Neurostructural imaging findings in children with post-traumatic stress disorder: Brief review

Child maltreatment has been associated with different psychiatric disorders. Studies on both animals and humans have suggested that some brain areas would be directly affected by severe psychological trauma. The pathophsysiology of post-traumatic stress disorder (PTSD) appears to be related to a complex interaction involving genetic and environmental factors. Advanced neuroimaging techniques have been used to investigate neurofunctional and neurostructural abnormalities in children, adolescents, and adults with PTSD. This review examined structural brain imaging studies that were performed in abused and traumatized children, and discusses the possible biological mechanisms involved in the pathophysiology of PTSD, the implications and future directions for magnetic resonance imaging (MRI) studies. Published reports in refereed journals were reviewed by searching Medline and examining references of the articles related to structural neuroimaging of PTSD. Structural MRI studies have been performed in adults and children to evaluate the volumetric brain alterations in the PTSD population. In contrast with studies involving adults, in which hippocampus volumetric reduction was the most consistent finding, studies involving children and adolescents with PTSD have demonstrated smaller medial and posterior portions of the corpus callosum.     

Developmental psychobiology and response to threats: relevance to trauma in children and adolescents.

Interest in developmental and psychobiological aspects of trauma has grown with recent research in adults with mood and anxiety disorders reporting histories of trauma during childhood. Studies conducted directly in children and adolescents could add much to ongoing research in this area. This review summarizes data in three areas of developmental science that might inform future studies. First, the review briefly summarizes current data on clinical aspects of trauma in juveniles, focusing on associations with psychopathology and moderators of outcome. Second, the review summarizes data from the basic sciences delineating experiential and developmental changes in brain systems involved in threat perception and response. This review incorporates knowledge gained from research examining the effects of rearing manipulations on regulation of the stress response in rodents and primates. Third, the review summarizes data from cognitive neuroscience studies among both adults and children, again focusing on studies examining aspects of the threat response. This summary includes a review from studies in patients with posttraumatic stress disorder.     

Dissociation in children and adolescents as reaction to trauma--an overview of conceptual issues and neurobiological factors

The discovery of trauma as an aetiological factor in mental dissociation is more than a century old, but neurobiological research in the last decade has started to clarify a neurobiological basis that may shed light on the complex symptomatology observed in traumatized children. Dysfunctional stress responses, emotional-based style of functioning, hyperarousal, anxiety, irritability, impulsivity, disengaged attention and educational underachievement may thus begin to be better understood. The aim of this overview is to give an update on the concept of dissociation and the links to new neurobiological findings, hopefully to reduce unawareness, wrong diagnostics or even neglect of dissociative symptomatology by clinicians in child and adolescent psychiatry in the Nordic countries. A systematic overview of studies of mental dissociation in children and adolescents published over the last decade disclosed a total of 1019 references; 309 papers regarding the concept of dissociation, memory, trauma and the neurobiological correlates were studied in detail. The assumption of a trauma-genic basis of dissociation is still most discussed in the literature. The importance of other childhood trauma in addition to sexual abuse is outlined, focusing on childhood interpersonal trauma. Recent research on traumatized children and adolescents has demonstrated some permanent neurochemical as well as functional and structural abnormalities in brain areas that are involved in the integrative process of cognition and memory. This research begins to clarify the cerebral basis and mechanisms for the trauma-related dissociation observed in dissociative (conversion) disorders, post-traumatic stress disorder (PTSD) and somatoform disorders. New perspectives on the nature of subcortical processes linking the phenomena of dissociation and traumatic experiences may have important implications for the understanding of dissociative disorders in children and adolescents. They may be regarded as complex environmentally induced developmental, supporting the view that PTSD and somatization disorders may be specific forms of dissociative processes to be categorized together with dissociative (conversion) disorders as "trauma-related dissociative disorders".     

