Faculty Bibliography

BACKGROUND: Animal studies have shown that stress is associated with damage to the hippocampus, inhibition of neurogenesis, and deficits in hippocampal-based memory dysfunction. Studies in patients with posttraumatic stress disorder (PTSD) found deficits in hippocampal-based declarative verbal memory and smaller hippocampal volume, as measured with magnetic resonance imaging (MRI). Recent preclinical evidence has shown that selective serotonin reuptake inhibitors promote neurogenesis and reverse the effects of stress on hippocampal atrophy. This study assessed the effects of long-term treatment with paroxetine on hippocampal volume and declarative memory performance in PTSD. METHODS: Declarative memory was assessed with the Wechsler Memory Scale-Revised and Selective Reminding Test before and after 9-12 months of treatment with paroxetine in PTSD. Hippocampal volume was measured with MRI. Of the 28 patients who started the protocol, 23 completed the full course of treatment and neuropsychological testing. Twenty patients were able to complete MRI imaging. RESULTS: Patients with PTSD showed a significant improvement in PTSD symptoms with treatment. Treatment resulted in significant improvements in verbal declarative memory and a 4.6% increase in mean hippocampal volume. CONCLUSIONS: These findings suggest that long-term treatment with paroxetine is associated with improvement of verbal declarative memory deficits and an increase in hippocampal volume in PTSD.

Animal studies have found that prior stressful events can result in increased reactivity in the HPA-axis. However, baseline function of the HPA-axis has typically been normal or decreased in post-traumatic stress disorder (PTSD). The first purpose of this study was to assess cortisol responsivity to traumatic reminders in women with PTSD related to childhood abuse. The second aim was to assess the relationship between stress-induced cortisol levels and neutral and emotional memory. Salivary cortisol levels were measured before, during and after exposure to personalized trauma scripts in abused women with (N=12) and without current PTSD (N=12). Memory for neutral and emotional material was assessed immediately after trauma scripts exposure and 3 days later. PTSD patients had 122% higher cortisol levels during script exposure, 69% higher cortisol levels during recovery, and 60% higher levels in the period leading up to the script exposure compared to controls. PTSD symptoms were highly predictive of cortisol levels during trauma script exposure (r=0.70), but not during periods of rest. Both in PTSD patients and controls, memory consolidation after the trauma scripts was impaired relative to baseline (P<0.001), with no differences between the two groups on memory performance. There was no association between memory performance and cortisol levels. These results are consistent with higher cortisol levels following exposure to traumatic stressors in PTSD.

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.

BACKGROUND: Borderline personality disorder (BPD) is a common psychiatric disorder that is often linked to early stressors. One particularly salient feature of the disorder is fear of abandonment. This pilot study was conducted to measure neural correlates of memories of abandonment in women with and without BPD. METHODS: Twenty women with a history of childhood sexual abuse underwent measurement of brain blood flow with positron emission tomography imaging while they listened to scripts describing neutral and personal abandonment events. Brain blood flow during exposure to abandonment and neutral scripts was compared among women with and without BPD. RESULTS: Memories of abandonment were associated with greater increases in blood flow in bilateral dorsolateral prefrontal cortex (middle frontal gyrus, Brodmann's areas 9 and 10) as well as right cuneus (area 19) in women with BPD than in women without BPD. Abandonment memories were associated with greater decreases in right anterior cingulate (areas 24 and 32) in women with BPD than in women without BPD. CONCLUSIONS: These findings implicate dysfunction of dorsolateral and medial prefrontal cortex including anterior cingulate, left temporal cortex, and visual association cortex in memories of abandonment in women with BPD. These brain areas may mediate symptoms of BPD.

