Dimensional depression severity in women with major depression and post-traumatic stress disorder correlates with fronto-amygdalar hypoconnectivty.

Depressive symptoms are common in multiple psychiatric disorders and are frequent sequelae of trauma. A dimensional conceptualization of depression suggests that symptoms should be associated with a continuum of deficits in specific neural circuits. However, most prior investigations of abnormalities in functional connectivity have typically focused on a single diagnostic category using hypothesis-driven seed-based analyses. Here, using a sample of 105 adult female participants from three diagnostic groups (healthy controls, n=17; major depression, n=38; and post-traumatic stress disorder, n=50), we examine the dimensional relationship between resting-state functional dysconnectivity and severity of depressive symptoms across diagnostic categories using a data-driven analysis (multivariate distance-based matrix regression). This connectome-wide analysis identified foci of dysconnectivity associated with depression severity in the bilateral amygdala. Follow-up seed analyses using subject-specific amygdala segmentations revealed that depression severity was associated with amygdalo-frontal hypo-connectivity in a network of regions including bilateral dorsolateral prefrontal cortex, anterior cingulate and anterior insula. In contrast, anxiety was associated with elevated connectivity between the amygdala and the ventromedial prefrontal cortex. Taken together, these results emphasize the centrality of the amygdala in the pathophysiology of depressive symptoms, and suggest that dissociable patterns of amygdalo-frontal dysconnectivity are a critical neurobiological feature across clinical diagnostic categories.

Functional network dysfunction in anxiety and anxiety disorders.

A recent paradigm shift in systems neuroscience is the division of the human brain into functional networks. Functional networks are collections of brain regions with strongly correlated activity both at rest and during cognitive tasks, and each network is believed to implement a different aspect of cognition. We propose here that anxiety disorders and high trait anxiety are associated with a particular pattern of functional network dysfunction: increased functioning of the cingulo-opercular and ventral attention networks as well as decreased functioning of the fronto-parietal and default mode networks. This functional network model can be used to differentiate the pathology of anxiety disorders from other psychiatric illnesses such as major depression and provides targets for novel treatment strategies.

Resting bold fMRI differentiates dementia with Lewy bodies vs Alzheimer disease.

OBJECTIVE: Clinicopathologic phenotypes of dementia with Lewy bodies (DLB) and Alzheimer disease (AD) often overlap, making discrimination difficult. We performed resting state blood oxygen level-dependent (BOLD) functional connectivity MRI (fcMRI) to determine whether there were differences between AD and DLB. METHODS: Participants (n = 88) enrolled in a longitudinal study of memory and aging underwent 3-T fcMRI. Clinical diagnoses of probable DLB (n = 15) were made according to published criteria. Cognitively normal control participants (n = 38) were selected for the absence of cerebral amyloid burden as imaged with Pittsburgh compound B (PiB). Probable AD cases (n = 35) met published criteria and had appreciable amyloid deposits with PiB imaging. Functional images were collected using a gradient spin-echo sequence sensitive to BOLD contrast (T2* weighting). Correlation maps selected a seed region in the combined bilateral precuneus. RESULTS: Participants with DLB had a functional connectivity pattern for the precuneus seed region that was distinct from AD; both the DLB and AD groups had functional connectivity patterns that differed from the cognitively normal group. In the DLB group, we found increased connectivity between the precuneus and regions in the dorsal attention network and the putamen. In contrast, we found decreased connectivity between the precuneus and other task-negative default regions and visual cortices. There was also a reversal of connectivity in the right hippocampus. CONCLUSIONS: Changes in functional connectivity in DLB indicate patterns of activation that are distinct from those seen in AD and may improve discrimination of DLB from AD and cognitively normal individuals. Since patterns of connectivity differ between AD and DLB groups, measurements of BOLD functional connectivity can shed further light on neuroanatomic connections that distinguish DLB from AD.

[11C]PIB in a nondemented population: potential antecedent marker of Alzheimer disease.

