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...

These results suggest multiple sources of dysregulation in emotional and cognitive control circuitry in depression, implicating both top-down and bottom-up dysfunction.

Objective: We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.Methods: Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.Results: Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p , 0.05) or bilateral (p , 0.001). Bilateral IED during the memory maintenance period had a similar effect (p , 0.01), particularly with spike-wave complexes of longer duration (p , 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.Conclusions: Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur. Neurology â 2013;81:18-24 GLOSSARY CI 5 confidence interval; DMTS 5 delayed-match-to-sample task; GEE 5 generalized estimating equations; IAT 5 intracarotid amobarbital testing; IED 5 interictal epileptiform discharges; OR 5 odds ratio; TLE 5 temporal lobe epilepsy.Temporal lobe epilepsy (TLE) is the most common focal epilepsy in adults, and is associated with memory impairment, 1,2 which affects psychosocial functioning and quality of life. 3 These deficits are attributed to etiologic changes in the hippocampus such as cell death and synaptic reorganization. 4 However, dynamic factors such as interictal abnormalities evident on EEG may impart an independent contribution to neuropsychological outcome. 5Interictal epileptiform discharges (IED) in the cortex, detected with routine scalp EEG recordings, are associated with transient cognitive impairment.6-12 By extension, it is likely that IED in the mesial temporal lobes may affect cognition given the role of these structures in learning and memory. One study 13 showed a 6% decline in working memory performance related to mesial temporal IED. However, as demonstrated in previous studies of cortical IED, 9,10 the degree of cognitive impact could have been underestimated since the authors did not consider 1) the precise timing of the IED within the memory task trials and 2) the specific components involved in memory processing.Using a rodent model of TLE, 14 we recently found that hippocampal IED w...

The sample was fairly homogeneous and this may limit generalizability.