CONTEXT: We previously used positron emission tomography (PET) measurement of brain metabolism with 18fluorodeoxyglucose to show that patients receiving selective serotonin reuptake inhibitors (SSRIs) who have a tryptophan depletion-induced return of depressive symptoms have an acute decrease in metabolism in orbitofrontal cortex, dorsolateral prefrontal cortex, and thalamus. Many patients with depression in remission while taking norepinephrine reuptake inhibitors (NRIs) (but not SSRIs) experience a return of depressive symptoms with depletion of norepinephrine and dopamine using alpha-methylparatyrosine (AMPT). OBJECTIVE: To assess brain metabolic correlates of AMPT administration in patients with depression in remission while receiving NRIs. DESIGN, SETTING, AND PARTICIPANTS: Randomized, controlled, double-blind trial in which 18 patients recruited in 1997-2000 from the general community who had depression in remission while taking NRIs had PET imaging in a psychiatric research unit following AMPT and placebo administration. INTERVENTIONS: After initial medication with desipramine and follow-up until response, patients underwent active AMPT (five 1-g doses administered orally over 28 hours) and placebo (diphenhydramine hydrochloride, five 50- mg doses administered similarly) catecholamine depletion challenges in randomized order of assignment, after which PET imaging was performed on day 3 of each condition. Both study conditions were performed 1 week apart. MAIN OUTCOME MEASURES: Regional brain metabolism rates in patients with and without AMPT-induced return of depressive symptoms. RESULTS: AMPT-induced return of depressive symptoms was experienced by 11 of the 18 patients and led to decreased brain metabolism in a number of cortical areas, with the greatest magnitude of effects in orbitofrontal (P =.002) and dorsolateral prefrontal (P =.03) cortex and thalamus (P =.006). Increased resting metabolism in prefrontal and limbic areas predicted vulnerability to return of depressive symptoms. CONCLUSIONS: Different neurochemical systems that mediate depression may have effects on a common brain circuitry. Baseline metabolism in successfully treated depressed patients may predict vulnerability to future episodes of depression.

BACKGROUND: Animal studies have shown that early stressors result in lasting changes in structure and function of brain areas involved in memory, including hippocampus and frontal cortex. Patients with childhood abuse-related posttraumatic stress disorder (PTSD) have alterations in both declarative and nondeclarative memory function, and imaging studies in PTSD have demonstrated changes in function during stimulation of trauma-specific memories in hippocampus, medial prefrontal cortex, and cingulate. The purpose of this study was to assess neural correlates of emotionally valenced declarative memory in women with early childhood sexual abuse and PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 10) and women without abuse or PTSD (n = 11) underwent positron emission tomographic (PET) measurement of cerebral blood flow during a control condition and during retrieval of neutral (e.g., "metal-iron") and emotionally valenced (e.g., "rape-mutilate") word pairs. RESULTS: During retrieval of emotionally valenced word pairs, PTSD patients showed greater decreases in blood flow in an extensive area, which included orbitofrontal cortex, anterior cingulate, and medial prefrontal cortex (Brodmann's areas 25, 32, 9), left hippocampus, and fusiform gyrus/inferior temporal gyrus, with increased activation in posterior cingulate, left inferior parietal cortex, left middle frontal gyrus, and visual association and motor cortex. There were no differences in patterns of brain activation during retrieval of neutral word pairs between patients and control subjects. CONCLUSIONS: These findings are consistent with dysfunction of specific brain areas involved in memory and emotion in PTSD. Regions implicated in this study of emotionally valenced declarative memory are similar to those from prior imaging studies in PTSD using trauma-specific stimuli for symptom provocation, adding further supportive evidence for a dysfunctional network of brain areas involved in memory, including hippocampus, medial prefrontal cortex, and cingulate, in PTSD.

OBJECTIVE: Animal studies have suggested that early stress is associated with alterations in the hippocampus, a brain area that plays a critical role in learning and memory. The purpose of this study was to measure both hippocampal structure and function in women with and without early childhood sexual abuse and the diagnosis of posttraumatic stress disorder (PTSD). METHOD: Thirty-three women participated in this study, including women with early childhood sexual abuse and PTSD (N=10), women with abuse without PTSD (N=12), and women without abuse or PTSD (N=11). Hippocampal volume was measured with magnetic resonance imaging in all subjects, and hippocampal function during the performance of hippocampal-based verbal declarative memory tasks was measured by using positron emission tomography in abused women with and without PTSD. RESULTS: A failure of hippocampal activation and 16% smaller volume of the hippocampus were seen in women with abuse and PTSD compared to women with abuse without PTSD. Women with abuse and PTSD had a 19% smaller hippocampal volume relative to women without abuse or PTSD. CONCLUSIONS: These results are consistent with deficits in hippocampal function and structure in abuse-related PTSD.