Studies in animals
Up to now, most studies on the association between ELA and cognitive outcomes have been conducted in rodents (Table
1). These animal models allow studies based on specific hypotheses and enable controlled conditions of experiments to avoid the inherent ethical issues in human studies. Preclinical animal studies have demonstrated that maternal care during early life profoundly impacts many aspects of the cognitive ability of offspring, and these effects can persist into adulthood [
47,
48]. Pups that received high levels of maternal caregiving express higher levels of neurotrophic factors and exhibit better spatial learning and memory [
47]. Based on these findings, many studies have been conducted in animal models to explore how inadequate maternal care influences the cognitive outcomes of the offspring. Several research groups have reported poor cognitive outcomes in adult rodents with a history of maternal separation/deprivation [
22,
49‐
54]. Notably, these deficits are not apparent in PND-21 female animals with maternal deprivation during the early postnatal period, in comparison to age-matched male animals [
55]. However, severe cognitive deficits have been observed in female animals on PND 40, indicating that the susceptibility to cognitive impairment might increase with age in female animals [
49]. Likewise, using a visual-discrimination task, Yajima and colleagues [
22] found that mice exposed to maternal deprivation display more evident cognitive impairment in middle age (1.4 years of age) than at a younger age. Intriguingly, lower levels of brain-derived neurotrophic factor (BDNF) and synapse-related proteins, accompanied by reduced number of mature neurons, were also detected in the hippocampus and prefrontal cortex of animals subjected to maternal separation/deprivation [
49,
54]. This further supports poor maternal care as a potential risk factor for abnormal brain development.
Table 1
Animal studies on ELA and cognitive impairment
LBN | Sprague Dawley rats/male | PND 2–9 | 4–5, and 12 months of age | At 12 months of age↓ | |
Chronic stress | Wistar rats/male | PND 26–28 | 2 and 3 months of age | ↓ | |
LBN | Sprague Dawley rats/male | PND 2–9 | 10–12 months of age | ↓ | |
LBN | CRF1-CKO mice or wild type mice/male | PND 2–9 | 6 months of age | ↓ | |
MD | Wistar rats/male and female | PND 9 | PND 40 | Male↓; Female↓↓ | |
LBN | C57Bl/6J mice | PND 2–9 | 5 months of age | Male↓↓; Female↓ | |
Foot shock | Wistar rats/male | PND 21–26 | Adulthood | ↓ | |
MS | Sprague Dawley rats/male and female | PND 2–21 | PND 55 | ↓ | |
Single prolonged stress | Sprague Dawley rats/male | PND 25 | PND 32, 60 and 90 | At PND 32 and 60↓ | |
MD | Wistar rats/female | PND 3 | 12–17 weeks of age | ↓ | |
Foot shock | Wistar rats/male | PND 21–27 | 10 weeks of age | ↓ | |
MS | Balb/cJ and C57Bl/6J mice/male and female | PND 2–15 | 2 months of age | ↓ | |
MD | C57BL/6J mice/male | PND 2–14 | 2.5 months and 1.4 years of age | At 2.5 months of age↓ and 1.4 years of age↓↓ | |
MD | Sprague Dawley rats/male and female | PND 9 | PND 74 | ↓ | |
MD | Sprague Dawley rats/male and female | PND 2–14 | PND 21 and 25 | Male↓ | |
MD | C57BL/6 mice/female | PND 2–14 | Adulthood | ↓ | |
Consistent with these findings, abnormal maternal behaviors, such as hypervigilance and abuse, which are induced by the LBN paradigm, profoundly impact the cognitive outcomes of their offspring [
56]. Several early studies revealed that animals subjected to sporadic maternal care exhibit progressive cognitive deficits in adulthood. They also display impaired hippocampal long-term potentiation (a molecular basis of learning and memory) and structural changes such as dendritic atrophy and synaptic degeneration [
56‐
58]. Furthermore, the survival of newborn neurons in the hippocampus is dramatically reduced in mice exposed to LBN from postnatal day 2 to day 9. These alterations are associated with aberrant cognitive performance. However, no changes in cell proliferation and neuronal differentiation were observed [
59].
In light of the evidence that early traumatic experiences increase the vulnerability to mental illness in adulthood, increasing research interest has been focused on the consequences of traumatic experiences in early life. Chronic exposure to unavoidable plantar electroshock in the early post-weaning period leads to impaired spatial memory in adulthood, as evidenced by poor performance in the Y-maze or Morris water maze [
44,
60]. Additionally, rats exposed to a single platform and acute swimming stress during adolescence also show inferior cognitive performance in adulthood, indicating that even relatively brief stress experiences early in life might exert profound, long-lasting effects on cognitive health [
41,
61]. Overall, these data from animal models provide new insights into the crosstalk between ELA and cognitive impairment later in life.
Studies in humans
The connection between ELA and neurological consequences has been an active area of research since the discovery that adverse childhood experiences are positively linked to poor health outcomes later in life [
16]. Numerous clinical studies have identified ELA as a potential risk factor for cognitive impairment (Table
2). These studies primarily focused on child neglect, physical abuse, and parental separation, thus providing an important context for understanding this health concern.
