An offshoot of the monoamine hypothesis suggests that monoamine oxidase A MAO-A , an enzyme which metabolizes monoamines, may be overly active in depressed people. The Lactose Operon Review 2 pages Concept 3: The model attempts to relate specific symptoms of depression to neurological abnormalities. A 40 percent solution of formaldehyde in water is formalin , a liquid used for preserving biological specimens. At present, assessment of zinc nutriture is complex, involving a number of chemical and functional measurements that have limitations in sensitivity and specificity.
This is supported by the observation that both acute and subchronic SSRI administration increases response to positive faces. The fusiform gyrus and other visual processing areas respond more strongly to positive stimuli with antidepressant treatment, which is thought to reflect the a positive processing bias.
One meta analysis of functional neuroimaging in depression observed a pattern of abnormal neural activity hypothesized to reflect an emotional processing bias.
Relative to controls, depressed patients showed hyperactivity of circuits in the salience network SN , composed of the pulvinar nuclei , the insula , and the dorsal anterior cingulate cortex dACC , as well as decreased activity in regulatory circuits composed of the striatum and dlPFC.
A neuroanatomical model called the limbic-cortical model has been proposed to explain early biological findings in depression. The model attempts to relate specific symptoms of depression to neurological abnormalities. Elevated resting amygdala activity was proposed to underlie rumination, as stimulation of the amygdala has been reported to be associated with the intrusive recall of negative memories.
The ACC was divided into pregenual pgACC and subgenual regions sgACC , with the former being electrophysiologically associated with fear, and the latter being metabolically implicated in sadness in healthy subjects. Hyperactivity of the lateral orbitofrontal and insular regions, along with abnormalities in lateral prefrontal regions was suggested to underlie maladaptive emotional responses, given the regions roles in reward learning.
Reduced striatal activity, elevated OFC activity, and elevated sgACC activity were all findings consistent with the proposed models.
However, amygdala activity was reported to be decreased, contrary to the limbic-cortical model. Furthermore, only lateral prefrontal regions were modulated by treatment, indicating that prefrontal areas are state markers i. While depression severity as a whole is not correlated with a blunted neural response to reward, anhedonia is directly correlated to reduced activity in the reward system.
Anhedonia is broadly defined as a reduced ability to feel pleasure , but questionnaires and clinical assessments rarely distinguish between motivational "wanting" and consummatory "liking". While a number of studies suggest that depressed subjects rate positive stimuli less positively and as less arousing, a number of studies fail to find a difference. Furthermore, response to natural rewards such as sucrose does not appear to be attenuated.
General affective blunting may explain "anhedonic" symptoms in depression, as meta analysis of both positive and negative stimuli reveal reduced rating of intensity. Residual anhedonia that is not well targeted by serotonergic antidepressants is hypothesized to result from inhibition of dopamine release by activation of 5-HT2C receptors in the striatum.
The lateral OFC shows sustained response to absence of reward or punishment, and it is thought to be necessary for modifying behavior in response to changing contingencies.
Hypersensitivity in the lOFC may lead to depression by producing a similar effect to learned helplessness in animals.
Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. However, this is only apparent when correcting for the prominent reduction in sgACC volume associated with depression; structural abnormalities are evident at a cellular level, as neuropathological studies report reduced sgACC cell markers.
The model of depression proposed from these findings by Drevets et al. More extensive sgACC and general prefrontal recruitment during positive emotional processing was associated with blunted subcortical response to positive emotions, and subject anhedonia. This was interpreted by the authors to reflect a downregulation of positive emotions by the excessive recruitment of the prefrontal cortex.
While a number of neuroimaging findings are consistently reported in people with major depressive disorder, the heterogeneity of depressed populations presents difficulties interpreting these findings. For example, averaging across populations may hide certain subgroup related findings; while reduced dlPFC activity is reported in depression, a subgroup may present with elevated dlPFC activity.
Averaging may also yield statistically significant findings, such as reduced hippocampal volumes, that are actually present in a subgroup of patients.
Meta analyses performed using seed-based d mapping have reported grey matter reductions in a number of frontal regions. One meta analysis of early onset general depression reported grey matter reductions in the bilateral anterior cingulate cortex ACC and dorsomedial prefrontal cortex dmPFC. Increases in thalamic and ACC grey matter was reported in the medication free and medicated populations respectively. Using statistical parametric mapping, one meta analysis replicated previous findings of reduced grey matter in the ACC, medial prefrontal cortex, inferior frontal gyrus, hippocampus and thalamus; however reductions in the OFC and ventromedial prefrontal cortex grey matter were also reported.
Two studies on depression from the ENIGMA consortium have been published, one on cortical thickness, and the other on subcortical volume.
Reduced cortical thickness was reported in the bilateral OFC, ACC, insula, middle temporal gyri, fusiform gyri, and posterior cingulate cortices, while surface area deficits were found in medial occipital, inferior parietal, orbitofrontal and precentral regions. Multiple meta analysis have been performed on studies assessing white matter integrity using fractional anisotropy FA. Reduced FA has been reported in the corpus callosum CC in both first episode medication naive,   and general major depressive populations.
Medication naive patients have been reported to have reductions only in the body of the CC  and only in the genu of the CC. Studies of resting state activity have utilized a number of indicators of resting state activity, including regional homogeneity ReHO , amplitude of low frequency fluctuations ALFF , fractional amplitude of low frequency fluctuations fALFF , arterial spin labeling ASL , and positron emission tomography measures of regional cerebral blood flow or metabolism.
Research on the brains of depressed patients usually shows disturbed patterns of interaction between multiple parts of the brain. Several areas of the brain are implicated in studies seeking to more fully understand the biology of depression:. Studies have shown that Brodmann area 25 , also known as subgenual cingulate, is metabolically overactive in treatment-resistant depression.
