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Preliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain Development

2008; American Psychiatric Association Publishing; Volume: 20; Issue: 3 Linguagem: Inglês

10.1176/jnp.2008.20.3.292

1545-7222

Susan L. Andersen, Akemi Tomada, Evelyn S. Vincow, Elizabeth Valente, Ann Polcari, Martin H. Teicher,

Birth, Development, and Health

Back to table of contents Previous article Next article REGULARFull AccessPreliminary Evidence for Sensitive Periods in the Effect of Childhood Sexual Abuse on Regional Brain DevelopmentSusan L. Andersen Ph.D.Akemi Tomada M.D., Ph.D.Evelyn S. VincowElizabeth Valente M.A.Ann Polcari R.N., C.S., Ph.D.Martin H. Teicher M.D., Ph.D.Susan L. Andersen Ph.D.Akemi Tomada M.D., Ph.D.Evelyn S. VincowElizabeth Valente M.A.Ann Polcari R.N., C.S., Ph.D.Martin H. Teicher M.D., Ph.D.Published Online:1 Jul 2008AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InEmail C hildhood abuse is a major risk factor in the development of psychopathology 1 – 4 and is also associated with a host of neuropsychological and neurocognitive consequences. 5 Recent studies suggest that clinical sequelae may stem, at least in part, from enduring adverse effects on brain development. 6 The nature and severity of the effects will likely depend on genetic predisposition, 7 , 8 frequency, severity, and multiplicity of the stressors, 1 , 8 – 10 gender, 9 , 11 and timing of the insult. 9 Generally, early onset and longer duration of abuse have been associated with greater morphological change, 9 but this may be an oversimplification. An alternative hypothesis is that stress-susceptible brain regions have their own unique sensitive periods (or windows of vulnerability) to the effects of early stress. 12 In practice these two hypotheses may not appear that different, as longer periods of abuse may be more likely to intersect a sensitive period, and many brain regions probably have a relatively early (prepubertal) window of vulnerability. Nevertheless, this is a critical distinction which could substantially enhance our understanding of the neuropsychiatric effects of abuse and shed new light on the underlying temporal aspects of gene × environment interactions that lay at the heart of most psychiatric vulnerabilities. The concept that brain regions go through stages when they are maximally sensitive to experience emerged from the landmark studies of Hubel and Wiesel. 13 They found that binocular deprivation affected development of the visual cortex in cats if it occurred early in postnatal life, but had no impact after puberty. Little evidence exists for sensitive periods in human brain development. Postnatal sensitive periods have been delineated for development of speech, language, 14 – 16 and binocular vision. 17 However, a vast array of stimuli and experiences are likely to affect brain development throughout a host of sensitive periods that await discovery. Stress has been identified as a key experiential factor that programs and modifies brain development. 12 , 18 Exposure to physical or sexual abuse resulting in psychopathology has been associated with attenuated left hemisphere maturation, 19 , 20 diminished size of the corpus callosum, 9 , 11 , 20 , 21 reduced hippocampal volume in adults 22 – 25 (but not children 9 , 21 , 26 , 27 ), and alterations in gray matter volume, symmetry, and neuronal integrity of the frontal cortex. 21 , 26 , 28The aim of this study was to test the hypothesis that stress-sensitive brain regions have their own developmental time windows when they are maximally vulnerable to the effects of early stress. This is a relatively easy hypothesis to test in a preclinical study, where stress can be administered during specific developmental stages. It is much harder to test this hypothesis in humans as there is a great deal of heterogeneity in onset and duration of abuse and frequent co-occurrence of other forms of stress. A secondary aim of this study was to propose an analytical strategy to facilitate the exploration of sensitive period effects for complex phenomena such as childhood sexual abuse. In order to test this hypothesis, measures of hippocampal, corpus callosum, frontal cortex, and amygdala size were obtained from MRI scans of female college students with self-reported histories of childhood sexual abuse that occurred at different ages, and from healthy socio-demographically comparable control subjects. The study was predicated on the hypotheses that the hippocampus would have an early period of vulnerability, based on the observation that hippocampal synaptogenesis is strongly influenced by variations in maternal care and availability. 29 , 30 The slowly maturing frontal cortex 31 would have a late period of vulnerability and may be resistant to the effects of early stress given our observation that exposure to early isolation stress in rats affected synaptic density in the hippocampus but had no sustained effect on synaptic density in the prefrontal cortex. 30 The corpus callosum would likely have an intermediate period of vulnerability in females based on our observation that sexual abuse was associated with reduced corpus callosum area in females, while neglect (generally an earlier problem) was associated with reduced corpus callosum area in males. 11 Finally, we predicted that the amygdala would not have a prominent period of vulnerability, based on reports of normal amygdaloid volumes in abused subjects. 