. R., Golding, C., & Wilkinson, T. J. (2020). The stress paradox: how stress can be good for learning. Medical education. doi: 10.1111/medu.13830
Sapolsky, R. M., Uno, H., Rebert, C. S., & Finch, C. E. (1990). Hippocampal damage associated with prolonged glucocorticoid exposure in primates. Journal of Neuroscience, 10(9), 2897-2902. doi: 10.1523/JNEUROSCI.10-09-02897.1990 Schiffer, F., Teicher, M. H., & Papanicolaou, A. C. (1995). Evoked potential evidence for
right brain activity during the recall of traumatic memories. The Journal of Neuropsychiatry and Clinical Neurosciences. doi: 10.1176/jnp.7.2.169
Shaw, P., Kabani, N. J., Lerch, J. P., Eckstrand, K., Lenroot, R., Gogtay, N., ... & Giedd, J. N. (2008). Neurodevelopmental trajectories of the human cerebral cortex. Journal of neuroscience, 28(14), 3586-3594. doi: 10.1523/JNEUROSCI.5309-07.2008 Sheline, Y. I., Barch, D. M., Donnelly, J. M., Ollinger, J. M., Snyder, A. Z., & Mintun, M. A.
(2001). Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study. Biological psychiatry, 50(9), 651-658. doi: 10.1016/S0006-3223(01)01263-X
symptoms in women presenting to a primary care practice. Child abuse & neglect, 27(11), 1247-1258. doi: 10.1016/j.chiabu.2003.05.001
Stein, M. B., Koverola, C., Hanna, C., Torchia, M. G., & McClarty, B. (1997). Hippocampal volume in women victimized by childhood sexual abuse. Psychological
medicine, 27(4), 951-959. doi: 10.1017/S0033291797005242
Squire, L. R., Stark, C. E., & Clark, R. E. (2004). The medial temporal lobe. Annu. Rev. Neurosci., 27, 279-306. doi: 10.1146/annurev.neuro.27.070203.144130
Teicher, M. H., Anderson, C. M., Ohashi, K., Khan, A., McGreenery, C. E., Bolger, E. A., … & Vitaliano, G. D. (2018). Differential effects of childhood neglect and abuse during sensitive exposure periods on male and female hippocampus.
Neuroimage, 169, 443-452. doi: 10.1016/j.neuroimage.2017.12.055
Teicher, M. H., Anderson, C. M., & Polcari, A. (2012). Childhood maltreatment is associated with reduced volume in the hippocampal subfields CA3, dentate gyrus, and subiculum. Proceedings of the National Academy of Sciences, 109(9). doi: 10.1073/pnas.1115396109
Teicher, M. H., Dumont, N. L., Ito, Y., Vaituzis, C., Giedd, J. N., & Andersen, S. L. (2004). Child neglect is associated with reduced corpus callosum area. Biological Psychiatry, 56, 80−85. doi: 10.1016/j.biopsych.2004.03.016
Teicher, M. H., & Samson, J. A. (2013). Childhood maltreatment and psychopathology: A case for ecophenotypic variants as clinically and neurobiologically distinct subtypes. American journal of psychiatry, 170(10), 1114-1133.