This region is extremely rich in serotonin transporters and is considered as a governor for a vast network involving areas like hypothalamus and brain stem , which influences changes in appetite and sleep; the amygdala and insula , which affect the mood and anxiety; the hippocampus , which plays an important role in memory formation; and some parts of the frontal cortex responsible for self-esteem.
Thus disturbances in this area or a smaller than normal size of this area contributes to depression. Deep brain stimulation has been targeted to this region in order to reduce its activity in people with treatment resistant depression. One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants.
However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results. The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis. Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis.
Through the dysfunction, the effects of stress can be exacerbated including its effects on 5-HT. Furthermore, some of these effects are reversed by antidepressant action, which may act by increasing hippocampal neurogenesis.
This leads to a restoration in HPA activity and stress reactivity, thus restoring the deleterious effects induced by stress on 5-HT. The hypothalamic-pituitary-adrenal axis is a chain of endocrine structures that are activated during the body's response to stressors of various sorts.
Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In depressed patients the often shows increased activation in depressed people, but the mechanism behind this is not yet known. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. One drug, ketoconazole, currently under development has shown promise in treating MDD.
A number of animal models exist for depression, but they are limited in that depression involves primarily subjective emotional changes. However, some of these changes are reflected in physiology and behavior, the latter of which is the target of many animal models. These models are generally assessed according to four facets of validity; the reflection of the core symptoms in the model; the predictive validity of the model; the validity of the model with regard to human characteristics of etiology;  and the biological plausibility.
Different models for inducing depressive behaviors have been utilized; neuroanatomical manipulations such as olfactory bulbectomy or circuit specific manipulations with optogenetics; genetic models such as 5-HT1A knockout or selectively bred animals;  models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness.
Anhedonia and motivational deficits may, for example, be assessed via examining an animals level of engagement with rewarding stimuli such as sucrose or intracranial self-stimulation. Anxious and irritable symptoms may be assessed with exploratory behavior in the presence of a stressful or novelty environment, such as the open field test, novelty suppressed feeding, or the elevated plus maze. Fatigue, psychomotor poverty, and agitation may be assessed with locomotor activity, grooming activity, and open field tests.
Animal models possess a number of limitations due to the nature of depression. Some core symptoms of depression, such as rumination, low self-esteem, guilt, and depressed mood cannot be assessed in animals as they require subjective reporting. Therefore, attempts to model depression that seek to induce defeat or despair may actually reflect adaption and not disease. Furthermore, while depression and anxiety are frequently comorbid, dissociation of the two in animal models is difficult to achieve.
Regions involved in reward are common targets of manipulation in animal models of depression, including the nucleus accumbens NAc , ventral tegmental area VTA , ventral pallidum VP , lateral habenula LHb and medial prefrontal cortex mPFC. In animal models of depression, elevated activity has been reported in LHb neurons that project to the ventral tegmental area ostensibly reducing dopamine release. The LHb also projects to aversion reactive mPFC neurons, which may provide an indirect mechanism for producing depressive behaviors.
Ventral pallidum firing is also elevated by stress induced depression, an effect that is pharmacologically valid, and silencing of these neurons alleviates behavioral correlates of depression. Massive destruction of VTA neurons enhances depressive behaviors, while VTA neurons reduce firing in response to chronic stress. However, more recent specific manipulations of the VTA produce varying results, with the specific animal model, duration of VTA manipulation, method of VTA manipulation, and subregion of VTA manipulation all potentially leading to differential outcomes.
Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress induced depression. For example, inhibiting mPFC neurons specifically in the intralimbic cortex attenuates depressive behaviors. The conflicting findings associated with mPFC stimulation, when compared to the relatively specific findings in the infralimbic cortex, suggest that the prelimbic cortex and infralimbic cortex may mediate opposing effects.
Specific activation of these regions reduce immobility in the forced swim test, but do not affect open field or forced swim behavior. Inhibition of the raphe shifts the behavioral phenotype of uncontrolled stress to a phenotype closer to that of controlled stress. Recent studies have called attention to the role of altered neuroplasticity in depression.
A review found convergence of three phenomena:. The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants. I frequently see women reporting continued bone loss, despite use of pharmaceutical bone resorption inhibitors, when salivary cortisol levels are very high.
With saliva testing we see that when people have very high cortisol and low androgens they tend to have bone loss even when their progesterone and estrogen are normal. I see the most bone loss in women who have had a total hysterectomy. What is the relationship between cortisol and melatonin, yet another hormone? Cortisol is released from the adrenal glands in a rhythmic pattern throughout the day. This is why a good sleep is so important. People with high salivary night cortisol levels are usually complaining of sleep problems.
It can counter the stimulating effects of cortisol at night when you need to be sleeping. It involves a nearly painless finger prick to get a very small amount of blood that is dried on filter paper and mailed back to us with a completed questionnaire. If you're experiencing the symptoms that Dr. Originally published in the John R. Stress creates high cortisol levels, which creates hormone imbalances.
John Lee and Virginia Hopkins. May Not Tell You About Stress If you think stress might be affecting your health, you'll want to read this article about how tired adrenal glands can cause poor health and hormone imbalances. John Lee and Virginia Hopkins explain how the adrenal hormone cortisol work in the body, and how too much or too little can affect your health. The Sex Drive Solution for Women: Adrenal Function Tests Test your adrenal hormone levels to help determine if stress could be affecting your hormone balance.
An increasing number of associations between diseases and zinc status and apparently normal states of health, where additional zinc might be efficacious to prevent certain conditions, point at the pharmacology of zinc compounds as a promising area.
For example, relationships between zinc and diabetes mellitus are an area where research might prove fruitful.