9 , 22 , 25 , 26In this article, we provide evidence for discrete regional periods sensitive to the effects of childhood sexual abuse, with the hippocampus having the earliest period of vulnerability and the frontal cortex having the latest.METHODSubjects Physically healthy, unmedicated, right-handed individuals ages 18–22 years were recruited via advertisements looking for individuals interested in participating in "psychiatric research." 5 Primary entry criterion was a history of three or more episodes of forced contact childhood sexual abuse that ended at least 2 years prior to enrollment. Childhood sexual abuse was defined as forced involuntary contact with the sexual part of the victim's or the perpetrator's body. Contact had to be accompanied by threats of harm to self or others, or feelings of fear or terror. History of childhood sexual abuse was supported by written response and by consistent results of a lengthy structured interview conducted by a certified clinician using the Traumatic Antecedents Questionnaire. 32Rigorous exclusion criteria were applied to select subjects in whom differences in brain morphology could be most clearly attributable to childhood sexual abuse. They included neurological disorders, medical disorder affecting growth or development, treatment with corticosteroids, pregnancy, past or present alcohol/substance abuse, premature birth or complications during mother's pregnancy or delivery, in utero exposure to alcohol or drugs, or a history of physical abuse. Exclusion criteria also included exposure to any other forms of preceding or subsequent trauma (e.g., motor vehicle accidents, natural disasters, fires, near drowning, witnessing abuse, animal attacks, gang violence, robbery). These criteria excluded 95% of the 732 initial respondents to our advertisement. Twenty-eight percent of the subjects who completed all of the prescreening instruments (N=564) had a self-reported history of childhood sexual abuse, but only 9.5% of the prescreened sample had a history of childhood sexual abuse unaccompanied by exposure to other forms of abuse. Using these criteria, 26 abused women (mean age=20.0 years, range=18–22) and 17 healthy female comparison subjects (mean age=19.4 years, range=18–22) were enrolled. Comparison subjects, selected from the same pool of respondents, had no current or past DSM-IV Axis I disorder on Structured Clinical Interviews 33 and had no history of abuse or exposure to other traumatic events. Subjects were predominantly middle class or above (96%) and the two groups were similar in measures of socioeconomic status (Hollingshead index 34 : 2.3±0.9 versus 2.0±0.6; F=1.95, df=1, 41, p=0.17). Subjects were paid for participation and provided written, informed consent. The study was approved and monitored by the McLean Hospital Institutional Review Board. Specific information about each subject is presented in Table 1 . None of the subjects recruited had more than a minimal history of drug or alcohol use, and no subject met criteria for borderline personality disorder. None of the subjects enrolled were seeking treatment. TABLE 1. Subjects' History of Abuse and Psychiatric DiagnosesTABLE 1. Subjects' History of Abuse and Psychiatric DiagnosesEnlarge tableRationale for Selection Procedure Subjects were selected based on exposure history regardless of psychiatric outcome (except for substance abuse, which could directly affect brain development). This differs from prior studies that focused on abused subjects with posttraumatic stress disorder (PTSD). 9 , 19 , 22 , 23 Selecting subjects with childhood sexual abuse regardless of outcome facilitates the relatively unbiased assessment of the morphometric effects of abuse during specific developmental stages. Preselection of subjects based on a history of PTSD (or other psychopathologies) would bias morphometric findings toward those brain regions involved in the disorder. This distinction is important when the goal is to ascertain the possible effects of exposure to early stress at key developmental points and less relevant if the goal is to delineate the neurobiology of an underlying psychiatric disorder such as PTSD. Imaging MethodsT1-weighted coronal sections (3-D, spoiled gradient recalled acquisition in the steady state; TR=40 msec; TE=5 msec; NEX=2; flip angle 40°; fov 24 cm; matrix 256×128; 124 sections of 1.5 mm thickness, no gaps) were acquired using a 1.5 T magnetic resonance scanner (Echospeed; GE Medical Systems). Raters were blind to the identity and history of each subject and provided results from images in which definitive measurements could be made based on the distinctiveness of landmarks, borders, image quality, and motion artifact. The hippocampus and amygdala were traced in their entirety according to the method detailed by Pruessner et al. 35 This technique yielded excellent reliability (intrarater ICC 0.91 to 0.95, interrater 0.83 to 0.94), though raters rejected 20% of the sample because of ambiguity in delineating one or more borders. Manual tracing is currently considered optimal for measuring the volume of these two regions. 36 The midsagittal corpus callosum area was manually traced using the NIH Image program and an automated algorithm divided it into seven regions as defined by Witelson. 37 Previous studies indicated that midbody regions 3–6 were most significantly affected by abuse or neglect. 