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 one's self in one's 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.cognitive reappraisal ͉ fMRI ͉ medial prefrontal network ͉ emotional dysregulation ͉ activation differences W hen we engage in almost any goal-directed behavior of a nonself-referential nature, certain areas of the brain decrease their activity (1) when compared with a quiet resting state (e.g., awake with eyes closed). The consistency with which certain areas of the brain do so, regardless of the nature of the goal-directed task, led to the notion of an organized default mode of brain function (2) in which some regions are most active when we are in a resting state. The areas of the brain most consistently displaying such behavior regardless of task have come to be known as the default mode network (DMN) (3, 4), which consists of areas in dorsal and ventral medial prefrontal cortices, medial and lateral parietal cortex, and parts of the medial and lateral temporal cortices.Recently summarized data (4) indicate that the DMN is involved in the evaluation of potentially survival-salient information from the body and the world: perspective taking of the desires, beliefs, and intentions of others and in remembering the past as well as planning the future (2-4). All of these putative functions are self-referential in nature. Reduction of activity in the DMN during effortful cognitive processing (1, 5) can be interpreted as re...

Aerobic glycolysis is defined as glucose utilization in excess of that used for oxidative phosphorylation despite sufficient oxygen to completely metabolize glucose to carbon dioxide and water. Aerobic glycolysis is present in the normal human brain at rest and increases locally during increased neuronal activity; yet its many biological functions have received scant attention because of a prevailing energy-centric focus on the role of glucose as substrate for oxidative phosphorylation. As an initial step in redressing this neglect, we measured the regional distribution of aerobic glycolysis with positron emission tomography in 33 neurologically normal young adults at rest. We show that the distribution of aerobic glycolysis in the brain is differentially present in previously well-described functional areas. In particular, aerobic glycolysis is significantly elevated in medial and lateral parietal and prefrontal cortices. In contrast, the cerebellum and medial temporal lobes have levels of aerobic glycolysis significantly below the brain mean. The levels of aerobic glycolysis are not strictly related to the levels of brain energy metabolism. For example, sensory cortices exhibit high metabolic rates for glucose and oxygen consumption but low rates of aerobic glycolysis. These striking regional variations in aerobic glycolysis in the normal human brain provide an opportunity to explore how brain systems differentially use the diverse cell biology of glucose in support of their functional specializations in health and disease. W hen glucose metabolism exceeds that used for oxidative phosphorylation despite sufficient oxygen to metabolize glucose to carbon dioxide and water, it has traditionally been referred to as aerobic glycolysis. Aerobic glycolysis has a long history in cancer cell biology, where the phenomenon was first noted by Otto Warburg (1), for whom it is often referred to as the "Warburg effect." Since Warburg's early work (2), much research has focused on the reasons for aerobic glycolysis mainly in cancer cells (3-5). Topics have included, but are not limited to, the role of aerobic glycolysis in biosynthesis, the maintenance of cellular redox states, the regulation of apoptosis and the provision of ATP for membrane pumps and protein phosphorylation. Little attention has been paid to the normal brain in this regard, despite the well documented presence of aerobic glycolysis (6-8; noteworthy recent exception in ref. 9).From a whole-brain perspective, aerobic glycolysis may account for ∼10-12% of the glucose used in the adult human (6-8). This percentage varies in interesting ways. In the newborn, it represents more than 30% of the glucose metabolized (10). In the adult, aerobic glycolysis varies diurnally from a low in the morning of ∼11% to nearly 20% in the evening (7). In none of these observations do we have any information on the regional distribution of aerobic glycolysis in the brain or its role in cell biology.The only information presently on regional brain aerobic glycolysis relates to task...

Amyloid-β (Aβ) plaque deposition can precede the clinical manifestations of dementia of the Alzheimer type (DAT) by many years and can be associated with changes in brain metabolism. Both the Aβ plaque deposition and the changes in metabolism appear to be concentrated in the brain's default-mode network. In contrast to prior studies of brain metabolism which viewed brain metabolism from a unitary perspective that equated glucose utilization with oxygen consumption, we here report on regional glucose use apart from that entering oxidative phosphorylation (so-called "aerobic glycolysis"). Using PET, we found that the spatial distribution of aerobic glycolysis in normal young adults correlates spatially with Aβ deposition in individuals with DAT and cognitively normal participants with elevated Aβ, suggesting a possible link between regional aerobic glycolysis in young adulthood and later development of Alzheimer pathology.Alzheimer's disease | default mode network | positron emission tomography C erebral amyloid-β (Aβ) plaque deposition is a hallmark of Alzheimer's disease (AD) (1, 2), and there is clinical pathological evidence that Aβ deposition may precede clinical manifestation of cognitive deficits and dementia of the Alzheimer type (DAT) (3, 4). However, it is unclear whether the site and extent of Aβ deposition is related to any preceding pattern of brain activity or metabolism.A radiotracer with high affinity to Aβ plaques, N-methyl-[ 11 C] 2-(4′-methylaminophenyl)-6-hydroxybenzothiazole (or 11 C-PIB, for "Pittsburgh Compound-B"), has been developed for PET study and has demonstrated substantially increased regional uptake in individuals with DAT and also in some cognitively normal older persons (5-7). The spatial distribution of Aβ plaques by PET imaging in individuals with DAT appears strikingly similar to the default mode network (DMN), a group of brain regions that are more active when normal individuals are not engaged in attentiondemanding, goal-directed task performance (8-10).The unique distribution of Aβ in DAT suggests that something unique to these brain areas predisposes them to the pathophysiology of AD (9, 11). One of the many features of these areas is their reliance on glucose outside its usual role as substrate for oxidative phosphorylation (12). In adequately oxygenated tissue, this use of glucose usually is referred to as "aerobic glycolysis" and accounts for 10-15% of the glucose metabolized by the brain (13-15). It should be noted that the term "aerobic glycolysis" includes glycolysis itself (metabolism of glucose-6-phosphate to pyruvate) as well as glucose entering the pentose phosphate shunt and glycogen synthesis.Because many critical functions are associated with glucose outside its traditional role in supplying energy through oxidative phosphorylation (16)(17)(18)(19), this relationship might signal a causal element in the chain of events leading to DAT. As a first step in exploring this possibility, we wanted to confirm the apparent spatial relationship between DAT and those brai...

