The brain is the key organ of the response to stress because it determines what is threatening and, therefore, potentially stressful, as well as the physiological and behavioral responses which can be either adaptive or damaging. Stress involves two-way communication between the brain and the cardiovascular, immune, and other systems via neural and endocrine mechanisms. Beyond the "flight-or-fight" response to acute stress, there are events in daily life that produce a type of chronic stress and lead over time to wear and tear on the body ("allostatic load"). Yet, hormones associated with stress protect the body in the short-run and promote adaptation ("allostasis"). The brain is a target of stress, and the hippocampus was the first brain region, besides the hypothalamus, to be recognized as a target of glucocorticoids. Stress and stress hormones produce both adaptive and maladaptive effects on this brain region throughout the life course. Early life events influence life-long patterns of emotionality and stress responsiveness and alter the rate of brain and body aging. The hippocampus, amygdala, and prefrontal cortex undergo stress-induced structural remodeling, which alters behavioral and physiological responses. As an adjunct to pharmaceutical therapy, social and behavioral interventions such as regular physical activity and social support reduce the chronic stress burden and benefit brain and body health and resilience.

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Physiology and Neurobiology of Stress and Adaptation: Central Role of the Brain

http://findlab.stanford.edu/Publications/Biol%20Psych_in%20press.pdf

Resting-State Functional Connectivity in Major Depression: Abnormally Increased Contributions from Subgenual Cingulate Cortex and Thalamus

Depression is related to the normal emotions of sadness and bereavement, but it does not remit when the external cause of these emotions dissipates, and it is disproportionate to their cause. Classic severe states of depression often have no external precipitating cause. It is difficult, however, to draw clear distinctions between depressions with and those without psychosocial precipitating events. 1 The diagnosis of major depressive disorder requires a distinct change of mood, characterized by sadness or irritability and accompanied by at least several psychophysiological changes, such as disturbances in sleep, appetite, or sexual desire; constipation; loss of the ability to experience pleasure in work or with friends; crying; suicidal thoughts; and slowing of speech and action. These changes must last a minimum of 2 weeks and interfere considerably with work and family relations. On the basis of this broad definition, the lifetime incidence of depression in the United States is more than 12% in men and 20% in women. 2 Some have advocated a much narrower definition of severe depression, which they call melancholia or vital depression. 3 A small percentage of patients with major depression have had or will have manic episodes consisting of hyperactivity, euphoria, and an increase in pleasure seeking. Although some pathogenetic mechanisms in these cases and in cases of major depressive disorder overlap, a history of mania defines a distinct illness termed bipolar disorder. 4 Depression is a heterogeneous disorder with a highly variable course, an inconsistent response to treatment, and no established mechanism. This review presents the major current approaches to understanding the biologic mechanisms of major depression.

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Major depressive disorder.

Central effects of stress hormones in health and disease: understanding the protective and damaging effects of stress and stress mediators

http://homepages.gac.edu/~jwotton2/PSY385/Neuroplasticity.pdf

Stress, Depression, and Neuroplasticity: A Convergence of Mechanisms

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithmic association between illness duration and hippocampal volume. Reductions in hippocampal volume may not antedate illness onset, but volume may decrease at the greatest rate in the early years after illness onset.

https://www.pnas.org/content/pnas/100/3/1387.full.pdf

Course of illness, hippocampal function, and hippocampal volume in major depression

Studies have examined hippocampal function and volume in depressed subjects, but none have systematically compared never-treated first-episode patients with those who have had multiple episodes. We sought to compare hippocampal function, as assessed by performance on hippocampal-dependent recollection memory tests, and hippocampal volumes, as measured in a 1.5-T magnetic resonance imager, in depressed subjects experiencing a postpubertal onset of depression. Twenty never-treated depressed subjects in a first episode of depression were compared with matched healthy control subjects. Seventeen depressed subjects with multiple past episodes of depression were also compared with matched healthy controls and to the first-episode patients. Both first- and multiple-episode depressed groups had hippocampal dysfunction apparent on several tests of recollection memory; only depressed subjects with multiple depressive episodes had hippocampal volume reductions. Curve-fitting analysis revealed a significant logarithm...

/pdf/course-of-illness-hippocampal-function-and-hippocampal-30a0r1wbjw.pdf

Course of Illness, Hippocampal Function, and Hippocampal Volume in Major Depression