BACKGROUND: Beta-amyloid (Abeta) plaques are the hallmark of Alzheimer disease (AD). A PET imaging tracer that binds to Abeta plaques in vivo, N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole (or [(11)C]PIB for "Pittsburgh Compound-B"), has significantly higher binding in subjects diagnosed with dementia of the Alzheimer type (DAT) compared to nondemented controls. The authors used this imaging technique to investigate whether abnormal binding occurs in clinically normal individuals, prior to the development of cognitive changes. METHODS: Forty-one nondemented subjects (age range 20 to 86 years) and 10 patients with DAT (age range 66 to 86 years) underwent [(11)C]PIB PET scanning. Regions of interest were drawn on the MRI over the cerebellar, prefrontal, lateral temporal, occipital, gyrus rectus, precuneus, and striatal cortex. Binding potential values (BPs), proportional to the density of [(11)C]PIB-Abeta binding sites, were calculated using the Logan graphical analysis and the cerebellar cortex for a reference tissue. RESULTS: Patients with DAT had elevated BP values vs nondemented subjects (p < 0.0001). Four of the 41 nondemented subjects had elevated cortical BP values and their BP values as a group were not significantly different from the DAT subjects' BP values. Two of these four nondemented subjects had [(11)C]PIB uptake, both visually and quantitatively, that was indistinguishable from the DAT subjects. CONCLUSIONS: Elevated [(11)C]PIB binding in nondemented subjects suggests that [(11)C]PIB amyloid imaging may be sensitive for detection of a preclinical Alzheimer disease state. Longitudinal studies will be required to determine the association of elevated [(11)C]PIB binding and risk of developing dementia of the Alzheimer type.

The hippocampus and depression.

The effect of depression on the hippocampus has become the focus of a number of structural and functional neuroimaging studies. In the past two decades, advances in neuroimaging techniques now allow the examination of subtle changes in both regional structure and function that are associated with the pathophysiology of depression. Many studies using 3-dimensional magnetic resonance imaging (MRI) volumetric measurement have reported decreases in hippocampal volume among depressed subjects compared with controls, whereas other studies have not found any volume loss. Differences among studies have been discussed. In some studies, the volume loss appears to have functional significance including an association with memory loss. Furthermore, we have found a trend towards loss of 5-HT(2A) receptors in the hippocampus using positron emission tomography (PET) to detect regional changes in [18F]altanserin binding. Functional imaging extends the sensitivity and specificity of structural imaging and will lead to a better understanding of affective disorders.

Increased amygdala response to masked emotional faces in depressed subjects resolves with antidepressant treatment: an fMRI study.

BACKGROUND: The amygdala has a central role in processing emotions, particularly fear. During functional magnetic resonance imaging (fMRI) amygdala activation has been demonstrated outside of conscious awareness using masked emotional faces. METHODS: We applied the masked faces paradigm to patients with major depression (n = 11) and matched control subjects (n = 11) during fMRI to compare amygdala activation in response to masked emotional faces before and after antidepressant treatment. Data were analyzed using left and right amygdala a priori regions of interest, in an analysis of variance block analysis and random effects model. RESULTS: Depressed patients had exaggerated left amygdala activation to all faces, greater for fearful faces. Right amygdala did not differ from control subjects. Following treatment, patients had bilateral reduced amygdala activation to masked fearful faces and bilateral reduced amygdala activation to all faces. Control subjects had no differences between the two scanning sessions. CONCLUSIONS: Depressed patients have left amygdala hyperarousal, even when processing stimuli outside conscious awareness. Increased amygdala activation normalizes with antidepressant treatment.

3D MRI studies of neuroanatomic changes in unipolar major depression: the role of stress and medical comorbidity.