Slow (Ͻ0.1 Hz), spontaneous fluctuations in the functional magnetic resonance imaging blood oxygen level-dependent (BOLD) signal have been shown to exhibit phase coherence within functionally related areas of the brain. Surprisingly, this phenomenon appears to transcend levels of consciousness. The genesis of coherent BOLD fluctuations remains to be fully explained. We present a resting state functional connectivity study of a 6-year-old child with a radiologically normal brain imaged both before and after complete section of the corpus callosum for the treatment of intractable epilepsy. Postoperatively, there was a striking loss of interhemispheric BOLD correlations with preserved intrahemispheric correlations. These unique data provide important insights into the relationship between connectional anatomy and functional organization of the human brain. Such observations have the potential to increase our understanding of large-scale brain systems in health and disease as well as improve the treatment of neurologic disorders.

These findings support the hypothesis that the strategic location of white matter hyperintensities may be critical in late-life depression. Further, the correlation of neuropsychological deficits with the volumes of whole brain white matter hyperintensities and gray and white matter in depressed subjects but not comparison subjects supports the hypothesis of an interaction between these structural brain components and depressed status.

The brain exhibits spontaneous neural activity that depends on the behavioral state of the organism. We asked whether the blood oxygenation level-dependent (BOLD) signal reflects these modulations. BOLD was measured under three steady-state conditions: while subjects kept their eyes closed, kept their eyes open, or while fixating. The BOLD spectral density was calculated across brain voxels and subjects. Visual, sensory-motor, auditory, and retrosplenial cortex showed modulations of the BOLD spectral density by resting state type. All modulated regions showed greater spontaneous BOLD oscillations in the eyes closed than the eyes open or fixation conditions, suggesting that the differences were endogenously driven. Next, we examined the pattern of correlations between regions whose ongoing BOLD signal was modulated by resting state type. Regional neuronal correlations were estimated using an analytic procedure from the comparison of BOLD-BOLD covariances in the fixation and eyes closed conditions. Most regions were highly correlated with one another, with the exception of the primary visual cortices, which showed low correlations with the other regions. In conclusion, changes in resting state were associated with synchronous modulations of spontaneous BOLD oscillations in cortical sensory areas driven by two spatially overlapping, but temporally uncorrelated signals.

Amnestic Alzheimer's disease (AD) is characterized by early atrophy of the hippocampus and medial temporal lobes before spreading to the neocortex. In contrast, nonamnestic Alzheimer's patients have relative sparing of the hippocampus, but the pattern in which the disease spreads is unclear. We examined spreading disease in nonamnestic AD using a novel magnetic resonance imaging-based analysis adapted from pathologic staging studies, applied here to cross-sectional imaging data. We selected 240 T1-weighted scans from 129 patients with pathology confirmed by autopsy or cerebrospinal fluid, and atrophy maps were computed relative to 238 scans from 115 elderly controls. For each phenotype, the frequency of atrophy in 116 brain regions was used to infer the anatomical origin of disease and its progression across 4 phases of atrophy. Results from the amnestic cohort were used to determine appropriate parameter settings for the phase assignment algorithm, based on correspondence to Braak pathology staging. Phase 1 regions, which represent the origin of disease, included the hippocampus for the amnestic group (comprising 33 scans); left lateral temporal lobe for logopenic-variant primary progressive aphasia (88 scans); occipitoparietal cortex for posterior cortical atrophy (51 scans); temporoparietal cortex for corticobasal syndrome (31 scans); and frontotemporal cortex for behavioral/dysexecutive variant AD (37 scans). In nonamnestic patients, atrophy spread to other neocortical areas in later phases, but the hippocampus exhibited only late-phase atrophy in posterior cortical atrophy and corticobasal syndrome. Region-specific phase values were also associated with regional measures of tau, beta amyloid, neuronal loss, and gliosis for the subset of patients (n = 17) with neuropathology findings; this comparison represented a first validation of the phase assignment algorithm. We subsequently assigned a phase to each patient scan based on the similarity of regional atrophy patterns with atrophy predicted for the corresponding phenotype at each phase. Scan-specific phases were correlated with disease duration as well as global and domain-specific cognition, supporting these phase values as global estimates of patients' disease progression. Logistic regression models based on spatial overlap with model-predicted atrophy patterns reliably discriminated nonamnestic phenotypes from each other and from amnestic AD. The frequency-based phase assignment algorithm used in the present study thus represents a promising approach for studying the neocortical origin and spread of disease in nonamnestic AD.

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