Table 2
Clinical data on ELA and cognitive impairment
Cohort study | 13 subjects with ELA, average age, 13(± 2.58) years of age; 21 healthy subjects, average age, 13 (± 1.96) years of age | Neglect, maltreatment, and unstable early environments | The change task (a variant of the stop-signal task) | Cognitive control ↓ | |
Cohort Study | 93 male subjects experienced child separation; 186 male subjects without child separation | Parental separation | The Finnish Defense Forces Basic Intellectual Ability Test | At 20 years: verbal and arithmetic cognitive ability↓; at 70 years: verbal, visuospatial, arithmetic, and general cognitive ability↓ | |
Cross-sectional study | 64 subjects with major depressive disorder and 65 non-depressed controls, 20 to 50 years of age | Assessed by the self-reported Early Life Stress Questionnaire | Composite neuropsychological measures | Working memory and processing speed↓ | |
Longitudinal study | 9942 subjects | Low childhood socioeconomic status, lack of friends, childhood parental mental health problems, and poor parent-child relationships | Orientation and calculation, immediate memory, and delayed memory test | ↓ | |
Longitudinal study | 5000 subjects | Domestic violence, physical cruelty, emotional cruelty, harsh parenting, and poly-victimization | The ‘triangles’ social cognition assessment (mean subject age: 13.75 years) and IQ assessment (mean subject age: 8 years) | General cognition↓ | |
Cross-sectional study | 215 undergraduate students, average age = 19.1, 295 community subjects, average age = 36.24 | Assessed by the self-reported adverse childhood experiences scale | Wisconsin Card Sorting Test | Cognitive flexibility↓ | |
Longitudinal study | 12,288 subjects, 18 to 42 years of age | Physical abuse and neglect | The Rey Auditory-Verbal Learning Test and Digit-Span Backward Task | Verbal memory and working memory↓ | |
Longitudinal study | 11,475 subjects, average age, 45 years | Low childhood family socioeconomic status and poor childhood social relationships | Telephone interview of cognitive status, word recall, and figure drawing | ↓ | |
Parent-child coregulation is a dynamic process that involves mutual influence and coordination of emotional, behavioral, and physiological states between parents and their children [
62]. Early coregulation is critical for the healthy development of children across multiple domains, including emotional and cognitive functioning [
63,
64]. The importance of coregulation has been further highlighted by a longitudinal study which indicates that a secure infant-caregiver attachment during infancy may predict adult competence of children, including educational attainment, occupational success, and social functioning [
65]. Intriguingly, a longitudinal study has demonstrated that positive mother–child interactions in kindergarten are associated with an increased likelihood of high school graduation and, for some students, a better academic performance [
66].
One study examined the cognitive performances of adolescents with a documented history of ELA. Results showed that individuals who experienced child neglect, maltreatment, and unstable early environments exhibited poorer performance in the change task, a task designed to specifically assess cognitive control [
67]. Similarly, a Helsinki birth cohort study investigated the ongoing effects of parental separation. At the age of 20 years, men who were separated from their parents during World War II scored lower in verbal, visuospatial, and general cognitive reasoning, and later at the age of 70, they exhibited lower scores in all tests in comparison to non-separated subjects [
68]. Of note, a more extended separation period is associated with poorer overall cognitive performances. Several longitudinal studies have assessed how childhood neglect and maltreatment can influence cognitive outcomes later in life, revealing a remarkable connection between childhood neglect/maltreatment and lower general cognition or poorer working memory [
23,
69]. Given that different forms of ELA often co-occur in some individuals, the effect of poly-victimization, which refers to experiencing multiple forms of victimization during a certain period, has been further analyzed. Those exposed to multiple types of ELA including physical/emotional abuse, harsh parenting, and domestic violence, experience more severe detrimental effects [
23]. The adverse effects of ELA are further supported by the Romanian orphanage studies performed by many groups, which showed that childhood neglect/deprivation led to long-lasting effects on cognitive and emotional development [
70,
71]. Children raised in institutions experienced severe deprivation (lack of individualized care and nurturing environment) early in life, and they exhibited lower executive functioning and increased diagnostic susceptibility to psychopathology compared to their peers who were never institutionalized [
70]. Early childhood deprivation is associated with structural changes of the brain in adulthood. Adoptees who experienced early deprivation exhibited smaller total-brain volumes compared to nondeprived adoptees, which may be linked to lower intelligence quotient and higher levels of attention-deficit/hyperactivity disorder symptoms [
71].
The effects of other types of ELA on cognition have also been examined. A nationally representative longitudinal cohort study analyzed the cumulative effects of multiple childhood adversities on cognitive decline in later life. The results of this study are profound: poor parent-child relationships, lack of friends, childhood parental mental health issues, and low socioeconomic status all negatively affected cognitive function among the middle-aged and elderly populations [
72]. These conclusions are further supported by a longitudinal study demonstrating that low family socioeconomic status and poor social relationships in childhood are positively associated with the risk of mild cognitive impairment [
73]. To gain more insights into the relationship between the number of ELA exposures and negative outcome expectations, scales with high internal consistency, validity, and test-retest reliability have been developed and employed in several cross-sectional studies. These studies showed that greater ELA exposure is associated with compromised cognitive flexibility, processing speed, and working memory [
74,
75]. Moreover, these negative consequences may be amplified in subjects with depression, as evidenced by smaller orbitofrontal cortex and hippocampal volumes compared to never-depressed individuals [
74]. Taken together, these human studies provide moderate evidence that ELA exposure is a risk factor for developing cognitive impairment later in life.