Increasing evidence has accumulated for structural brain changes associated with unipolar recurrent major depression. Studies of neuroanatomic structure in early-onset recurrent depression have only recently found evidence for depression-associated structural change. Studies using high-resolution three-dimensional magnetic resonance imaging (MRI) are now available to examine smaller brain structures with precision. Brain changes associated with early-onset major depression have been reported in the hippocampus, amygdala, caudate nucleus, putamen, and frontal cortex, structures that are extensively interconnected. They comprise a neuroanatomic circuit that has been termed the limbic-cortical-striatal-pallidal-thalamic tract. Of these structures, volume loss in the hippocampus is the only consistently observed change to persist past the resolution of the depression. Possible mechanisms for tissue loss include neuronal loss through exposure to repeated episodes of hypercortisolemia; glial cell loss, resulting in increased vulnerability to glutamate neurotoxicity; stress-induced reduction in neurotrophic factors; and stress-induced reduction in neurogenesis. Many depressed patients, particularly those with late-onset depression, have comorbid physical illnesses producing a high rate of hyperintensities in deep white matter and subcortical gray matter and brain damage to key structures involved in the modulation of emotion. Combining MRI studies with functional studies has the potential to localize abnormalities in blood flow, metabolism, and neurotransmitter receptors and provide a better integrated model of depression.

Absence of striatal volume differences between depressed subjects with no comorbid medical illness and matched comparison subjects.

OBJECTIVE: The striatum (caudate and putamen) appears to be important in the pathogenesis of depression. Some studies show smaller than normal striatal structure volumes in depressed subjects. This study compared striatal volumes in depressed and nondepressed women, screened to exclude major cerebrovascular disease risk factors and comorbid medical illness. METHOD: Caudate and putamen volumes were measured from magnetic resonance imaging scans of 24 depressed women and 24 matched nondepressed comparison subjects. RESULTS: Caudate and putamen volumes were not significantly different between depressed and nondepressed groups. CONCLUSIONS: These findings differ from those of previous studies, possibly because of the exclusion of subjects with cerebrovascular risk factors in this study.

White matter hyperintensities and gray matter lesions in physically healthy depressed subjects.

OBJECTIVE: Previous studies reported that depressed subjects had more white matter hyperintensities on magnetic resonance imaging scans than control subjects, but the subjects had cerebrovascular disease risk factors. This study used subjects with a history of recurrent major depression and matched comparison subjects, screened to exclude cerebrovascular disease risk factors, to determine whether depressed subjects had more white matter hyperintensities and other lesions. METHOD: A semiautomated volumetric computer program was used to compare numbers and volumes of white matter hyperintensities, basal ganglia lesions, and total lesions in 24 women with a history of recurrent major depression and 24 comparison subjects case-matched on age and education and group-matched on height. In addition, images were measured with the use of a validated categorical scale. All subjects were screened to exclude cerebrovascular disease risk factors. RESULTS: There were no significant differences in the total volumes or total numbers of lesions. However, multiple linear regression showed a significant correlation of age and depression with number of lesions; this was accounted for by a greater number of small lesions (diameter < or = 0.4 cm). CONCLUSIONS: These findings suggest that cerebrovascular disease risk factors most likely mediated the relationship between depression and white matter hyperintensities seen in previous studies. However, the independent effect of depression, as well as an age-by-depression interaction, for small lesions suggests a causal role of depression in certain types of white matter pathology irrespective of other cerebrovascular disease risk factors. The volumetric method used in this study may be more sensitive than other methods in determining lesion characteristics and correlations with clinical variables.

Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression.

This study takes advantage of continuing advances in the precision of magnetic resonance imaging (MRI) to quantify hippocampal volumes in a series of human subjects with a history of depression compared with controls. We sought to test the hypothesis that both age and duration of past depression would be inversely and independently correlated with hippocampal volume. A sample of 24 women ranging in age from 23 to 86 years with a history of recurrent major depression, but no medical comorbidity, and 24 case-matched controls underwent MRI scanning. Subjects with a history of depression (post-depressed) had smaller hippocampal volumes bilaterally than controls. Post-depressives also had smaller amygdala core nuclei volumes, and these volumes correlated with hippocampal volumes. In addition, post-depressives scored lower in verbal memory, a neuropsychological measure of hippocampal function, suggesting that the volume loss was related to an aspect of cognitive functioning. In contrast, there was no difference in overall brain size or general intellectual performance. Contrary to our initial hypothesis, there was no significant correlation between hippocampal volume and age in either post-depressive or control subjects, whereas there was a significant correlation with total lifetime duration of depression. This suggests that repeated stress during recurrent depressive episodes may result in cumulative hippocampal injury as reflected in volume loss.

