Longitudinal associations between self-reported experiences of discrimination and depressive symptoms in young women and men post- myocardial infarction.

Objectives: Research suggests that following a myocardial infarction (MI), women under the age of 60 have more elevated depressive symptoms and adverse outcomes than similarly aged men. Identifying risk factors that contribute to gender differences in depressive symptoms among this group may be critical to the development of psychosocial interventions. Experiences of discrimination may be an important correlate of depressive symptoms in this group; however, studies of this relationship have largely been cross-sectional and focused on healthy populations. This study examines longitudinal associations among gender, discrimination, and depressive symptoms in a young post-MI cohort. Methods: Participants were 313 adults from the Myocardial Infarction and Mental Stress Ischemia Study 2 of young (≤60 yrs) post-MI patients. At baseline and 6 month follow-up, depressive symptoms were measured with the Beck Depression Inventory-II and discrimination was assessed with the 10-item version Everyday Discrimination scale. Linear regression models were used to assess the longitudinal association between reports of discrimination and depressive symptoms adjusted for sociodemographic characteristics, psychosocial factors and health status indicators and tested for gender differences. Results: The mean age was 51.2, 49.6% were women, and 69.5% were African-American. Although the discrimination-by-gender interaction was marginally significant (p=.09) in the fully adjusted model, findings suggest that the association between changes in reports of discrimination and depressive symptoms over time may be more pronounced for women (ß=.61, standard error=.15, p<.001) than men (ß=.27, standard error=.13, p=.033). Conclusion: Our findings suggest that discrimination is a risk factor for depressive symptoms in young post-MI populations over time.

Script-driven imagery of self-injurious behavior in patients with borderline personality disorder: a pilot FMRI study.

OBJECTIVE: Self-injurious behavior (SIB) is one of the most distinctive features of borderline personality disorder (BPD) and related to impulsivity and emotional dysregulation. METHOD: Female patients with BPD (n = 11) and healthy controls (n = 10) underwent functional magnetic resonance imaging while listening to a standardized script describing an act of self-injury. Experimental sections of the script were contrasted to the neutral baseline section and group-specific brain activities were compared. RESULTS: While imagining the reactions to a situation triggering SIB, patients with BPD showed significantly less activation in the orbitofrontal cortex compared with controls. Furthermore, only patients with BPD showed increased activity in the dorsolateral prefrontal cortex during this section and a decrease in the mid-cingulate while imagining the self-injurious act itself. CONCLUSION: This pattern of activation preliminary suggests an association with diminished emotion regulation, impulse control as well as with response selection and reappraisal during the imagination of SIB.

Heritability of flow-mediated dilation: a twin study.

BACKGROUND: Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker for early atherosclerotic vascular disease and future cardiovascular events. OBJECTIVE: To estimate the heritability of brachial artery FMD using a twin design. METHODS: We estimated the heritability of FMD using 94 middle-aged male twin pairs. FMD was measured by ultrasound, and traditional coronary heart disease risk factors were measured. Genetic modeling techniques were used to determine the relative contributions of genes and environment to the variation in FMD. RESULTS: The mean age of the twin participants was 54.9 +/- 2.8 years. The mean FMD was 0.047 +/- 0.030. The intraclass correlation coefficient was higher in MZ twins [0.38, 95% confidence interval (CI) 0.32-0.43] than in DZ twins (0.19, 95% CI 0.11-0.26), suggesting a role of genetic influence in FMD variation. Structural equation modeling showed that both genetic and unique environmental factors contributed significantly to the variation in FMD. The crude FMD heritability was 0.37 (95% CI 0.15-0.54). After adjustment for traditional cardiovascular risk factors, including age, total cholesterol, blood pressure, and body mass index, the heritability of FMD was 39% (95% CI 0.18-0.56). The remaining variation in FMD could be explained by individual-specific environment. CONCLUSION: This is the first study using twins to estimate the relative contributions of genetics and environment to the variation in FMD in a US population. Our results demonstrate a moderate genetic effect on brachial artery FMD, independent of traditional coronary risk factors. Our data also highlight the importance of unique environment on the variability in FMD.

Functional neuroimaging studies in posttraumatic stress disorder: review of current methods and findings.

