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Biomedical subjects

J D Bremner

Publications and source records attributed to J D Bremner.

At least 37 records · Page 2Linked to original sources
PubMed1999

Quantitation of benzodiazepine receptor binding with PET [11C]iomazenil and SPECT [123I]iomazenil: preliminary results of a direct comparison in healthy human subjects.

Although positron emission tomography (PET) and single photon emission computed tomography (SPECT) are increasingly used for quantitation of neuroreceptor binding, almost no studies to date have involved a direct comparison of the two. One study found a high level of agreement between the two techniques, although there was a systematic 30% increase in measures of benzodiazepine receptor binding in SPECT compared with PET. The purpose of the current study was to directly compare quantitation of benzodiazepine receptor binding in the same human subjects using PET and SPECT with high specific activity [11C]iomazenil and [123I]iomazenil, respectively. All subjects were administered a single bolus of high specific activity iomazenil labeled with 11C or 123I followed by dynamic PET or SPECT imaging of the brain. Arterial blood samples were obtained for measurement of metabolite-corrected radioligand in plasma. Compartmental modeling was used to fit values for kinetic rate constants of transfer of radioligand between plasma and brain compartments. These values were used for calculation of binding potential (BP = Bmax/Kd) and product of BP and the fraction of free non-protein-bound parent compound (V3'). Mean values for V3' in PET and SPECT were as follows: temporal cortex 23+/-5 and 22+/-3 ml/g, frontal cortex23+/-6 and 22+/-3 ml/g, occipital cortex 28+/-3 and 31+/-5 ml/g, and striatum 4+/-4 and 7+/-4 ml/g. These preliminary findings indicate that PET and SPECT provide comparable results in quantitation of neuroreceptor binding in the human brain.

Adult↗
PubMed1999

Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study.

BACKGROUND: Patients with posttraumatic stress disorder (PTSD) show a reliable increase in PTSD symptoms and physiological reactivity following exposure to traumatic pictures and sounds. In this study neural correlates of exposure to traumatic pictures and sounds were measured in PTSD. METHODS: Positron emission tomography and H2[15O] were used to measure cerebral blood flow during exposure to combat-related and neutral pictures and sounds in Vietnam combat veterans with and without PTSD. RESULTS: Exposure to traumatic material in PTSD (but not non-PTSD) subjects resulted in a decrease in blood flow in medial prefrontal cortex (area 25), an area postulated to play a role in emotion through inhibition of amygdala responsiveness. Non-PTSD subjects activated anterior cingulate (area 24) to a greater degree than PTSD patients. There were also differences in cerebral blood flow response in areas involved in memory and visuospatial processing (and by extension response to threat), including posterior cingulate (area 23), precentral (motor) and inferior parietal cortex, and lingual gyrus. There was a pattern of increases in PTSD and decreases in non-PTSD subjects in these areas. CONCLUSIONS: The findings suggest that functional alternations in specific cortical and subcortical brain areas involved in memory, visuospatial processing, and emotion underlie the symptoms of patients with PTSD.

Analysis of Variance↗
PubMed1999

Does stress damage the brain?

Studies in animals showed that stress results in damage to the hippocampus, a brain area involved in learning and memory, with associated memory deficits. The mechanism involves glucocorticoids and possibly serotonin acting through excitatory amino acids to mediate hippocampal atrophy. Patients with posttraumatic stress disorder (PTSD) from Vietnam combat and childhood abuse had deficits on neuropsychological measures that have been validated as probes of hippocampal function. In addition, magnetic resonance imaging (MRI) showed reduction in volume of the hippocampus in both combat veterans and victims of childhood abuse. In combat veterans, hippocampal volume reduction was correlated with deficits in verbal memory on neuropsychological testing. These studies introduce the possibility that experiences in the form of traumatic stressors can have long-term effects on the structure and function of the brain.

Animals↗
PubMed1999

Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder.

