Heather C. Abercrombie

Regional brain function, emotion and disorders of emotion

Significant progress has been made in our understanding of the neural substrates of emotion and its disorders. Neuroimaging methods have been used to characterize the circuitry underlying disorders of emotion. Particular emphasis has been placed on the prefrontal cortex, anterior cingulate, parietal cortex, and the amygdala as critical components of the circuitry that may be dysfunctional in both depression and anxiety.

Functional but not structural subgenual prefrontal cortex abnormalities in melancholia

Major depression is a heterogeneous condition, and the search for neural correlates specific to clinically defined subtypes has been inconclusive. Theoretical considerations implicate frontostriatal, particularly subgenual prefrontal cortex (PFC), dysfunction in the pathophysiology of melancholia—a subtype of depression characterized by anhedonia—but no empirical evidence has been found yet for such a link. To test the hypothesis that melancholic, but not nonmelancholic depression, is associated with the subgenual PFC impairment, concurrent measurement of brain electrical (electroencephalogram, EEG) and metabolic (positron emission tomography, PET) activity were obtained in 38 unmedicated subjects with DSM-IV major depressive disorder (20 melancholic, 18 nonmelancholic subjects), and 18 comparison subjects. EEG data were analyzed with a tomographic source localization method that computed the cortical three-dimensional distribution of current density for standard frequency bands, allowing voxelwise correlations between the EEG and PET data. Voxel-based morphometry analyses of structural magnetic resonance imaging (MRI) data were performed to assess potential structural abnormalities in melancholia. Melancholia was associated with reduced activity in the subgenual PFC (Brodmann area 25), manifested by increased inhibitory delta activity (1.5–6.0 Hz) and decreased glucose metabolism, which themselves were inversely correlated. Following antidepressant treatment, depressed subjects with the largest reductions in depression severity showed the lowest post-treatment subgenual PFC delta activity. Analyses of structural MRI revealed no group differences in the subgenual PFC, but in melancholic subjects, a negative correlation between gray matter density and age emerged. Based on preclinical evidence, we suggest that subgenual PFC dysfunction in melancholia may be associated with blunted hedonic response and exaggerated stress responsiveness.

Cortisol variation in humans affects memory for emotionally laden and neutral information.

In a test of the effects of cortisol on emotional memory, 90 men were orally administered placebo or 20 or 40 mg cortisol and presented with emotionally arousing and neutral stimuli. On memory tests administered within 1 hr of stimulus presentation, cortisol elevations caused a reduction in the number of errors committed on free-recall tasks. Two evenings later, when cortisol levels were no longer manipulated, inverted-U quadratic trends were found for recognition memory tasks, reflecting memory facilitation in the 20-mg group for both negative and neutral information. Results suggest that the effects of cortisol on memory do not differ substantially for emotional and neutral information. The study provides evidence of beneficial effects of acute cortisol elevations on explicit memory in humans.

Flattened cortisol rhythms in metastatic breast cancer patients

Allostatic load, the physiological accumulation of the effects of chronic stressors, has been associated with multiple adverse health outcomes. Flattened diurnal cortisol rhythmicity is one of the prototypes of allostatic load, and has been shown to predict shorter survival among women with metastatic breast cancer. The current study compared diurnal cortisol slope in 17 breast cancer patients and 31 controls, and tested associations with variables previously found to be related to cortisol regulation, i.e, abdominal adiposity, perceived stress, social support, and explicit memory. Women with metastatic breast cancer had significantly flatter diurnal cortisol rhythms than did healthy controls. Patients with greater disease severity showed higher mean cortisol levels, smaller waist circumference, and a tendency toward flatter diurnal cortisol rhythms. There were no relations between cortisol slope and psychological or cognitive functioning among patients. In contrast, controls with flatter rhythms showed the expected allostatic load profile of larger waist circumference, poorer performance on explicit memory tasks, lower perceived social support, and a tendency toward higher perceived stress. These findings suggest that the cortisol diurnal slope may have important but different correlates in healthy women versus those with breast cancer.