Posttraumatic stress disorder (PTSD) is an anxiety disorder associated with changes in neural circuitry involving frontal and limbic systems. Altered metabolism in these brain structures after a traumatic event is correlated to PTSD. Developments in the field of neuroimaging have allowed researchers to look at the structural and functional properties of the brain in PTSD. Despite the relative novelty of functional imaging and its application to the field of PTSD, numerous publications have brought to light several of the circuits implied in this disorder. This article summarizes the findings with regard to PTSD in the functional imaging techniques of single-photon emission computed tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI). Furthermore, we discuss strengths and weaknesses of the various techniques and studies. Finally, we explore the future potential of functional neuroimaging studies in PTSD.

MR-based in vivo hippocampal volumetrics: 2. Findings in neuropsychiatric disorders.

Magnetic resonance imaging (MRI) has opened a new window to the brain. Measuring hippocampal volume with MRI has provided important information about several neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. Smaller hippocampal volumes have been reported in epilepsy, Alzheimer's disease, dementia, mild cognitive impairment, the aged, traumatic brain injury, cardiac arrest, Parkinson's disease, Huntington's disease, Cushing's disease, herpes simplex encephalitis, Turner's syndrome, Down's syndrome, survivors of low birth weight, schizophrenia, major depression, posttraumatic stress disorder, chronic alcoholism, borderline personality disorder, obsessive-compulsive disorder, and antisocial personality disorder. Significantly larger hippocampal volumes have been correlated with autism and children with fragile X syndrome. Preservation of hippocampal volume has been reported in congenital hyperplasia, children with fetal alcohol syndrome, anorexia nervosa, attention-deficit and hyperactivity disorder, bipolar disorder, and panic disorder. Possible mechanisms of hippocampal volume loss in neuropsychiatric disorders are discussed.

MR-based in vivo hippocampal volumetrics: 1. Review of methodologies currently employed.

The advance of neuroimaging techniques has resulted in a burgeoning of studies reporting abnormalities in brain structure and function in a number of neuropsychiatric disorders. Measurement of hippocampal volume has developed as a useful tool in the study of neuropsychiatric disorders. We reviewed the literature and selected all English-language, human subject, data-driven papers on hippocampal volumetry, yielding a database of 423 records. From this database, the methodology of all original manual tracing protocols were studied. These protocols differed in a number of important factors for accurate hippocampal volume determination including magnetic field strength, the number of slices assessed and the thickness of slices, hippocampal orientation correction, volumetric correction, software used, inter-rater reliability, and anatomical boundaries of the hippocampus. The findings are discussed in relation to optimizing determination of hippocampal volume.

Positron emission tomography in female patients with borderline personality disorder.

The pathology of Borderline personality disorder (BPD) is poorly understood and its biological basis remains largely unknown. One functional brain imaging study using [(18)F]Deoxyglucose-PET previously reported frontal and prefrontal hypometabolism. We studied brain metabolism at baseline in 12 medication-free female patients with BPD without current substance abuse or depression and 12 healthy female controls by [(18)F]Deoxyglucose-PET and statistical parametric mapping. We found significant frontal and prefrontal hypermetabolism in patients with BPD relative to controls as well as significant hypometabolism in the hippocampus and cuneus. This study demonstrated limbic and prefrontal dysfunction under resting conditions in patients with BPD by FDG-PET. Dysfunction in this network of brain regions, which has been implicated in the regulation of emotion, may underlie symptoms of BPD.

Cortisol response to a cognitive stress challenge in posttraumatic stress disorder (PTSD) related to childhood abuse.

Preclinical studies show that animals with a history of chronic stress exposure have increased hypothalamic-pituitary-adrenal (HPA) axis reactivity following reexposure to stress. Patients with posttraumatic stress disorder (PTSD) have been found to have normal or decreased function of the HPA axis, however no studies have looked at the HPA response to stress in PTSD. The purpose of this study was to assess cortisol responsivity to a stressful cognitive challenge in patients with PTSD related to childhood abuse. Salivary cortisol levels, as well as heart rate and blood pressure, were measured before and after a stressful cognitive challenge in patients with abuse-related PTSD (N=23) and healthy comparison subjects (N=18). PTSD patients had 61% higher group mean cortisol levels in the time period leading up to the cognitive challenge, and 46% higher cortisol levels during the time period of the cognitive challenge, compared to controls. Both PTSD patients and controls had a similar 66-68% increase in cortisol levels from their own baseline with the cognitive challenge. Following the cognitive challenge, cortisol levels fell in both groups and were similar in PTSD and control groups. PTSD patients appeared to have an increased cortisol response in anticipation of a cognitive challenge relative to controls. Although cortisol has been found to be low at baseline, there does not appear to be an impairment in cortisol response to stressors in PTSD.