Dissociation in children and adolescents as reaction to trauma – an overview of conceptual issues and neurobiological factors

The discovery of trauma as an aetiological factor in mental dissociation is more than a century old, but neurobiological research in the last decade has started to clarify a neurobiological basis that may shed light on the complex symptomatology observed in traumatized children. Dysfunctional stress responses, emotional-based style of functioning, hyperarousal, anxiety, irritability, impulsivity, disengaged attention and educational underachievement may thus begin to be better understood. The aim of this overview is to give an update on the concept of dissociation and the links to new neurobiological findings, hopefully to reduce unawareness, wrong diagnostics or even neglect of dissociative symptomatology by clinicians in child and adolescent psychiatry in the Nordic countries. A systematic overview of studies of mental dissociation in children and adolescents published over the last decade disclosed a total of 1019 references; 309 papers regarding the concept of dissociation, memory, trauma and the neurobiological correlates were studied in detail. The assumption of a trauma-genic basis of dissociation is still most discussed in the literature. The importance of other childhood trauma in addition to sexual abuse is outlined, focusing on childhood interpersonal trauma. Recent research on traumatized children and adolescents has demonstrated some permanent neurochemical as well as functional and structural abnormalities in brain areas that are involved in the integrative process of cognition and memory. This research begins to clarify the cerebral basis and mechanisms for the trauma-related dissociation observed in dissociative (conversion) disorders, post-traumatic stress disorder (PTSD) and somatoform disorders. New perspectives on the nature of subcortical processes linking the phenomena of dissociation and traumatic experiences may have important implications for the understanding of dissociative disorders in children and adolescents. They may be regarded as complex environmentally induced developmental, supporting the view that PTSD and somatization disorders may be specific forms of dissociative processes to be categorized together with dissociative (conversion) disorders as “trauma-related dissociative disorders”.     

Impact, psychological sequelae and management of trauma affecting children and adolescents

PURPOSE OF REVIEW: In this review we examine the most recent literature on the impact, psychological sequelae and management of trauma affecting children and adolescents. We focus on consequences of early traumatic events in childhood, adolescence and adulthood; mediating variables (risk and protective factors) intervention strategies and available treatments. RECENT FINDINGS: Increasingly often, mental health professionals are being asked to address the needs of children and adolescents who have been exposed to traumatic events, either as individuals or in groups. Studies on a wide range of age groups, populations and types of trauma revealed that traumatized children and adolescents are at high risk for developing a range of different behavioural, psychological and neurobiological problems. Social support may have a protective effect on the relationship between exposure to traumatic events and psychosocial symptoms. SUMMARY: Several recent studies analyze a wide range of early traumatic events that may be directly or indirectly experienced by youth. These studies raise many fundamental questions such as validity of current diagnostic criteria for post-traumatic stress disorder, comorbidity with anxiety, depressive disorders and childhood traumatic grief symptoms. Vulnerability and protective factors, mainly gender, age and social support are considered. A common problem in research into the impact of trauma on children is the presence of many limitations: studies are often retrospective, use self-report questionnaires and the results may not be generalizable (i.e. they are trauma or population specific). There is a lack of well designed studies, addressing in particular treatments for post-traumatic symptoms in children and adolescents.     

Salivary cortisol responses to dexamethasone in adolescents with posttraumatic stress disorder

OBJECTIVE: Previous studies of adults with posttraumatic stress disorder (PTSD) have found various abnormalities in the regulation of the hypothalamic-pituitary-adrenal axis, including enhanced suppression of cortisol following low-dose dexamethasone. The purpose of the present study was to investigate salivary cortisol responses to low-dose dexamethasone in adolescents with PTSD. METHOD: Forty-eight adolescents (20 with current PTSD, 9 trauma controls without PTSD, and 19 healthy nontraumatized controls) were enrolled in the study. On day 1, baseline saliva samples were obtained at 8 a.m. and 0.5 mg of dexamethasone was administered at 11 p.m. Cortisol and dexamethasone levels were assessed at 8 a.m. the following day. RESULTS: Adolescents with current PTSD showed no difference in the suppression of salivary cortisol in response to low-dose (0.5 mg) dexamethasone compared to trauma controls without PTSD and nontraumatized controls. More severely affected PTSD subjects with co-occurring major depression showed higher pre- and post-dexamethasone salivary cortisol levels compared to controls. CONCLUSIONS: The present study did not find evidence for enhanced suppression of salivary cortisol at 8 a.m. following low-dose dexamethasone in multiply traumatized adolescents with PTSD. This result differs from findings in adults with PTSD. Further investigations of hypothalamic-pituitary-adrenal axis abnormalities in traumatized children and adolescents are needed.     

