Faculty Bibliography

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.

Borderline personality disorder (BPD) is a common disorder associated with emotional dysregulation and other symptoms that have been hypothesized to be related to dysfunction of limbic brain areas including hippocampus and amygdala. The purpose of this study was to measure hippocampal and amygdala volumes in BPD. Hippocampal and amygdala volumes were measured with magnetic resonance imaging (MRI) in 10 patients with BPD and 23 control subjects. Patients with BPD had a 21.9% smaller mean amygdala volume and a 13.1% smaller hippocampal volume, compared to controls. These findings are consistent with the hypothesis that alterations in the hippocampus and amygdala are associated with BPD.

BACKGROUND: Memory for odors that are associated with intense emotional experiences is often strongly engraved. Odors are claimed to be more closely connected to affect than other sensory experiences. They can serve as potent contextual cues for memory formation and emotional conditioning and can also serve as cues for olfactory flashbacks. Though trauma-related smells have long been noted by clinicians to be precipitants of traumatic memories in patients with posttraumatic stress disorder (PTSD), very few reports have been published that document this. CASE REPORTS: We review olfactory memories and olfactory flashbacks by presenting 3 cases that illustrate the role of olfaction in PTSD. In these cases olfaction is either a precipitant of PTSD symptoms or an important component of reexperiencing. DISCUSSION: In PTSD, seemingly nonspecific cues have the potential to precipitate traumatic memories with strong emotional components. These conditioned responses in PTSD are hypothesized to be mediated by specific brain areas, i.e., amygdala, hippocampus, and orbitofrontal cortex. Questions about smells as a traumatic reminder should be part of the routine assessment of intrusive memories in PTSD. In addition, smells may have the potential to provide cues to exposure situations in therapy or to facilitate de novo conditioning.

OBJECTIVE: Smaller hippocampal volume has been reported only in some but not all studies of unipolar major depressive disorder. Severe stress early in life has also been associated with smaller hippocampal volume and with persistent changes in the hypothalamic-pituitary-adrenal axis. However, prior hippocampal morphometric studies in depressed patients have neither reported nor controlled for a history of early childhood trauma. In this study, the volumes of the hippocampus and of control brain regions were measured in depressed women with and without childhood abuse and in healthy nonabused comparison subjects. METHOD: Study participants were 32 women with current unipolar major depressive disorder-21 with a history of prepubertal physical and/or sexual abuse and 11 without a history of prepubertal abuse-and 14 healthy nonabused female volunteers. The volumes of the whole hippocampus, temporal lobe, and whole brain were measured on coronal MRI scans by a single rater who was blind to the subjects' diagnoses. RESULTS: The depressed subjects with childhood abuse had an 18% smaller mean left hippocampal volume than the nonabused depressed subjects and a 15% smaller mean left hippocampal volume than the healthy subjects. Right hippocampal volume was similar across the three groups. The right and left hippocampal volumes in the depressed women without abuse were similar to those in the healthy subjects. CONCLUSIONS: A smaller hippocampal volume in adult women with major depressive disorder was observed exclusively in those who had a history of severe and prolonged physical and/or sexual abuse in childhood. An unreported history of childhood abuse in depressed subjects could in part explain the inconsistencies in hippocampal volume findings in prior studies in major depressive disorder.