Are the neural substrates of memory the final common pathway in posttraumatic stress disorder (PTSD)?

A model for the posttraumatic stress disorder (PTSD) as a disorder of memory is presented drawing both on psychological and neurobiological data. Evidence on intrusive memories and deficits in declarative memory function in PTSD-patients is reviewed in relation to three brain areas that are involved in memory functioning and the stress response: the hippocampus, amygdala, and the prefrontal cortex. Neurobiological studies have shown that the noradrenergic stress-system is involved in enhanced encoding of emotional memories, sensitization, and fear conditioning, by way of its effects on the amygdala. Chronic stress also affects the hippocampus, a brain area involved in declarative memories, suggesting that hippocampal dysfunction may partly account for the deficits in declarative memory in PTSD-patients. Deficits in the medial prefrontal cortex, a structure that normally inhibits the amygdala, may further enhance the effects of the amygdala, thereby increasing the frequency and intensity of the traumatic memories. Thus, by way of its influence on these brain structures, exposure to severe stress may simultaneously result in strong emotional reactions and in difficulties to recall the emotional event. This model is also relevant for understanding the distinction between declarative and non-declarative memory-functions in processing trauma-related information in PTSD. Implications of our model are reviewed.

Increased pituitary and adrenal reactivity in premenopausal women with posttraumatic stress disorder.

BACKGROUND: Limited studies of hypothalamic-pituitary-adrenal axis regulation in posttraumatic stress disorder have been performed in premenopausal women. We therefore undertook a study of hypothalamic-pituitary-adrenal axis regulation in this population. METHODS: Outpatient posttraumatic stress disorder subjects were compared with healthy, age- and weight-matched nontraumatized subjects. Subjects were free from psychotropic medications, alcohol and other illicit substances for at least 4 weeks before study. Menstrual cycle phase was determined by monitoring the LH surge and plasma progesterone levels. Corticotropin releasing factor and adrenocorticotropin stimulation tests, as well as 24-hour urinary-free cortisol measurements were performed. RESULTS: Corticotropin releasing factor test: Baseline adrenocorticotropic hormone and cortisol levels did not differ between the 12 PTSD and 11 comparison subjects, but the posttraumatic stress disorder group had greater adrenocorticotropic hormone and cortisol responses to corticotropin releasing factor, as well as a later cortisol peak. Adrenocorticotropic hormone test: Baseline cortisol levels did not differ between the 10 posttraumatic stress disorder subjects and seven controls, but the posttraumatic stress disorder group showed greater cortisol responses to adrenocorticotropic hormone. Peak cortisol responses to corticotropin releasing factor and adrenocorticotropic hormone were correlated with each other and with 24-hour urinary-free cortisol excretion. CONCLUSIONS: Pituitary and adrenal hyperreactivity to exogenous corticotropin releasing factor and adrenocorticotropic hormone is demonstrated in premenopausal women with chronic posttraumatic stress disorder. Cortisol hyperreactivity thus may play a role in the pathophysiology of posttraumatic stress disorder in women.

Gender differences in cognitive and neural correlates of remembrance of emotional words.

Studies suggest that men and women have important differences in specific cognitive functions. Men show superior spatial memory and women demonstrate superior verbal memory, and women rely on emotional content to a greater degree in the processing of information. In spite of extensive research in neural correlates of human cognition, little is known about possible gender differences or the role of emotional content in the mediation of cognition. Two sets of lists of word pairs were developed, one with neutral (e.g., school-grocery) and the other with emotional (e.g., mutilate-beat) content. Male and female subjects were asked to rate emotions related to the words on several dimensions (e.g., nervous, fearful, happy). In a second experiment, men and women underwent positron emission tomographic (PET) measurement of brain blood flow during retrieval of word pairs. Words in the "emotional" category were rated more highly on the emotional dimensions, and women rated them as having more emotional impact than did the men. During retrieval of emotional words (but not neutral words) there was a different pattern of activation among the women compared with the men, with greater activation in bilateral posterior hippocampus and cerebellum, and decreased activity in medial prefrontal cortex, which are brain areas previously implicated in emotion. There were no significant differences in retrieval of emotional versus neutral words, or in differences in memory performance between men and women. The findings suggest differences in cognitive appraisal and involvement of a broader network of brain regions mediating emotion during remembrance of emotional words in women compared with men.