9 , 11 , 21 Region 3, rostral body, was selected for sensitive period analysis as this region showed the greatest overall vulnerability to childhood sexual abuse (regardless of age of abuse) in the present sample. Gray matter volume of frontal cortex was assessed using a semiautomated program for cortical surface-based analysis (FreeSurfer). 38 – 40 A composite measure of average frontal lobe gray matter volume was obtained by combining measures from all parts of the inferior frontal, middle frontal, superior frontal, orbital, suborbital, transverse, frontopolar and cingulate gyri, and sulci. Data AnalysisStatistical analyses were conducted to provide evidence for sensitive periods in a clinical population where abuse occurred over a variable number of years. Subjects with childhood sexual abuse had experienced abuse for an average of 4.2±2.4 years. In most cases abuse occurred in continuous years (70%). The remainder had an average gap of 5.0±2.7 years between clusters of abuse. This situation presents challenges to conventional between-group designs, so alternative statistical methods were used.The first method was multiple regression analysis (SPSS), in which the primary assumption was that abuse during different stages of development would exert additive effects on regional brain morphometry. If this assumption is true, then it is possible to determine whether abuse during one or more stages of development was associated with a particularly significant reduction in regional brain size. The reality may be more complicated; there may be interactive effects between abuse at different stages, but an additive multiple regression model provides a parsimonious initial approach and is a good starting point if the model provides a reasonable fit to the available data. Subjects were characterized by the density of childhood sexual abuse they experienced during sequential developmental stages. Density of childhood sexual abuse was defined as number of years of abuse experienced during the stage divided by number of years in the stage. The designated stages we compared were preschool (3–5 years), latency (6–8 years), prepubertal (9–10 years), pubertal (11–13 years), and adolescent (14–16 years), based on the ages of exposure. The numbers of subjects who experienced abuse during sequential stages were 13, 16, 7, 10, and 7, respectively. Stages were selected to be relatively short to make it possible to detect multiple distinct windows of vulnerability during the prepubertal period, as preclinical studies suggest that vulnerable periods may be brief. 41 Additional independent variables of potential significance were intracranial volume, midsagittal area, total gray matter volume, socioeconomic status, list recall, history of depression, and history of posttraumatic stress disorder (PTSD). List recall was selected as a potential covariate for hippocampal volume given the role of the hippocampus in verbal declarative memory, and observation of a strong correlation between hippocampal volume and measures of list recall. 42 Multiple regression analyses were performed without data transformations as all of the morphometric measures were normally distributed (Kolmogorov-Smirnov test, hippocampus: z=0.457, p>0.9; amygdala: z=0.622, p>0.8; corpus callosum: z=0.820, p>0.5; frontal cortex: z=0.508, p>0.9). Path analysis was performed using structural equation modeling with Amos Graphics (http://www.assess.com/Software/AMOS.htm) as a confirmatory statistical procedure. Path analysis is a specific form of structural equation modeling in which there are no latent variables (all variables are directly measured). This approach makes several assumptions, particularly that there are an adequate number of known correlations or covariances as inputs to generate a sensible set of results, and that there is a unique or best solution. Path analysis was guided by the robust results of the multiple regression analysis and made feasible with limited sample size given the strength of the associations and normality of the data. Structural equation modeling provides a sophisticated analysis that accounts for the tendency of abusive experiences to carry over into subsequent stages. Further, structural equation modeling controls for problems with multiple comparisons by placing the entire analysis into a single statistical model. Full-information maximum likelihood estimation was used to minimize the discrepancy fit function defined by the available data points, pathways and coefficients.With structural equation modeling, the null hypothesis is that the model fits the data. Statistically, the absolute fit of the model is tested using a chi-square procedure in which a p value 0.05 one can then provisionally accept the given model along with p values indicating the significance of the individual pathways. The Tucker-Lewis Index and Comparative Fit Index served as measures of relative fit to ascertain how parsimoniously the model fit the data in comparison to other models.Data from all subjects were used but brain sizes for all regions could not be ascertained with confidence in every subject. Thus, the number of subjects for analysis were 21 abuse subjects/16 comparison subjects for hippocampus and amygdala, 23 abuse subjects/16 comparison subjects for corpus callosum, and 21 abuse subjects/15 comparison subjects for frontal cortex gray matter volume. Path analysis evaluated associations between morphometric measures and density of abuse during each stage. Density of abuse was used instead