Amygdala core nuclei volumes are decreased in recurrent major depression.

The amygdala is a key structure in the brain's integration of emotional meaning with perception and experience. Patients with depression have impaired functioning in emotional tasks involving the amygdala, and have abnormal resting amygdala blood flow. To better understand the anatomical basis for these functional changes we measured the volumes of the total amygdala and of the core amygdala nuclei in 20 patients with a history of depression and 20 pair-wise matched controls. Depressed subjects had bilaterally reduced amygdala core nuclei volumes and no significant differences in total amygdala volumes or in whole brain volumes. Since patients with a depression history have bilateral hippocampal volume reduction the volume loss in this closely related structure suggests a shared effect on both structures, potentially glucocorticoid-induced neurotoxicity mediated by the extensive reciprocal glutamatergic connections.

Higher cerebrospinal fluid MHPG in subjects with dementia of the Alzheimer type. Relationship with cognitive dysfunction.

The authors sought to determine the relationships between cerebrospinal fluid (CSF) levels of three neurotransmitter monoamine metabolites and cognitive function. CSF was collected from subjects with dementia of the Alzheimer's type ([DAT] n = 28) and control subjects (n = 10) for determination of CSF 5-hydroxyindole acetic acid (5-HIAA), 3-methoxy-4-hydroxy-phenylglycol (MHPG), and homovanillic acid (HVA) levels. All subjects underwent systematic assessment to determine cognitive function. Subjects with DAT had higher concentrations of CSF MHPG. In the overall sample, cognitive function was inversely correlated with CSF levels of MHPG but not with 5-HIAA or HVA. Within the DAT sample, these correlations did not achieve significance.

Personality disorder scores improve with effective pharmacotherapy of depression.

INTRODUCTION: We hypothesized that the probability of personality disorder ('PROB') predicted by the Temperament and Character Inventory ('TCI') would decline after successful pharmacotherapy of depression. METHODS: We administered a computerized version of the TCI to 15 patients with DSM-III-R major depression, before and after treatment with serotonergic antidepressants. RESULTS: PROB declined from 58.9% +/- 18.0% to 42.4% +/- 22.8% (P < 0.003), due to a significant increase in the Self-Directedness scale. This change in PROB correlated with improvement in self-rated severity of depression (P < 0.02). CONCLUSION: TCI prediction of personality disorder is susceptible to state effects of depression.

Impulsive aggression in personality disorder correlates with platelet 5-HT2A receptor binding.

The purpose of this study was to examine the relationship between platelet 5-HT2A receptor binding and aggressive behavior. 125I-LSD Bmax and Kd values were measured for 22 subjects meeting DMS-III-R criteria for one or more personality disorders and 12 healthy volunteer subjects. Aggression and impulsivity were assessed using the Buss-Durkee Hostility Inventory (BDHI) Assault scale, Life History of Aggression (LHA) scale, and the Barratt-11 Impulsiveness scale (BIS-11). Bmax and Kd values did not differ between personality disordered subjects and healthy volunteers. However, both Bmax and Kd values correlated positively with BDHI Assault scores in personality-disordered subjects but not in healthy volunteer subjects. These results suggest that assaultiveness in personality-disordered subjects may covary with increasing numbers, but decreasing affinity, of platelet 5-HT2A receptor sites labeled by 125I-LSD.

Depression and coronary heart disease: a review for cardiologists.

Major depression is a common comorbid condition in patients with coronary heart disease (CHD). Although mild emotional distress may be a normal reaction to myocardial infarction or other manifestations of CHD, major depression should not be considered a normal reaction, nor should it be ignored. Major depression is a debilitating comorbid disorder that can seriously complicate recovery and increase the risks of further cardiac morbidity and mortality. Fortunately, it is one that can be successfully treated in the majority of cases. The purpose of this review is to present the evidence for the negative prognostic effects of depression in cardiac patients and to discuss methods for assessing and treating depression in these patients.

How safe are serotonin reuptake inhibitors for depression in patients with coronary heart disease?

