Yvette I. Sheline

Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory

Alzheimers disease (AD) and antecedent factors associated with AD were explored using amyloid imaging and unbiased measures of longitudinal atrophy in combination with reanalysis of previous metabolic and functional studies. In total, data from 764 participants were compared across five in vivo imaging methods. Convergence of effects was seen in posterior cortical regions, including posterior cingulate, retrosplenial, and lateral parietal cortex. These regions were active in default states in young adults and also showed amyloid deposition in older adults with AD. At early stages of AD progression, prominent atrophy and metabolic abnormalities emerged in these posterior cortical regions; atrophy in medial temporal regions was also observed. Event-related functional magnetic resonance imaging studies further revealed that these cortical regions are active during successful memory retrieval in young adults. One possibility is that lifetime cerebral metabolism associated with regionally specific default activity predisposes cortical regions to AD-related changes, including amyloid deposition, metabolic disruption, and atrophy. These cortical regions may be part of a network with the medial temporal lobe whose disruption contributes to memory impairment.

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.

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.

Mood Disorders in the Medically Ill: Scientific Review and Recommendations

OBJECTIVE The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research. DATA SOURCES Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors. STUDY SELECTION/DATA EXTRACTION Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized, controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed. CONCLUSIONS A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

The default mode network and self-referential processes in depression

The recently discovered default mode network (DMN) is a group of areas in the human brain characterized, collectively, by functions of a self-referential nature. In normal individuals, activity in the DMN is reduced during nonself-referential goal-directed tasks, in keeping with the folk-psychological notion of losing ones self in ones work. Imaging and anatomical studies in major depression have found alterations in both the structure and function in some regions that belong to the DMN, thus, suggesting a basis for the disordered self-referential thought of depression. Here, we sought to examine DMN functionality as a network in patients with major depression, asking whether the ability to regulate its activity and, hence, its role in self-referential processing, was impaired. To do so, we asked patients and controls to examine negative pictures passively and also to reappraise them actively. In widely distributed elements of the DMN [ventromedial prefrontal cortex prefrontal cortex (BA 10), anterior cingulate (BA 24/32), lateral parietal cortex (BA 39), and lateral temporal cortex (BA 21)], depressed, but not control subjects, exhibited a failure to reduce activity while both looking at negative pictures and reappraising them. Furthermore, looking at negative pictures elicited a significantly greater increase in activity in other DMN regions (amygdala, parahippocampus, and hippocampus) in depressed than in control subjects. These data suggest depression is characterized by both stimulus-induced heightened activity and a failure to normally down-regulate activity broadly within the DMN. These findings provide a brain network framework within which to consider the pathophysiology of depression.

Resting-state functional MRI in depression unmasks increased connectivity between networks via the dorsal nexus

To better understand intrinsic brain connections in major depression, we used a neuroimaging technique that measures resting state functional connectivity using functional MRI (fMRI). Three different brain networks—the cognitive control network, default mode network, and affective network—were investigated. Compared with controls, in depressed subjects each of these three networks had increased connectivity to the same bilateral dorsal medial prefrontal cortex region, an area that we term the dorsal nexus. The dorsal nexus demonstrated dramatically increased depression-associated fMRI connectivity with large portions of each of the three networks. The discovery that these regions are linked together through the dorsal nexus provides a potential mechanism to explain how symptoms of major depression thought to arise in distinct networks—decreased ability to focus on cognitive tasks, rumination, excessive self-focus, increased vigilance, and emotional, visceral, and autonomic dysregulation—could occur concurrently and behave synergistically. It suggests that the newly identified dorsal nexus plays a critical role in depressive symptomatology, in effect “hot wiring” networks together; it further suggests that reducing increased connectivity of the dorsal nexus presents a potential therapeutic target.

Neuroimaging studies of mood disorder effects on the brain

Studies of early-onset recurrent depression, late life depression associated with neurologic disorders, and bipolar illness have revealed structural brain changes within a neuroanatomical circuit. This circuit, originally described by, has been termed the limbic-cortical-striatal-pallidal-thalamic tract and is comprised of structures which are extensively interconnected. In three-dimensional magnetic resonance imaging studies of affective illness, many of the structures that comprise this tract have been found to have volume loss or structural abnormalities. Mechanisms proposed to explain volume loss in depression include glucocorticoid neurotoxicity, decreased brain-derived growth factor, decreased neurogenesis, and loss of plasticity.

Amygdala core nuclei volumes are decreased in recurrent major depression.

THE amygdala is a key structure in the brains integration of emotional meaning with perception and experience.1 Patients with depression have impaired functioning in emotional tasks involving the amygdala,2 and have abnormal resting amygdala blood flow.3 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 reduction4 the volume loss in this closely related structure suggests a shared effect on both structures, potentially glucocorticoid-induced neurotoxicity5 mediated by the extensive reciprocal glutamatergic connections.

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.

Amyloid Plaques Disrupt Resting State Default Mode Network Connectivity in Cognitively Normal Elderly

BACKGROUND Important functional connections within the default mode network (DMN) are disrupted in Alzheimers disease (AD), likely from amyloid-beta (Abeta) plaque-associated neuronal toxicity. Here, we sought to determine if pathological effects of Abeta amyloid plaques could be seen, even in the absence of a task, by examining functional connectivity in cognitively normal participants with and without preclinical amyloid deposition. METHODS Participants with Alzheimers disease (AD) (n = 35) were compared with 68 cognitively normal participants who were further subdivided by positron emission tomography (PET) Pittsburgh Compound-B (PIB) imaging into those without evidence of brain amyloid (PIB-) and those with brain amyloid (PIB+) deposition. RESULTS Resting state functional magnetic resonance imaging (fMRI) demonstrated that, compared with the PIB- group, the PIB+ group differed significantly in functional connectivity of the precuneus to hippocampus, parahippocampus, anterior cingulate, dorsal cingulate, gyrus rectus, superior precuneus, and visual cortex. These differences were in the same regions and in the same direction as differences found in the AD group. CONCLUSIONS Thus, before any manifestations of cognitive or behavioral changes, there were differences in resting state connectivity in cognitively normal subjects with brain amyloid deposition, suggesting that early manifestation of Abeta toxicity can be detected using resting state fMRI.