Cerebrospinal fluid corticotropin-releasing hormone in healthy humans: effects of yohimbine and naloxone.

CRH neurons projecting from the paraventricular nucleus (PVN) of the hypothalamus to the median eminence control hypothalamic-pituitary-adrenal (HPA) axis activity. However, CRH neurons outside the PVN as well as PVN neurons projecting to sites other than the median eminence also contribute to the stress response and may play a role in mood and anxiety disorders. We have attempted to investigate possible noradrenergic and opioid regulation of these non-HPA CRH neurons. We hypothesized that yohimbine (an alpha2-adrenergic antagonist) would have stimulatory action on non-HPA CRH neurons, whereas naloxone (a mu-opioid receptor antagonist) would not have this effect. Adult normal volunteers received i.v. yohimbine (n = 5; 0.4 microg/kg), naloxone (n = 4; 125 microg/kg), or placebo (n = 3; 0.9% saline). Cerebrospinal fluid (CSF) was collected continuously, and concentrations of CSF CRH, CSF norepinephrine (NE), and plasma cortisol were measured. Administration of either yohimbine or naloxone caused significant increases in plasma cortisol concentrations over time. Although yohimbine robustly increased CSF NE levels and appeared to increase CSF CRH levels, these effects were not seen after naloxone or placebo administration. Intraindividual correlations were not observed between the measured concentrations of plasma cortisol and CSF CRH for any of the subjects. The results support the idea that CSF CRH concentrations reflect the activity of non-HPA CRH neurons. Although both yohimbine and naloxone stimulated the HPA axis, only yohimbine appeared to have stimulatory effects on central NE and non-HPA CRH.

Development and preliminary psychometric properties of an instrument for the measurement of childhood trauma: the Early Trauma Inventory.

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.

Temporal lobe volume in panic disorder--a quantitative magnetic resonance imaging study.

Although previous studies have used magnetic resonance imaging (MRI) to demonstrate qualitative abnormalities of the temporal lobes in patients with panic disorder, no study to date has applied quantitative volumetric methods to evaluate brain changes in panic disorder. The purpose of this study was to measure the volume of the temporal lobe and the hippocampus in patients with panic disorder and healthy control subjects using quantitative MRI measures. The volume of the temporal lobe, hippocampus and whole brain was measured in 13 patients with panic disorder and 14 healthy subjects. The mean volume of the left and right temporal lobes was significantly smaller in panic disorder compared to healthy subjects (16770+/-909 mm(3) vs. 18343+/-1740 mm(3)). This result was significant after controlling for differences in whole brain volume. There was no significant difference in volume of the hippocampus between patients and control subjects. These findings are consistent with smaller temporal lobe volume in panic disorder despite normal hippocampal volume.

Decreased benzodiazepine receptor binding in prefrontal cortex in combat-related posttraumatic stress disorder.

OBJECTIVE: Animals exposed to stress exhibit a decrease in benzodiazepine receptor binding in the frontal cortex. No studies have examined central benzodiazepine receptor binding in patients with posttraumatic stress disorder (PTSD). The purpose of this study was to examine measures of benzodiazepine receptor binding in PTSD. METHOD: From 13 patients with Vietnam combat-related PTSD and 13 case-matched healthy comparison subjects, a quantitative measure related to benzodiazepine receptor binding (distribution volume) was obtained with single photon emission computed tomography (SPECT) imaging of [(123)I]iomazenil binding and measurement of radioligand concentration in plasma. Distribution volume image data were analyzed by means of statistical parametric mapping. RESULTS: Lower distribution volumes were found in the prefrontal cortex (Brodmann's area 9) of PTSD patients than in comparison subjects. CONCLUSIONS: These findings of lower values for the benzodiazepine receptor binding measure of distribution volume are consistent with fewer benzodiazepine receptors and/or reduced affinity of receptor binding in the medial prefrontal cortex in patients with PTSD. Alterations in benzodiazepine receptor function in this area may underlie many of the symptoms of PTSD.

Low baseline and yohimbine-stimulated plasma neuropeptide Y (NPY) levels in combat-related PTSD.