OBJECTIVE: Childhood sexual abuse is very common in our society, but little is known about the long-term effects of abuse on brain function. The purpose of this study was to measure neural correlates of memories of childhood abuse in sexually abused women with and without the diagnosis of posttraumatic stress disorder (PTSD). METHOD: Twenty-two women with a history of childhood sexual abuse underwent injection of [15O]H2O, followed by positron emission tomography imaging of the brain while they listened to neutral and traumatic (personalized childhood sexual abuse events) scripts. Brain blood flow during exposure to traumatic and neutral scripts was compared for sexually abused women with and without PTSD. RESULTS: Memories of childhood sexual abuse were associated with greater increases in blood flow in portions of anterior prefrontal cortex (superior and middle frontal gyri-areas 6 and 9), posterior cingulate (area 31), and motor cortex in sexually abused women with PTSD than in sexually abused women without PTSD. Abuse memories were associated with alterations in blood flow in medial prefrontal cortex, with decreased blood flow in subcallosal gyrus (area 25), and a failure of activation in anterior cingulate (area 32). There was also decreased blood flow in right hippocampus, fusiform/inferior temporal gyrus, supramarginal gyrus, and visual association cortex in women with PTSD relative to women without PTSD. CONCLUSIONS: These findings implicate dysfunction of medial prefrontal cortex (subcallosal gyrus and anterior cingulate), hippocampus, and visual association cortex in pathological memories of childhood abuse in women with PTSD. Increased activation in posterior cingulate and motor cortex was seen in women with PTSD. Dysfunction in these brain areas may underlie PTSD symptoms provoked by traumatic reminders in subjects with PTSD.

Adult↗
PubMed1999

Neuroanatomic substrates of late-life mental disorders.

Advances in magnetic resonance imaging (MRI) techniques have made it possible to quantify anatomic brain abnormalities in neuropsychiatric disorders. This review focuses on controlled, quantitative MRI studies in depression, degenerative disorders, and psychosis in the elderly. Although many of the anatomic abnormalities detected are observed across disorders, the patterns of regional involvement may be more selective and disorder specific. We integrate MRI findings with relevant clinical and neurobiologic observations in an attempt to develop a cohesive model of late-life psychiatric illness. Although the model primarily alludes to the pathophysiology of late-life depression, it may have broader biologic implications for other mental disorders in the elderly.

Age of Onset↗
PubMed1999

Neurotransmitter alterations in PTSD: catecholamines and serotonin.

In this chapter we review trauma-related studies involving epinephrine (E), norepinephrine (NE), and serotonin (5-HT). Central catecholamine neurons seem to play a critical role in level of alertness, vigilance, orienting, selective attention, memory, fear conditioning, and cardiovascular responses to life-threatening stimuli. Evidence of catecholamine dysregulation in post-traumatic stress disorder (PTSD) includes exaggerated increases in heart rate and blood pressure when exposed to visual and auditory reminders of trauma, elevated 24-hour urine catecholamine excretion, decreased platelet alpha-2 adrenergic receptor number, exaggerated behavioral, cardiovascular, and biochemical responses to IY yohimbine, decreased cortical brain metabolism secondary to IV yohimbine, and clinical efficacy of adrenergic blocking agents. Serotonin seems to play numerous roles in the central nervous system, including regulation of sleep, aggression, appetite, cardiovascular and respiratory activity, motor output, anxiety, mood, neuroendocrine secretion, and analgesia. Evidence of serotonergic dysregulation in PTSD includes frequent symptoms of aggression, impulsivity, depression and suicidality, decreased platelet paroxetine binding, blunted prolactin response to fenfluramine, exaggerated reactivity to m-chloro-phenyl-piperazine, and clinical efficacy of serotonin reuptake inhibitors. It has been suggested that alterations in NE, E, and 5-HT may have relevance for symptoms commonly seen in survivors with PTSD, including hypervigilance, exaggerated startle, irritability, impulsivity, aggression, intrusive memories, depressed mood, and suicidality.