doi:10.1176/appi.ajp.2013.12070957
Teicher, M. H., Tomoda, A., & Andersen, S. L. (2006). Neurobiological consequences of early stress and childhood maltreatment: are results from human and animal studies comparable?. Annals of the New York Academy of Sciences, 1071(1), 313-323. doi: 10.1196/annals.1364.024
Teicher, M. H., Andersen, S. L., Polcari, A., Anderson, C. M., Navalta, C. P., & Kim, D. M. (2003). The neurobiological consequences of early stress and childhood maltreatment. Neuroscience & biobehavioral reviews, 27(1-2), 33-44. doi: 10.1016/S0149-7634(03)00007-1
Tomoda, A., Suzuki, H., Rabi, K., Sheu, Y. S., Polcari, A., & Teicher, M. H. (2009). Reduced prefrontal cortical gray matter volume in young adults exposed to harsh corporal punishment. Neuroimage, 47, T66-T71. doi: 10.1016/j.neuroimage.2009.03.005
Tottenham, N., Hare, T. A., Quinn, B. T., McCarry, T. W., Nurse, M., Gilhooly, T., ... & Thomas, K. M. (2010). Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation. Developmental science, 13(1), 46-61. doi: 10.1111/j.1467-7687.2009.00852.x Tottenham, N., & Sheridan, M. A. (2010). A review of adversity, the amygdala and the
hippocampus: a consideration of developmental timing. Frontiers in human neuroscience, 3, 68. doi:10.3389/neuro.09.068.2009
van Harmelen, A. L., van Tol, M. J., van der Wee, N. J., Veltman, D. J., Aleman, A., Spinhoven, P., ... & Elzinga, B. M. (2010). Reduced medial prefrontal cortex volume in adults reporting childhood emotional maltreatment. Biological psychiatry, 68(9), 832-838. doi: 10.1016/j.biopsych.2010.06.011
van Harmelen, A. L., van Tol, M. J., Demenescu, L. R., van der Wee, N. J., Veltman, D. J., Aleman, A., ... & Elzinga, B. M. (2013). Enhanced amygdala reactivity to emotional faces in adults reporting childhood emotional maltreatment. Social cognitive and affective neuroscience, 8(4), 362-369. doi: 10.1093/scan/nss007 Vermetten, E., & Bremner, J. D. (2002). Circuits and systems in stress. I. Preclinical studies.
Depression and anxiety, 15(3), 126-147. doi: 10.1002/da.10016
Watts‐English, T., Fortson, B. L., Gibler, N., Hooper, S. R., & De Bellis, M. D. (2006). The psychobiology of maltreatment in childhood. Journal of Social Issues, 62(4), 717-736. doi: 10.1111/j.1540-4560.2006.00484.x
Weber, D. A., & Reynolds, C. R. (2004). Clinical perspectives on neurobiological effects of psychological trauma. Neuropsychology Review, 14(2), 115-129. doi:
10.1023/B:NERV.0000028082.13778.14
Vythilingam, M., Heim, C., Newport, J., Miller, A. H., Anderson, E., Bronen, R., ... & Nemeroff, C. B. (2002). Childhood trauma associated with smaller
hippocampal volume in women with major depression. American Journal of Psychiatry, 159(12), 2072-2080. doi: 10.1176/appi.ajp.159.12.2072
Whittle, S., Dennison, M., Vijayakumar, N., Simmons, J. G., Yücel, M., Lubman, D. I., ... & Allen, N. B. (2013). Childhood maltreatment and psychopathology affect brain development during adolescence. Journal of the American Academy of Child &Adolescent Psychiatry, 52(9), 940-952. doi: 10.1016/j.jaac.2013.06.007 Wilson, K. R., Hansen, D. J., & Li, M. (2011). The traumatic stress response in child
maltreatment and resultant neuropsychological effects. Aggression and Violent Behavior, 16(2), 87-97. doi: 10.1016/j.avb.2010.12.007
Wolfensberger, S. P., Veltman, D. J., Hoogendijk, W. J., Boomsma, D. I., & de Geus, E. J. (2008). Amygdala responses to emotional faces in twins discordant or
concordant for the risk for anxiety and depression. Neuroimage, 41(2), 544-552. doi: 10.1016/j.neuroimage.2008.01.053
Yazgan, M. Y., Wexler, B. E., Kinsbourne, M., Peterson, B., & Leckman, J. F. (1995). Functional significance of individual variations in callosal area.
Neuropsychologia, 33(6), 769-779.
Zach, P., Mrzilkova, J., Rezacova, L., Stuchlik, A., & Vales, K. (2010). Delayed effects of elevated corticosterone level on volume of hippocampal formation in laboratory rat. Physiological research, 59(6), 985.