Neuroimaging of childhood trauma

Childhood abuse is a major public health problem affecting as many as a third of children in this country today at some point before their 18(th) birthday. The effects of childhood trauma on the brain are increasingly an area of interest. In trying to understand the effects of early stressors on the brain we use animal models of early stress to guide the development of hypotheses. An important potential tool in understanding the effects of abuse on the brain is neuroimaging. Neuroimaging studies in traumatized children are in a relative state of infancy. A number of methodological and ethical issues make this a difficult area for research, including problems ranging from patient motion during scanning to the ethical issues of the duty to report abuse and working with child protective services. Some studies have shown that adults abused as children have smaller volume of the hippocampus, a brain area involved in learning and memory, as measured with magnetic resonance imaging (MRI). One study in children with posttraumatic stress disorder (PTSD) did not find smaller hippocampal volume, but did find smaller brain volume and corpus callosum. Functional neuroimaging studies are consistent with alteration in function and structure of medial prefrontal cortex and hippocampus in patients with childhood sexual trauma and PTSD. These initial results suggest that childhood abuse in the setting of PTSD is associated with long-term changes in brain structure and function.     

Autobiographical memory and trauma in adolescents

Several clinicians who work with traumatized children have noted that these children exhibit a poor autobiographical memory. The present study was a first attempt to subject this clinical impression to formal testing. Memory for autobiographical facts (i.e., semantic autobiographical memory) was assessed in 10 adolescents with an alleged history of trauma and 17 adolescents without such a background. Results suggest that traumatized adolescents, indeed, have more difficulty with semantic personal memory than non-traumatized adolescents. Implications of the present findings for future research on trauma and autobiographical memory in children and adolescents are discussed.     

Sleep problems in children and adolescents following traumatic life events

Rates of childhood trauma exposure are extremely high, with approximately 70% of children and adolescents experiencing at least one traumatic event. Among the most common non-specific consequences of stress and trauma are disruptions of sleep. Sleep problems, such as shorter sleep duration, difficulty falling asleep, frequent awakenings, nightmares, sleepless nights, and early-morning wakefulness appear to have a higher prevalence among children and adolescents following traumatic events. This review will illustrate the role of sleep problems in traumatized children and adolescents, and emphasize the need to consider a wide range of etiological mechanisms for these symptoms. However, the relationship of trauma exposure to sleep problems among children and adolescents needs further investigation in future research. Moreover, in view of the adverse consequences of long-term disrupted sleep on mental health outcomes following trauma, the need to effectively address sleep disturbances in traumatized children and adolescents is crucial.     

Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder

ObjectiveThe neurophysiological basis of bipolar disorder in youths remains poorly understood. Neurofunctional and neuropathologic studies have implicated the amygdala as a primary brain structure involved in the regulation of emotion. Because one of the cardinal features of bipolar disorder is mood dysregulation, structural and functional amygdala abnormalities identified with neuroimaging may serve as useful disease and treatment response biomarker. Therefore, we conducted a meta-analysis summarizing the literature examining amygdala size obtained from magnetic resonance imaging in bipolar youths and adults.MethodA literature search using the National Institutes of Health's PubMed was conducted to identify published peer-reviewed neuroimaging studies of amygdala size in children, adolescents, and adults with bipolar disorder. Eleven studies that met inclusion and exclusion criteria were identified.ResultsSmaller amygdala volumes were found in children and adolescents with bipolar disorder compared with the control children and adolescents (standardized mean difference −0.74; 95% confidence interval −1.36 to −0.15). Amygdala volumes in bipolar adults were not significantly different from the control adults (standardized mean difference 0.20; 95% confidence interval −0.31 to 0.73).ConclusionsThe results of this meta-analysis suggest that structural amygdala abnormalities are present in bipolar youths but that these structural differences do not seem to be present in bipolar adults. Future studies examining whether structural, functional, and neurochemical amygdala differences between bipolar and control youths may be useful as age-specific biomarkers of illness and treatment response are needed.     

Mixed lateral preference in posttraumatic stress disorder

Recent research indicates that adults with posttraumatic stress disorder (PTSD) have a higher incidence of mixed laterality with respect to handedness than the rest of the population. To test if this relationship also occurs early in life, we evaluated children with history of interpersonal trauma. Fifty-nine traumatized children were evaluated with the Clinician Administered PTSD Scale for Children and Adolescents and the Edinburgh Handedness Inventory. Forty matched healthy controls were used for comparison. Increased mixed laterality was found in all children exhibiting symptoms of PTSD when compared with healthy controls, and children who met DSM-IV diagnostic criteria for PTSD had more mixed laterality than the subthreshold traumatized group (F = 7.71; df = 2,96; p = 0.001). Within the entire traumatized group, there was a positive correlation between PTSD symptom severity and mixed laterality. Mixed laterality was positively associated with PTSD symptoms in traumatized children, suggesting that neurological abnormalities may be related to degree of PTSD symptom expression.     