Animals↗
PubMed1999

Alterations in brain structure and function associated with post-traumatic stress disorder.

Neuroimaging studies in post-traumatic stress disorder (PTSD) have revealed changes in brain structure and function that may underlie the symptoms of PTSD. Two brain areas that have been consistently implicated in PTSD include the hippocampus and prefrontal cortex. Several studies showed that PTSD is associated with reduction in volume of the hippocampus, a brain area involved in learning and memory, as measured with magnetic resonance imaging (MRI). Positron emission tomography (PET) studies showed dysfunction of medial and orbital prefrontal cortex during PTSD symptom provocation and in response to traumatic reminders. Decreased benzodiazepine receptor binding was found in the medial prefrontal cortex as measured with neuroimaging in PTSD. The hippocampus and medial prefrontal cortex play important roles in memory and emotional regulation, and dysfunction in these areas may underlie memory deficits and pathological emotions in PTSD.

Brain↗
PubMed1999

Glutamate and post-traumatic stress disorder: toward a psychobiology of dissociation.

Dissociative cognitive and perceptual alterations commonly occur at the time of traumatization and as an enduring feature of post-traumatic stress disorder (PTSD). After stress exposure, dissociative symptoms are a predictor of the development of PTSD. Recent preclinical data suggest that stress stimulates the cortico-limbic release of glutamate. The glutamate that is released during stress in animal models influences behavior, induces a variety of changes in neural plasticity that may have long-lasting effects on brain function and behavior, and contributes to neural toxicity. Antagonist of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor also stimulates transient cortico-limbic glutamate release in animals. Further, some of the effects of NMDA antagonists in animals are blocked by drugs that attenuate glutamate release. Clinical studies suggest that NMDA antagonists may transiently stimulate glutamate release and produce symptoms resembling dissociative states in humans. A recent study suggests that a drug that reduces glutamate release also attenuates the perceptual effects of the NMDA antagonist, ketamine, in humans. Because of the possible contributions of hyperglutamatergic states to the acute and long-lasting consequences of traumatic stress exposure, the therapeutic and neuroprotective potential of drugs that attenuate glutamate release should be explored in traumatized individuals with dissociative symptoms.

Animals↗
PubMed1998

Cerebral cortical hyperactivation in response to mental stress in patients with coronary artery disease.

The central nervous system (CNS) effects of mental stress in patients with coronary artery disease (CAD) are unexplored. The present study used positron emission tomography (PET) to measure brain correlates of mental stress induced by an arithmetic serial subtraction task in CAD and healthy subjects. Mental stress resulted in hyperactivation in CAD patients compared with healthy subjects in several brain areas including the left parietal cortex [angular gyrus/parallel sulcus (area 39)], left anterior cingulate (area 32), right visual association cortex (area 18), left fusiform gyrus, and cerebellum. These same regions were activated within the CAD patient group during mental stress versus control conditions. In the group of healthy subjects, activation was significant only in the left inferior frontal gyrus during mental stress compared with counting control. Decreases in blood flow also were produced by mental stress in CAD versus healthy subjects in right thalamus (lateral dorsal, lateral posterior), right superior frontal gyrus (areas 32, 24, and 10), and right middle temporal gyrus (area 21) (in the region of the auditory association cortex). Of particular interest, a subgroup of CAD patients that developed painless myocardial ischemia during mental stress had hyperactivation in the left hippocampus and inferior parietal lobule (area 40), left middle (area 10) and superior frontal gyrus (area 8), temporal pole, and visual association cortex (area 18), and a concomitant decrease in activation observed in the anterior cingulate bilaterally, right middle and superior frontal gyri, and right visual association cortex (area 18) compared with CAD patients without myocardial ischemia. These findings demonstrate an exaggerated cerebral cortical response and exaggerated asymmetry to mental stress in individuals with CAD.

Adult↗
PubMed1998

Interactive effects of subanesthetic ketamine and subhypnotic lorazepam in humans.

Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

Adult↗
PubMed1998

The effects of stress on memory and the hippocampus throughout the life cycle: implications for childhood development and aging.

Studies in animals showing hippocampal atrophy and associated memory deficits in stress and aging have implications for stress and aging in humans. Clinical studies in traumatized human populations with posttraumatic stress disorder (PTSD) have replicated studies in animals, showing reduction in volume of the hippocampus measured with magnetic resonance imaging and associated memory deficits. Trauma at different stages of development (early childhood abuse versus trauma in later life due to combat) may influence the nature of memory deficits and hippocampal atrophy. Studies in aging human subjects are consistent with animal studies, although future research is needed in this area. The similarities between biological findings related to cortisol and the hippocampus in stress and aging in both animal and human studies raises the question of whether PTSD can be seen as a form of accelerated aging. Evidence that stress affects the hippocampus and the capacity for learning has broad implications for public health policy, underlying the need for additional resources in this important area and a reexamination of our understanding of factors influencing academic achievement.

Adult↗
PubMed1998

Measurement of dissociative states with the Clinician-Administered Dissociative States Scale (CADSS).

The purpose of this study was to develop an instrument for the measurement of present-state dissociative symptoms, the Clinician Administered Dissociative States Scale (CADSS). Reported here are interrater reliability and internal consistency of the CADSS, validity as assessed by comparisons with other instruments for the assessment of dissociation, and sensitivity of the CADSS to discriminate patients with dissociative disorders from patients with other psychiatric disorders and healthy subjects. Initial analyses indicated good interrater reliability and construct validity for the CADSS. Scores on the CADSS discriminated patients with dissociative disorders from the other groups.

Adult↗
PubMed1998

Safety of mirtazapine in overdose.

INTRODUCTION: We report 6 confirmed cases of substantial overdose with mirtazapine, a new antidepressant compound, that occurred up to January 1997 in the United States during postmarketing surveillance or in the clinical trials. RESULTS: In 6 patients, the mirtazapine doses ranged from 10 to 30 times the maximum recommended dose, and there were no serious adverse effects of overdose. Two patients at special risk, a 90-year-old man and a 3-year-old child, took higher-than-usual doses without serious sequelae. The 4 patients who combined other central nervous system (CNS) depressants with mirtazapine appeared to experience more CNS depression. One patient who ingested 60 mg of alprazolam had clinically significant respiratory depression in the emergency room but recovered fully within 24 hours. CONCLUSION: After an overdose of substantial multiples of mirtazapine that exceed the maximum recommended daily dosage, the new antidepressant mirtazapine appears to be safe in a limited number of cases.

Adult↗
PubMed1997

Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse--a preliminary report.

We have previously reported smaller hippocampal volume and deficits in short-term memory in patients with combat-related posttraumatic stress disorder (PTSD) relative to comparison subjects. The purpose of this study was to compare hippocampal volume in adult survivors of childhood abuse to matched controls. Magnetic resonance imaging was used to measure volume of the hippocampus in adult survivors of childhood abuse (n = 17) and healthy subjects (n = 17) matched on a case-by-case basis for age, sex, race, handedness, years of education, body size, and years of alcohol abuse. All patients met criteria for PTSD secondary to childhood abuse. PTSD patients had a 12% smaller left hippocampal volume relative to the matched controls (p < .05), without smaller volumes of comparison regions (amygdala, caudate, and temporal lobe). The findings were significant after controlling for alcohol, age, and education, with multiple linear regression. These findings suggest that a decrease in left hippocampal volume is associated with abuse-related PTSD.

Adult↗
PubMed1997

Positron emission tomography measurement of cerebral metabolic correlates of yohimbine administration in combat-related posttraumatic stress disorder.

