Faculty Bibliography

This paper follows the preclinical work on the effects of stress on neurobiological and neuroendocrine systems and provides a comprehensive working model for understanding the pathophysiology of posttraumatic stress disorder (PTSD). Studies of the neurobiology of PTSD in clinical populations are reviewed. Specific brain areas that play an important role in a variety of types of memory are also preferentially affected by stress, including hippocampus, amygdala, medial prefrontal cortex, and cingulate. This review indicates the involvement of these brain systems in the stress response, and in learning and memory. Affected systems in the neural circuitry of PTSD are reviewed (hypothalamic-pituitary-adrenal axis (HPA-axis), catecholaminergic and serotonergic systems, endogenous benzodiazepines, neuropeptides, hypothalamic-pituitary-thyroid axis (HPT-axis), and neuro-immunological alterations) as well as changes found with structural and functional neuroimaging methods. Converging evidence has emphasized the role of early-life trauma in the development of PTSD and other trauma-related disorders. Current and new targets for systems that play a role in the neural circuitry of PTSD are discussed. This material provides a basis for understanding the psychopathology of stress-related disorders, in particular PTSD.

This paper reviews the preclinical literature related to the effects of stress on neurobiological and neuroendocrine systems. Preclinical studies of stress provide a comprehensive model for understanding neurobiological alterations in post-traumatic stress disorder (PTSD). The pathophysiology of stress reflects long-standing changes in biological stress response systems and in systems involved in stress responsivity, learning, and memory. The neural circuitry involved includes systems mediating hypothalamic-pituitary-adrenal (HPA) axis, norepinephrine (locus coeruleus), and benzodiazepine, serotonergic, dopaminergic, neuropeptide, and central amino acid systems. These systems interact with brain structures involved in memory, including hippocampus, amygdala, and prefrontal cortex. Stress responses are of vital importance in living organisms; however excessive and/or repeated stress can lead to long-lasting alterations in these circuits and systems involved in stress responsiveness. Intensity and duration of the stressor, and timing of the stressor in life, have strong impact in this respect.

Childhood abuse is an important public health problem; however, little is known about the effects of abuse on the brain and neurobiological development. This article reviews the behavioral and biological consequences of childhood abuse and places them in a developmental context. Animal studies show that both positive and negative events early in life can influence neurobiological development in unique ways. Early stressors such as maternal separation result in lasting effects on stress-responsive neurobiological systems, including the hypothalamic-pituitary-adrenal (HPA) axis and noradrenergic systems. These studies also implicate a brain area involved in learning and memory, the hippocampus. in the long-term consequences of early stress. Clinical studies of patients with a history of abuse also implicate dysfunction in the HPA axis and the noradrenergic and hippocampal systems; however, there are multiple questions related to chronicity of stress, developmental epoch at the time of the stressor, presence of stress-related psychiatric disorders including posttraumatic stress disorder and depression. and psychological factors mediating the response to trauma that need to be addressed in this field of research. Understanding the effects of abuse on the development of the brain and neurobiology will nevertheless have important treatment and policy implications.

Research on the effects of childhood trauma has been limited by the lack of a comprehensive, reliable, and valid instrument that assesses the occurrence of early traumatic experiences. This paper presents the development and preliminary psychometric properties of an instrument, the Early Trauma Inventory (ETI), for the assessment of reported childhood trauma. The clinician-administered ETI is a 56-item interview for the assessment of physical, emotional, and sexual abuse, as well as general traumatic experience (including items which range from parental loss to natural disaster). For each item of the ETI, frequency of abuse/trauma by developmental stage, onset and termination of abuse/trauma, perpetrator of the abuse/trauma, and impact on the individual are assessed. Initial analyses indicate acceptable inter-rater reliability, test-retest reliability, and internal consistency for the ETI. Comparisons between the ETI and other instruments for the assessment of trauma, as well as instruments for the measurement of symptoms related to abuse, such as dissociation and PTSD, demonstrated good convergent validity. Validity was also demonstrated based on the ability of the ETI to discriminate patients with PTSD from comparison subjects. Based on these findings, the ETI appears to be a reliable and valid instrument for the measurement of reported childhood trauma.

A patient with central pontine myelinolysis (CPM) underwent neurological and mental status examination, as well as neuropsychological testing, during the acute stage of the disease. After correction of the hyponatremia, a gross change in his neuropsychiatric status was observed. The patient underwent extensive neurological, psychiatric, and neuropsychological testing during the acute phase of the disease and at follow-up 4 months later. All major neurological and neuropsychiatric symptoms present at onset were fully reversible. Neuropsychological examination revealed deficits in the domains of attention and concentration, short-term memory and memory consolidation, visual motor and fine motor speeds, and learning ability. Although improved, neuropsychological testing still revealed remarkable deficits at follow-up. We conclude that neuropsychological deficits can accompany CPM, and that these deficits do not necessarily diminish simultaneously with the radiological or clinical neurological findings but may persist for a longer period of time, or even become permanent. In his recovery the patient started to manifest new neurological symptoms consisting of a mild resting tremor of both hands and slow choreoathetotic movements of the trunk and the head, which we considered to be late neurological sequelae of CPM. The significance of CPM in the differential diagnosis of acute behavioral changes after correction of hyponatremia is stressed, even if correction is achieved slowly and carefully.

Although positron emission tomography (PET) provides important physiological information, a major limitation of this technique is poor anatomical resolution. Combining the superior anatomical resolution of magnetic resonance imaging (MRI) with the physiologic information of PET could be an important advance for clinical and research applications of PET. The purpose of this study was to develop reliable methods for using MRI in the definition of brain regions of interest (ROIs) for application to coregistered PET brain images. First, specific criteria were developed for definition of ROIs on coregistered MRI using anatomical landmarks from a standard anatomical atlas. ROIs were then drawn by three independent raters using the criteria on 11 MRI scans, which had been coregistered to PET [(18)F]2-fluoro-2-deoxyglucose (FDG) brain scans. These MRI-based templates were used to determine activity in various brain regions on the PET scans, which were used in the determination of regional brain metabolic rates. There was a high level of agreement between raters for the measurement of regional metabolic rates, with intra-class correlation coefficients ranging from 0.63-0.98. These findings suggest that specific ROI criteria based on coregistered MRI are a reliable method of measuring activity from PET images. The use of a standard and widely available atlas and readily applicable criteria for ROIs should facilitate a standard method of measurement which can be applied in a similar manner at different PET sites.