Depression occurs frequently in patients with coronary heart disease (CHD), and confers significant risk for additional morbidity and mortality. The cardiac effects of the tricyclic antidepressants (TCAs) have been well characterized. In contrast, the cardiac effects of the selective serotonin reuptake inhibitors (SSRIs) have been less thoroughly investigated. The Medline database from 1986 to 1996 was searched for all reports of cardiac effects of SSRIs, and this literature is summarized. In addition, potential drug interactions, reports of side effects, and efficacy studies in the elderly are reviewed. Finally, recommendations are made considering the risk/benefit ratio.

Stereological MRI volumetry of the frontal lobe.

Stereology was used to measure frontal lobe volume on magnetic resonance imaging (MRI) scans in a multi-observer repeated-measures trial in 17 adults. Prior to measurement, MR image volumes were reoriented into coronal sections perpendicular to the bicommissural plane. Three observers blinded to subject identify repeatedly used fixed grid stereology to estimate frontal lobe volumes, defined as all sections of the frontal lobe anterior to the anterior commissure. The lateral ventricles were excluded. Stereological measurement yielded high repeatability and precision, and was time efficient for the raters. The coefficient of error was 0.03. The inter-rater correlation coefficient = 0.95 for three raters; intra-rater correlation coefficients = 0.95-0.98. A comparison was made between stereological and traditional edge tracing measurement of the frontal lobe volumes. The overall correlation between the two methods was 0.95. The use of internal landmarks to define orientation and 3-D orthogonal views to define frontal lobe boundaries on 3-D images was critical to obtaining repeatable measurements. Frontal lobe volumetry by brain MR used to estimate small differences postulated to occur in certain psychiatric and neurologic disorders requires high precision and repeatability. Stereology, a semi-automated method, can reliably estimate frontal lobe volumes. This method may distinguish small frontal lobe volume differences within individuals and between groups.

CSF excitatory amino acids and severity of illness in Alzheimer's disease.

Researchers have proposed that increased release of excitatory amino acids (EAAs) is involved in the pathogenesis of dementia of the Alzheimer type (DAT), and CSF EAA concentrations have been measured to obtain evidence in support of this hypothesis. However, previous comparisons of CSF EAA concentrations in patients with DAT and in controls have yielded inconsistent results, perhaps because patient samples have been heterogeneous as to dementia severity. To determine whether there are changes in CSF concentrations of EAAs related to severity of illness in patients with DAT, we measured CSF concentrations of glutamate, aspartate, and taurine in 32 subjects with DAT, in whom we also assessed the severity of illness using clinical and neuropsychological measures, and 11 age-matched controls. The results suggested that increased CSF aspartate and glutamate concentrations, as well as decreased taurine concentrations, may occur in some persons with more advanced symptoms of DAT.

Impulsive aggression in personality disorder correlates with tritiated paroxetine binding in the platelet.

BACKGROUND: To examine the relationship between binding parameters of the platelet central serotonergic (5-HT) transporter and measures of aggression and impulsivity in adult human subjects. METHODS: Maximal number of platelet tritiated paroxetine binding sites (Bmax) and dissociation constant (Kd) values were measured in patients with personality disorder (n = 24) and healthy volunteers (n = 12). Measures of aggression and impulsivity included the total score and aggression subscale of the Life History of Aggression, the Motor Aggression factor and the assault subscale of the Buss-Durkee Hostility Inventory, and the total score and motor impulsivity subscale of the Barratt Impulsiveness Scale. RESULTS: The Bmax, but not Kd, values of platelet tritiated paroxetine binding was inversely correlated with the Life History of Aggression total score and aggression score and with the Buss-Durkee Hostility Inventory assault score in patients with personality disorder but not in healthy volunteer subjects. This relationship was independent of influences of factors related to depression, global function, or history of alcoholism or drug abuse. CONCLUSIONS: Reduced numbers of platelet 5-HT transporter sites may covary with life history of aggressive behavior in patients with personality disorder. This may represent another abnormality in 5-HT function in individuals with personality disorder and aggressive behavior.