BACKGROUND: Consistent with many studies demonstrating enhanced reactivity of the sympathetic nervous system in posttraumatic stress disorder (PTSD), the administration of yohimbine, a noradrenergic alpha(2)-antagonist, has been shown to increase core symptoms of PTSD and to induce greater increases in plasma 3-methyl-4-hydroxy-phenyl-glycol (MHPG) in subjects with PTSD compared with healthy control subjects. In turn, neuropeptide Y (NPY) has been shown to inhibit the release of norepinephrine from sympathetic noradrenergic neurons. METHODS: In the following study, plasma NPY responses to yohimbine and placebo were measured in a subgroup of 18 subjects with PTSD and 8 healthy control subjects who participated in the previous study of the effect of yohimbine on plasma MHPG. RESULTS: The PTSD subjects had lower baseline plasma NPY and blunted yohimbine-stimulated increases in plasma NPY compared with the healthy control subjects. Within the PTSD group, baseline plasma NPY levels correlated negatively with combat exposure scale scores, baseline PTSD and panic symptoms, and yohimbine-stimulated increases in MHPG and systolic blood pressure. CONCLUSIONS: This study suggests that combat stress-induced decreases in plasma NPY may mediate, in part, the noradrenergic system hyperreactivity observed in combat-related PTSD. The persistence of this decrease in plasma NPY may contribute to symptoms of hyperarousal and the expression of exaggerated alarm reactions, anxiety reactions, or both in combat veterans with PTSD long after war.

SPECT [I-123]iomazenil measurement of the benzodiazepine receptor in panic disorder.

BACKGROUND: Alterations in benzodiazepine receptor function have long been hypothesized to play a role in anxiety. Animal models of anxiety involving exposure to chronic stress have shown a specific decrease in benzodiazepine receptor binding in frontal cortex and hippocampus. The purpose of this study was to examine benzodiazepine receptor binding patients with panic disorder and comparison subjects. METHODS: A quantitative measure related to benzodiazepine receptor binding (Distribution Volume (DV)) was obtained with single photon emission computed tomography (SPECT) imaging of [123I]iomazenil and measurement of radioligand concentration in plasma in patients with panic disorder and healthy controls. DV image data were analyzed using statistical parametric mapping (spm96). RESULTS: A decrease in measures of benzodiazepine receptor binding (DV) was found in left hippocampus and precuneus in panic disorder patients relative to controls. Panic disorder patients who had a panic attack compared to patients who did not have a panic attack at the time of the scan had a decrease in benzodiazepine receptor binding in prefrontal cortex. CONCLUSIONS: Findings of a decrease in left hippocampal and precuneus benzodiazepine receptor binding may be related to alterations in benzodiazepine receptor binding, or other factors including changes in GABAergic transmission or possible endogenous benzodiazepine compounds. Benzodiazepine receptor function in prefrontal cortex appears to be involved in changes in state-related panic anxiety.

Hippocampal volume reduction in major depression.

OBJECTIVE: Elevated levels of glucocorticoids in depression have been hypothesized to be associated with damage to the hippocampus, a brain area involved in learning and memory. The purpose of this study was to measure hippocampal volume in patients with depression. METHOD: Magnetic resonance imaging was used to measure the volume of the hippocampus in 16 patients with major depression in remission and 16 case-matched nondepressed comparison subjects. RESULTS: Patients with depression had a statistically significant 19% smaller left hippocampal volume than comparison subjects, without smaller volumes of comparison regions (amygdala, caudate, frontal lobe, and temporal lobe) or whole brain volume. The findings were significant after brain size, alcohol exposure, age, and education were controlled for. CONCLUSIONS: These findings are consistent with smaller left hippocampal volume in depression.

False memories in women with self-reported childhood sexual abuse: an empirical study.

Although controversy exists about the validity of memories of childhood abuse, little is known about memory function in individuals reporting childhood abuse. This study assessed memories for previously presented words, including the capacity for false memory of critical lures not actually present in the word list, in 63 subjects, including abused women with posttraumatic stress disorder (PTSD), abused women without PTSD, and men and women without abuse or PTSD. Abused women with PTSD had a higher frequency of false recognition memory of critical lures (95%) than abused women without PTSD (78%), nonabused women without PTSD (79%), or nonabused men without PTSD (86%). PTSD women also showed poorer memory for studied words and increased insertions of non-studied words other than critical lures. These findings are consistent with a broad range of memory alterations in abused women with PTSD.