Limbic structures and networks in children and adolescents with schizophrenia

Studies of adults with schizophrenia provide converging evidence for abnormalities in the limbic system. Limbic structures that show consistent patient/control differences in both postmortem and neuroimaging studies include the anterior cingulate and hippocampus, although differences in the amygdala, parahippocampal gyrus, and fornix have also been observed. Studies of white matter in children and adolescents with schizophrenia tend to show findings that are more focal than those seen in adults. Interestingly, these focal abnormalities in early-onset schizophrenia tend to be more localized to limbic regions. While it is unclear if these early limbic abnormalities are primary in the etiology of schizophrenia, there is evidence that supports a developmental progression with early limbic abnormalities evolving over time to match the neuroimaging profiles seen in adults with schizophrenia. Alternatively, the aberrations in limbic structures may be secondary to a more widespread or global pathological processes occurring with the brain that disrupt neural transmission. The goal of this article is to provide a review of the limbic system and limbic network abnormalities reported in children and adolescents with schizophrenia. These findings are compared with the adult literature and placed within a developmental context. These observations from neuroimaging studies enrich our current understanding of the neurodevelopmental model of schizophrenia and raise further questions about primary vs secondary processes. Additional research within a developmental framework is necessary to determine the putative etiologic roles for limbic and other brain abnormalities in early-onset schizophrenia.     

The relationship of gender and trauma characteristics to posttraumatic stress disorder in a community sample of traumatized northern plains American Indian adolescents and young adults

OBJECTIVE: Previous studies have identified a high prevalence (25%-80%) of trauma among American Indian and non-American Indian adolescents and adults. However, only a fraction of traumatized individuals develop posttraumatic stress disorder (PTSD). This article examines the relationships of gender and trauma characteristics to a diagnosis of PTSD among a community sample of traumatized American Indian adolescents and young adults. METHOD: Complete data were collected from 349 American Indians aged 15 to 24 years who participated in a cross-sectional community-based study from July 1997 to December 1999 and reported experiencing at least 1 traumatic event. Traumatic events and PTSD were assessed using a version of the Composite International Diagnostic Interview. Logistic regression determined the relationships of gender, trauma type, age at first trauma, and number of traumas to the development of PTSD. RESULTS: Forty-two participants (12.0% of those who experienced a traumatic event) met criteria for lifetime PTSD. While all 4 of the independent variables noted above demonstrated univariate associations with PTSD, multivariate logistic regression analyses indicated that only experiencing a sexual trauma (odds ratio [OR] = 4.45, 95% confidence interval [CI] = 1.76 to 11.28) and having experienced 6 or more traumas (OR = 2.53, 95% CI = 1.06 to 6.04) were independent predictors of meeting criteria for PTSD. CONCLUSION: American Indian children and adolescents who experience sexual trauma and multiple traumatic experiences may be at particularly high risk for developing PTSD.     

Fronto-limbic brain abnormalities in juvenile onset bipolar disorder.

BACKGROUND: Advances in brain imaging techniques and cognitive neuropsychology have brought new possibilities for the in vivo study of the pathophysiology of neuropsychiatric disorders, including bipolar disorder (BD). Recently, such studies have been extended to the pediatric age range. Here we review the neuroimaging and neuropsychological studies conducted in BD children and adolescents. METHODS: A review of the peer-reviewed published literature was conducted in Medline for the period of 1966 to April 2005. RESULTS: Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) studies suggest abnormalities in fronto-limbic structures in pediatric BD patients, similar to those found in adults. A notable exception in pediatric BD patients is smaller amygdala volumes compared to healthy controls, contrary to what has been reported in most adult studies. CONCLUSIONS: Further research evaluating children and adolescents is needed to study the normal neurodevelopmental process and to answer how and when the illness processes that result in bipolar disorder exert their effects on the developing brain.     