Functional Coupling of Simultaneous Electrical and Metabolic Activity in the Human Brain

The relationships between brain electrical and metabolic activity are being uncovered currently in animal models using invasive methods; however, in the human brain this relationship remains not well understood. In particular, the relationship between noninvasive measurements of electrical activity and metabolism remains largely undefined. To understand better these relations, cerebral activity was measured simultaneously with electroencephalography (EEG) and positron emission tomography using [18f]‐fluoro‐2‐deoxy‐D‐glucose (PET‐FDG) in 12 normal human subjects during rest. Intracerebral distributions of current density were estimated, yielding tomographic maps for seven standard EEG frequency bands. The PET and EEG data were registered to the same space and voxel dimensions, and correlational maps were created on a voxel‐by‐voxel basis across all subjects. For each band, significant positive and negative correlations were found that are generally consistent with extant understanding of EEG band power function. With increasing EEG frequency, there was an increase in the number of positively correlated voxels, whereas the lower α band (8.5–10.0 Hz) was associated with the highest number of negative correlations. This work presents a method for comparing EEG signals with other more traditionally tomographic functional imaging data on a 3‐D basis. This method will be useful in the future when it is applied to functional imaging methods with faster time resolution, such as short half‐life PET blood flow tracers and functional magnetic resonance imaging. Hum. Brain Mapping 21:257–270, 2004.

Brain electrical tomography in depression: the importance of symptom severity, anxiety, and melancholic features

BACKGROUND The frontal lobe has been crucially involved in the neurobiology of major depression, but inconsistencies among studies exist, in part due to a failure of considering modulatory variables such as symptom severity, comorbidity with anxiety, and distinct subtypes, as codeterminants for patterns of brain activation in depression. METHODS Resting electroencephalogram was recorded in 38 unmedicated subjects with major depressive disorder and 18 normal comparison subjects, and analyzed with a tomographic source localization method that computes the cortical three-dimensional distribution of current density for standard electroencephalogram frequency bands. Symptom severity and anxiety were measured via self-report and melancholic features via clinical interview. RESULTS Depressed subjects showed more excitatory (beta3, 21.5-30.0 Hz) activity in the right superior and inferior frontal lobe (Brodmanns area 9/10/11) than comparison subjects. In melancholic subjects, this effect was particularly pronounced for severe depression, and right frontal activity correlated positively with anxiety. Depressed subjects showed posterior cingulate and precuneus hypoactivity. CONCLUSIONS While confirming prior results implicating right frontal and posterior cingulate regions, this study highlights the importance of depression severity, anxiety, and melancholic features in patterns of brain activity accompanying depression.

Endogenous cortisol elevations are related to memory facilitation only in individuals who are emotionally aroused

Animal research suggests that cortisol facilitates memory only during emotional arousal. Thus, we predicted that during mild emotion and stress elicitation, endogenous cortisol elevations would predict memory facilitation only in individuals who report high stress-related negative affect. Thirty-one men viewed neutral and emotional stimuli and then were subjected to a public speaking stress task. Area under the curve for overall cortisol output during the speech was computed. Negative affect (NA) using the PANAS state version [Watson, D., Clark, L.A., Tellegen, A., 1988. Development and validation of brief measures of positive and negative affect: the PANAS scales. J. Personality Social Psychol. 54, 1063-1070.] was measured at baseline and immediately after the speech stressor. Cortisol output during the speech and change in NA interactively predicted free recall performance assessed 2 days later. This interaction was due to the finding that higher cortisol output was related to memory facilitation only in subjects who reported high stress-related negative affect (i.e. only in those individuals whose NA increased compared to baseline). This relation was especially prominent for recall of unpleasant pictures. Subjects who reported low stress-related negative affect, no relation was found between cortisol output during the speech and memory performance. Thus, the relation between cortisol and memory appears to depend on an increase in negative affect related to stress.

Relations between PET-derived measures of thalamic glucose metabolism and EEG alpha power

Electroencephalogram (EEG) alpha power has been demonstrated to be inversely related to mental activity and has subsequently been used as an indirect measure of brain activation. The thalamus has been proposed as an important site for modulation of rhythmic alpha activity. Studies in animals have suggested that cortical alpha rhythms are correlated with alpha rhythms in the thalamus. However, little empirical evidence exists for this relation in humans. In the current study, resting EEG and a fluorodeoxyglucose positron emission tomography scan were measured during the same experimental session. Over a 30-min period, average EEG alpha power across 28 electrodes from 27 participants was robustly inversely correlated with glucose metabolic activity in the thalamus. These data provide the first evidence for a relation between alpha EEG power and thalamic activity in humans.