of presence or absence of abuse during each stage, as Amos Graphics cannot use simple dichotomous variables, and density of abuse was the simplest acceptable alternative.RESULTS Multiple regression analysis identified three variables that were significantly associated with hippocampal volume (overall r=0.837, adjusted r 2 =0.580, F=5.84, df=10, 25, p<0.0001; Table 2 ). Density of abuse at index stage 3–5 years old (p<0.0004) was associated with reduced volume. List recall (p 0.10). This covariate did not compensate for group differences but reduced the degree of scatter between subjects in both groups. A measure of list recall was also found to be highly correlated with hippocampal volume by Tischler et al. 42 While including list recall in the multiple regression analysis enhanced goodness of fit, and is appropriate, the same basic results were obtained without this covariate (e.g., overall correlation: r=0.740, p=0.006; density of abuse stage 3–5 years old: β=-0.535, p=0.004). TABLE 2. Multiple Regression Analysis Indicating Relationship between Measures of Regional Brain Size and Density of Abuse During Different StagesTABLE 2. Multiple Regression Analysis Indicating Relationship between Measures of Regional Brain Size and Density of Abuse During Different StagesEnlarge tableMultiple regression analysis failed to identify any index stage that was associated with a significant effect on the total volume of the amygdala. Two variables were associated with reduced callosal area (r=0.691, adjusted r 2 =0.321, F=3.05, df=9, 30, p<0.01). These were midsagittal area (p<0.002) and density of abuse at index stage 9–10 years old (p=0.03). Multiple regression analysis identified two variables that were associated with frontal cortex gray matter volume (r=0.793, adjusted r 2 =0.512, F=5.08, df=9, 26, p<0.001). The first was total gray matter volume (p<0.0001) and the second was density of abuse at index stage 14–16 years old (p 0.1). Hippocampal volume was significantly influenced by density of abuse at stages 3–5 years old (p<0.0001) and 11–13 years old (p<0.05). Corpus callosum was influenced by density of abuse at 9–10 years old (p<0.005) and frontal cortex gray matter volume was influenced by abuse at 14–16 years old (p<0.005). There was also a strong tendency for abuse (or lack of abuse) to carry over from one stage to another until age 13 (p 0.30) with a reasonable degree of parsimony (Tucker-Lewis=0.94 and Comparative Fit Index=0.96). FIGURE 1. Path Analysis Indicating Relationships Between Density of Abuse During Different Stages of Development and Measures of Brain Size Derived from Structural Equation ModelingPath analysis examined two main components. The first was that childhood sexual abuse or absence of abuse during one period would predict childhood sexual abuse (or absence of abuse) during the subsequent period. The second component examined the association between density of childhood sexual abuse during each stage and all morphometric measures. Numerical values represent standardized beta-weights and their associated p values. Light gray lines were evaluated in the model but were not significantly predictive of any relationship between the variables. Morphometric measures for corpus callosum and frontal cortex gray matter volume were covaried by midsagittal area and total gray matter volume, respectively. Hippocampal volume was covaried by intracranial volume and list recall, based on results of the multiple regression analyses (see Table 2).a p<10 −7b p<0.05 c p<0.005 d p 0.90). Hence, it seems unlikely that morphometric effects related to childhood sexual abuse during specific stages were an artifact of differential exposure to other forms of maltreatment. Childhood abuse has been associated with vulnerability to a host of psychiatric disorders and behavioral problems. Based on the present findings there may be different abuse-related syndromes associated with particular ages of abuse and specific regional brain changes. For example, we found using regression analysis that current symptoms of depression on the Kellner Symptom Questionnaire 50 were specifically associated with abuse during stage 3–5 years old (r=0.459, p=0.001), but with no other stage. In contrast, PTSD-like symptoms as measured by the revised Mississippi Civilian PTSD scale 51 were only associated with abuse during stage 9–10 years old (r=0.349, p=0.02). It will be useful in future studies to ascertain if a sensitive period approach can more specifically delineate morphometric changes associated with psychopathology. Identifying sensitive periods may also provide insight into key ages at which stimulation or environmental enrichment may optimally benefit the development of specific brain regions. Theoretically, periods of maximal sensitivity to early stress could occur during phases of rapid development, during times of high plasticity, or during times when systems are programmed to establish enduring set-points. 52Received November 21, 2006; revised April 25, 2007; accepted May 10, 2007. Drs. Andersen, Tomada, and Teicher are affiliated with the Department of Psychiatry at Harvard Medical School; Drs. Andersen, Tomada, Valente, Polcari, and Teicher are affiliated with the Developmental Biopsychiatry Research Program at McLean Hospital in Belmont, Mass.; Ms. Vincow is affiliated with the Graduate Program in Neurobiology and Behavior at the University of Washington in Seattle, Wash. Address correspondence t