Neuroimaging of emotional brain circuitry in bipolar disorder

Abnormalities in the regulation of emotion and motivational behavior are core features of bipolar disorder (BD) implicating the brain structures that subserve these functions. Converging neuroimaging evidence supports the involvement in BD of a neural system comprised of ventral prefrontal cortex, amygdala, and ventral striatum. Neuroimaging studies demonstrate abnormalities in both the structure and function of these brain regions. Findings in amygdala and ventral striatum in adolescents with BD suggest a neurodevelopmental trajectory for the appearance of regional abnormalities in this neural system. Preliminary studies suggest that mood-stabilizing medications may provide beneficial effects for the structure and functioning of this circuitry. New research directions, including those that integrate genetic studies with neuroimaging research, may provide important insights into the pathophysiologic mechanisms contributing to BD, and point to new strategies for its detection and treatment.     

Primary headache pathophysiology in children: The contribution of clinical neurophysiology

Although primary headaches are very prevalent also in pediatric age, most neurophysiologic studies in these diseases concerned only the adulthood. The neurophysiologic investigation of the pathophysiological mechanisms subtending migraine and tension-type headache in children and adolescents could be particularly interesting, since during the developmental age the migrainous phenotype is scarcely influenced by many environmental factors that can typically act on adult headache patients. The neurophysiologic abnormality most frequently found in adult migraineurs, that is the reduced habituation of evoked potentials, was confirmed also in migraine children, although it was shown to involve also children with tension-type headache. Some studies showed abnormalities in the maturation of brain functions in migraine children and adolescents. While the visual system maturation seems slowed in young migraineurs, the psychophysiological mechanisms subtending somatosensory spatial attention in migraine children are more similar to those of healthy adults than to those of age-matched controls. There are some still unexplored fields that will have to be subjects of future studies. The nociceptive modality, which has been investigated in adult patients with primary headaches, should be studied also in pediatric migraine. Moreover, the technique of transcranial magnetic stimulation, not yet used in young migraineurs, will possibly provide further elements about brain excitability in migraine children.     

The age-dependent effects of selective serotonin reuptake inhibitors in humans and rodents: A review

The selective serotonin reuptake inhibitor (SSRI) Prozac® (fluoxetine) is widely prescribed for the treatment of depression and anxiety-related disorders. While extensive research has established that fluoxetine is safe for adults, safety is not guaranteed for (unborn) children and adolescents. Some clinical studies have reported adverse outcomes, such as premature birth, neonatal cardiovascular abnormalities, and pulmonary hypertension in children whose mothers used SSRIs during pregnancy. In addition, several reports show that adolescent fluoxetine treatment increases risk for suicidal behavior. Despite these studies, fluoxetine is not contraindicated in the treatment of depressed pregnant women and adolescents. Longitudinal research in humans is limited because of ethical reasons and time constraints, and to overcome these limitations, rodents are used to increase insight in the age-dependent effects of fluoxetine exposure. It has been established that neonatal and adolescent fluoxetine exposure leads to paradoxical anxiety- and depression-like features in later life of rats and mice, although in some studies adolescent fluoxetine exposure was without effects. These age-dependent outcomes of fluoxetine may be explained by serotonin's neurotrophic effects, which may vary according to the developmental stage of the brain due to epigenetic modifications. Here we review the existing evidence for the age-dependent effects of fluoxetine in humans and rodents, address the gaps in our current knowledge and propose directions for future research. Given the overlap between human and rodent findings, rodents provide heuristic value in further research on the age-dependent effects of SSRIs.     

Brain anatomy and development in autism: review of structural MRI studies

Autism is a neurodevelopmental disorder that severely disrupts social and cognitive functions. MRI is the method of choice for in vivo and non-invasively investigating human brain morphology in children and adolescents. The authors reviewed structural MRI studies that investigated structural brain anatomy and development in autistic patients. All original MRI research papers involving autistic patients, published from 1966 to May 2003, were reviewed in order to elucidate brain anatomy and development of autism and rated for completeness using a 12-item check-list. Increased total brain, parieto-temporal lobe, and cerebellar hemisphere volumes were the most replicated abnormalities in autism. Interestingly, recent findings suggested that the size of amygdala, hippocampus, and corpus callosum may also be abnormal. It is conceivable that abnormalities in neural network involving fronto-temporo-parietal cortex, limbic system, and cerebellum may underlie the pathophysiology of autism, and that such changes could result from abnormal brain development during early life. Nonetheless, available MRI studies were often conflicting and could have been limited by methodological issues. Future MRI investigations should include well-characterized groups of autistic and matched healthy individuals, while taking into consideration confounding factors such as IQ, and socioeconomic status.