Hippocampal morphometry in depressed patients and control subjects: relations to anxiety symptoms

BACKGROUND Although it has been hypothesized that glucocorticoid hypersecretion in depressed patients leads to neuronal atrophy in the hippocampus, magnetic resonance imaging (MRI) -based morphometry studies of the hippocampus to date have produced mixed results. METHODS In our MRI study, hippocampal volumes were measured in 25 depressed patients (13 with melancholia and 12 without melancholia) and 15 control subjects. RESULTS No significant differences in hippocampus volumes were found between any of the subject groups, although within subjects right hippocampal volumes were found to be significantly larger than left hippocampal volumes. Additionally, right and total (left + right) hippocampal volumes in control and depressed subjects were found to be positively correlated with trait anxiety as measured by the state/trait anxiety inventory. CONCLUSIONS Because our subject group is younger than those in studies reporting hippocampal atrophy, we conclude that longitudinal studies will be necessary for investigation of the lifelong course of hippocampal volumetry.

Depression and stress reactivity in metastatic breast cancer

Objective: Cancer-related distress due to the psychological and physical challenges of metastatic breast cancer (MBC) may result in symptoms of depression, which negatively affects quality and may influence quantity of life. This study investigated how depression affects MBC stress reactivity, including autonomic (ANS) and hypothalamic–pituitary–adrenal (HPA) axis function. Method: Forty-five nondepressed and 45 depressed patients with MBC underwent a modified Trier Social Stress Test (TSST) while affect, cardiovascular, respiratory, and cortisol responses were measured. Results: At study entry, depressed compared with nondepressed patients had significantly lower log cortisol waking rise levels (p = .005) but no other HPA differences. Positive affect (p = .025) and high-frequency heart-rate variability (lnHF) (p = .002) were significantly lower at TSST baseline in depressed patients. In response to the TSST, depressed patients reported significantly lower positive (p = .050) and greater negative affect (p = .037) and had significantly reduced lnHF (p = .031). In secondary analyses, at TSST baseline both low-frequency (lnLF) (p = .002) and very-low-frequency (lnVLF) (p = .0001) heart rate variability were significantly lower in the depressed group. In secondary analyses during the TSST, those who were depressed had significantly lower lnVLF (p = .008) and did not increase aortic impedance reactivity as much as did the nondepressed during the stressor (p = .005). Conclusion: Depression in patients with MBC was associated with alterations in autonomic regulation, particularly reductions in respiratory sinus arrhythmia, a measure of cardiac vagal control, at baseline and during the TSST. In addition, depression was associated with blunted HPA response to awakening. Both MBC groups had relative cortisol hyporesponsiveness to acute stress. ANS = autonomic nervous system; BMI = body mass index; BP = blood pressure; BRC = baroreflex control of heart rate; CO = cardiac output; CVD = cardiovascular disease; DBP = diastolic blood pressure; ECG = electrocardiogram; HDL = high-density lipoprotein; HPA axis = hypothalamic–pituitary–adrenal axis; HR = heart rate; HRSD = Hamilton Rating Scale of Depression; HRV = heart rate variability; ICG = impedance cardiogram; lnHF = natural log of high-frequency HRV; lnLF = natural log of low-frequency HRV; lnVLF = natural log of very low frequency HRV; LDL = low-density lipoprotein; MBC = metastatic breast cancer; MDD = major depressive disorder; ND = nondepressed; PANAS = Positive and Negative Affect Schedule; pCO2 = partial pressure of carbon dioxide; PEP = preejection period; RR interval = time between two consecutive R waves of the ECG; RSA = respiratory sinus arrhythmia; RSATF = transfer function respiratory sinus arrhythmia; SBP = systolic blood pressure; SNRI = serotonin–norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TSST = Trier Social Stress Test; VLDL = very-low-density lipoprotein.