Iodine-123-α-methyl tyrosine has proven to be a promising SPECT agent for imaging amino acid uptake in tumors. We developed L-[3-18F]-α-methyl tyrosine (FMT) for PET studies. The aim of this study was to investigate its potential use as a tumor-detecting agent by using tumor-bearing mice. Methods: We investigated the biodistribution in normal BALB/C mice and BALB/cA nude mice bearing human rectal cancer cell line (LS180) until 120 min postinjection. FMT tumor uptake at 60 min postinjection in mice with LS180 rectal cancer, RPMI1788 B-cell lymphoma and MCF7 mammary cell carcinoma was assessed, and the results were compared with 18F-fluoro-2-deoxy-D-glucose (FDG) tumor uptake. The effect of competitive inhibition of large neutral amino acid transport system using unlabeled L-alanine was also investigated. Results: The amount of FMT in blood fell to 1.05%ID/20 g at 60 min postinjection, whereas that in the pancreas was 15.2%ID/20 g, resulting in a high pancreas-to-blood ratio of 14.5. In other organs, initial uptake peaked at 5 min postinjection and then declined with time. In LS180 tumor-bearing mice, peak FMT uptake in tumor was observed at 60 min postinjection.Tumor-to-blood and tumor-to-muscle ratios ranged from 1.60 to 2.94 and from 2.79 to 3.25 over the 120-min observation period. Tumor uptake of FMT was clearly reduced by inhibition of the amino acid transport system. In mice with LS180 and MCF7 tumors, FMT tumor uptake at 60 min postinjection was significantly higher than FDG tumor uptake, whereas in RPMI1788 lymphoma, uptake of FDG was significantly higher than FMT tumor uptake. Tumor-to-blood ratios of FMT in mice with LS180, RPMI1788 and MCF7 tumor at 60 min postinjection were 1.82, 5.88 and 3.56, respectively. Conclusion: FMT, like other fluorinated amino acids, may become a promising tumor-detecting agent for PET, assuming that efficient methods of radiosynthesis are developed.

https://jnm.snmjournals.org/content/39/4/663.full.pdf

Biodistribution studies on L-3-[Fluorine-18]Fluoro-α-methyl tyrosine: A potential tumor-detecting agent

UNLABELLED We have developed 18F-labeled alpha-methyl tyrosine (FMT) for PET imaging. The aim of this study was to evaluate the clinical application potential of FMT for patients with brain tumors. METHODS Eleven healthy volunteers and 20 patients with brain tumors were injected with 185 MBq (5 mCi) FMT. In 3 healthy volunteers, whole-body imaging and urinary and plasma analysis were conducted for the assessment of the biodistribution of FMT. The normal range of cortical standardized uptake value (SUV) as a reference for comparing tumor SUV of FMT was estimated by using PET data obtained at 30 min postinjection in 8 healthy volunteers. Dynamic PET scans were conducted for 100 min in 4 healthy volunteers and for 30 min in 15 patients with brain tumors. The 10-min static images in another 4 volunteers and all patients were obtained at 30 min postinjection. In 13 patients, FMT uptake in the brain tumor was compared with 18F-fluorodeoxyglucose (FDG). Tumor-to-normal cortex count (T/N) ratio and tumor-to-white matter count (T/W) ratio and SUVs of brain tumors were determined on FMT and FDG PET images. RESULTS Approximately 1480 MBq (40 mCi) FMT were produced in one radiosynthesis. Percentage injected dose (%ID) of FMT in the brain ranged from 2.8% to 4.9%, and approximately 50%ID of FMT was excreted in urine during 60 min postinjection, of which 86.6% was unmetabolized FMT. A faint physiological brain uptake with SUV of 1.61 +/- 0.32 (mean +/- SD, n = 8) was observed in healthy volunteers. Tumor SUV of FMT ranged from 1.2 to 8.2, with mean value of 2.83 +/- 1.57 (n = 23), which was significantly higher than that of the cortical area in healthy volunteers (P < 0.01). T/N and T/W ratios of FMT were significantly higher than those of FDG (2.53 +/- 1.31 versus 1.32 +/- 1.46, P < 0.001; 3.99 +/- 2.10 versus 1.39 +/- 0.65, P < 0.0001, respectively). CONCLUSION FMT, like other radiolabeled amino acids, can provide high-contrast PET images of brain tumors.

18F α-methyl tyrosine PET studies in patients with brain tumors

We assessed the accuracy of the standardized uptake value (SUV) measured by simultaneous emission and transmission scanning in cancer patients using FDG positron emission tomography (PET). Conventional, independent emission (E)/transmission (T) scans and simultaneous E/T scans were conducted consecutively in 30 patients who underwent FDG PET examinations. The SUVs of 35 mass lesions and 34 selected normal tissues were derived from the independent E/T scan and simultaneous E/T scan. Experimental studies using a cylindrical phantom were also conducted to evaluate the accuracy and reproducibility of the SUV derived from a simultaneous E/T scan. The SUVs of 18 F solution in the phantom were estimated to be approximately 1, with high reproducibility in the range of total counts observed in the clinical examinations. There were no significant differences in the SUVs in 35 tumours derived from simultaneous E/T scans and those derived from independent scans, and there was a strong positive correlation between the two (r = 0.99, P < 0.01). There were also no significant differences in the SUVs in 34 normal tissue regions derived from simultaneous E/T scans and those derived from independent scans. In conclusion, simultaneous E/T scanning with FDG in patients with malignant tumours is a valid method, since the SUV derived from the simultaneous scan is accurate and reproducible.

Shigeko Amano

Papers

Course of illness, hippocampal function, and hippocampal volume in major depression

Course of Illness, Hippocampal Function, and Hippocampal Volume in Major Depression

Biodistribution studies on L-3-[Fluorine-18]Fluoro-α-methyl tyrosine: A potential tumor-detecting agent

18F α-methyl tyrosine PET studies in patients with brain tumors

Accuracy of standardized uptake value measured by simultaneous emission and transmission scanning in PET oncology.