Premature birth an indicator of disorder laterby Heather WoolwinePublic Relations This article is the third in a series of four on the 2004 Update in Psychiatry held June 4 and 5. Two percent of all live births in the United States are those of premature infants, or babies whose birth weight dips below 1,500 grams. Although survival rates for those children are at 85 percent, evidence discovered in the last several years notes that not only do these babies handle stress differently than their full-term counterparts, but that stress related to a premature birth may result in an increased risk for psychiatric and/or cognitive disturbances later in life. Rates of anxiety disorders, attention problems, thought disturbances, impairments in social skills, and learning problems are much higher than in the general population, and intelligence on average is lower than population means. Bradley S. Peterson, M.D., Suzanne Crosby Murphy associate professor in pediatric neuropsychiatry and MRI research director, Columbia University College of Physicians and Surgeons, presented a series of neuroimaging studies related to the topic at the 2004 Update in Psychiatry on June 5. His October 2000 study, a first in quantitative MRI research of the long-term outcome of regional brain volumes in pre-term infants, sought to determine whether regional brain volumes differ between term and pre-term children and the association of regional brain volumes in premature children with long-term cognitive outcomes. Twenty-five 8-year-old pre-term children were recruited from a longitudinal follow-up study of pre-term infants and compared to 39 full-term children recruited from the community. All the children were comparable in age, sex, maternal education and minority status. Peterson and his colleagues found the pre-term children had significantly smaller regional cortical volumes most predominately in the sensorimotor regions, and those volumes were positively associated with full-scale, verbal, and performance IQ scores. Thus, they concluded pre-term birth is associated with regionally specific, long-term reductions in brain volume and that morphological abnormalities are in turn associated with poorer cognitive outcome. But while these abnormalities were now described, Peterson and his fellow researchers wanted direct evidence that demonstrated abnormal neural processing in pre-term children existed. Their aim in this second study was to compare brain activity associated with phonologic and semantic processing of language between full-term and pre-term children using functional magnetic resonance imaging (fMRI). During a passive language task, fMRI scans for 26 pre-term children and 13 full-term children were acquired. The study found pre-term children with the poorest language comprehension didn’t fully engage normal semantic processing pathways in a language comprehension task. Instead, these children engaged in pathways that full-term children used to process meaningless phonologic sounds. Peterson concluded that aberrant processing of semantic content in pre-term children may account in part for their lower verbal IQ scores. Peterson concluded his discussion with a study that enveloped all of his research of the anatomical and functional consequences of pre-term birth for human brain development. “We do not know the pathophysiology or molecular mediators of the anatomical and functional brain disturbances of pre-term birth,” Peterson said. “Hypoxia-ischemia likely plays a prominent role in generating brain abnormalities in at least some of these children, probably by disrupting the timing and complex orchestration of brain maturational events variably across brain regions. Sensorimotor, parietal, and temporal brain regions seem to be particularly vulnerable. “Knowledge of the location of anatomical disturbances in the brains of pre-term infants may suggest new therapeutic strategies to help prevent the development of these disturbances and preserve the functional capacities that these regions presumably subserve. However, identification of the physiological and molecular mediators of these disturbances will be necessary if we are ever able to develop full effective prevention or early intervention strategies for the adverse consequences of pre-term birth on human brain development. “Developing safe and better preventions for the anatomical, functional, and behavioral abnormalities of pre-term birth will require further improvements in our animal models for prematurity, better knowledge of the molecular mediators that produce these abnormalities, and careful monitoring of the effects of our interventions on those molecular pathways through the brain. This program of research will require a concerted, close collaboration of basic scientists and clinicians who will take knowledge from the bench to the bedside and back again.” Does Stress Damage the Brain?
“Our group has followed up preclinical studies showing that stress is associated with changes in hippocampal morphology and memory deficits by applying these findings to patients with exposure to extreme stress and the diagnosis of posttraumatic stress disorder (PTSD),” Bremner said. “These studies are beginning to map out a neural circuitry of PTSD.” Bremner presented evidence for an association between stress and damage in the brain including: stress is associated with hippocampal neuronal damage in multiple animal species and stress causes hippocampal-based memory deficits in animal studies; increased glucocorticoids (cortisol), decreased brain deprived neurotrophic factor (BDNF), and decreased neuronal growth (neurogenesis) all reflect stress-induced damage; and stress and PTSD in human subjects are associated with hippocampal volume reduction, visible by MRI and memory deficits. But not to neglect the other side of the argument, Bremner also said that some studies in primates did not support an association between direct cortisol exposure and damage; studies in humans are cross sectional and do not confer causality, and there is possible genetic vulnerability (smaller hippocampal volume and poor memory at birth) that may increase the risk for PTSD following a stressful event. According to Bremner, evidence suggests that stress results in decreased hippocampal volume, and developmental studies show that an enriched environment can promote hippocampal neurogen-esis, a phenomenon also observed during the course of antidepressant treatment in adults. In addition, Bremner and his colleagues found deficits in verbal memory in patients suffering from combat-related PTSD, as well as decreased right hippocampal volume. Similar results were found in women suffering from depression who were also victims of childhood sexual abuse. In abused women, PTSD symptom severity correlated with impaired memory. Those who experienced disassociative states were among this classification. In animal models, CRF (corticotopin releasing factor) also played an important role in the stress response, as exposure to stress is associated with increased levels of CRF and central CRF administration is associated with fear-related behaviors (decreased exploration, increased startle, and decreased grooming). Other aspects of Bremner’s presentation included results of norepinephrine (NE) and PTSD, specifically that NE played a critical role in “fight or flight” response. Elevated NE results in increased heart rate and blood pressure and increased attention during stress, and increased NE in patients with PTSD results in increased symptoms which are associated with decreased medial prefrontal (orbitofrontal) and hippocampal metabolism. He noted that tryptophan depletion in depression is evidenced through multiple studies that demonstrate decreased prefrontal function at baseline in depression. Acute tryptophan depletion is associated with reduction in brain serotonin. Brain function in patients with treated major depression who had a depressive relapse when given tryptophan was compared to brain function in those who did not, and decreased orbitofrontal cortical metabolism was demonstrated in the patients with tryptophan-depletion- induced depressive relapse. Lastly, Bremner mentioned preclinical studies that showed a reduction
in benzodiazepine receptor binding in the prefrontal cortex and hippocampus
with both acute and chronic stress, suggesting that benzodiazepines are
efficacious in the treatment of stress-induced anxiety disorders.
Friday, July 2, 2004
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