BACKGROUND: We have previously reported an increase in symptoms of anxiety in patients with posttraumatic stress disorder (PTSD) following administration of the beta 2-antagonist yohimbine, which stimulates brain norepinephrine release. Preclinical studies show decreased metabolism in the neocortex and the caudate nucleus with high-dose yohimbine-induced norepinephrine release, but low levels of norepinephrine release result in an increase in metabolism in these areas. METHODS: We used positron emission tomography and fludeoxyglucose F 18 to measure brain metabolism in Vietnam combat veterans with PTSD (n = 10) and healthy age-matched control subjects (n = 10), following administration of yohimbine (0.4 mg/kg) or placebo in a randomized, double-blind fashion. RESULTS: Yohimbine resulted in a significant increase in anxiety in the patients with PTSD, but not in healthy subjects. There was a significant difference in brain metabolic response to yohimbine in patients with PTSD compared with healthy subjects in prefrontal, temporal, parietal, and orbitofrontal cortexes. Metabolism tended to decrease in patients with PTSD and increase in healthy subjects following administration of yohimbine. CONCLUSION: These findings are consistent with our previous hypothesis of enhanced norepinephrine release in the brain with yohimbine in patients with PTSD.

Anxiety Disorders↗
PubMed1997

Positron emission tomography measurement of cerebral metabolic correlates of tryptophan depletion-induced depressive relapse.

BACKGROUND: Short-term depletion of plasma tryptophan has been shown to result in depressive relapse in patients with remission of major depression. Positron emission tomography and single photon emission computed tomography studies implicated the dorsolateral prefrontal cortex, orbitofrontal cortex, thalamus, and caudate nucleus in the pathogenesis of depression. The purpose of this study was to measure cerebral metabolic correlates of tryptophan depletion-induced depressive relapse. METHODS: Patients diagnosed as having major depression (N = 21) who clinically improved with serotonin reuptake inhibitors underwent 2 test days involving tryptophan depletion or placebo, followed 6 hours later by positron emission tomography scanning with fludeoxy-glucose F18. Brain metabolism was compared in patients with (n = 7) and without (n = 14) a tryptophan depletion-induced depressive relapse. RESULTS: Tryptophan depletion resulted in a decrease in brain metabolism in the middle frontal gyrus (dorsolateral prefrontal cortex), thalamus, and orbitofrontal cortex in patients with a depletion-induced depressive relapse (but not in patients without depletion-induced relapse). Decreased brain metabolism in these regions correlated with increased depressive symptoms. Baseline metabolism was increased in prefrontal and limbic regions in relapse-prone patients. CONCLUSION: Specific brain regions, including the middle frontal gyrus, thalamus, and orbitofrontal cortex, may mediate the symptoms of patients with major depression.

Antidepressive Agents↗
PubMed1997

Noradrenergic and serotonergic function in posttraumatic stress disorder.

BACKGROUND: Yohimbine hydrochloride produces marked behavioral and cardiovascular effects in combat veterans with posttraumatic stress disorder (PTSD). In the present study, yohimbine was used as a probe of noradrenergic activity, and meta-chlorophenylpiperazine (m-CPP) as a probe of serotonergic activity. To our knowledge, this is the first study to describe the behavioral and cardiovascular effects of meta-CPP in patients with PTSD, and to compare these effects with those of yohimbine. METHOD: Twenty-six patients with PTSD and 14 healthy subjects each received an intravenous infusion of yohimbine hydrochloride (0.4 mg/kg), m-CPP (1.0 mg/kg), or saline solution on 3 separate test days in a randomized balanced order and in double-blind fashion. Behavioral and cardiovascular measurements were determined at multiple times. RESULTS: Eleven (42%) of the patients with PTSD experienced yohimbine-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, but not in cardiovascular measurements. Eight patients (31%) with PTSD experienced m-CPP-induced panic attacks and had significantly greater increases compared with controls in anxiety, panic, and PTSD symptoms, and in standing diastolic blood pressure. Yohimbine-induced panic attacks tended to occur in different patients from m-CPP-induced panic attacks. CONCLUSION: These data suggest the presence of 2 neurobiological subgroups of patients with PTSD, one with a sensitized noradrenergic system, and the other with a sensitized serotonergic system.

Adult↗