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Saturday, May 13, 2023

Large-scale brain network

From Wikipedia, the free encyclopedia

Large-scale brain networks (also known as intrinsic brain networks) are collections of widespread brain regions showing functional connectivity by statistical analysis of the fMRI BOLD signal or other recording methods such as EEG, PET and MEG. An emerging paradigm in neuroscience is that cognitive tasks are performed not by individual brain regions working in isolation but by networks consisting of several discrete brain regions that are said to be "functionally connected". Functional connectivity networks may be found using algorithms such as cluster analysis, spatial independent component analysis (ICA), seed based, and others. Synchronized brain regions may also be identified using long-range synchronization of the EEG, MEG, or other dynamic brain signals.

The set of identified brain areas that are linked together in a large-scale network varies with cognitive function. When the cognitive state is not explicit (i.e., the subject is at "rest"), the large-scale brain network is a resting state network (RSN). As a physical system with graph-like properties, a large-scale brain network has both nodes and edges and cannot be identified simply by the co-activation of brain areas. In recent decades, the analysis of brain networks was made feasible by advances in imaging techniques as well as new tools from graph theory and dynamical systems.

Large-scale brain networks are identified by their function and provide a coherent framework for understanding cognition by offering a neural model of how different cognitive functions emerge when different sets of brain regions join together as self-organized coalitions. The number and composition of the coalitions will vary with the algorithm and parameters used to identify them. In one model, there is only the default mode network and the task-positive network, but most current analyses show several networks, from a small handful to 17. The most common and stable networks are enumerated below. The regions participating in a functional network may be dynamically reconfigured.

Disruptions in activity in various networks have been implicated in neuropsychiatric disorders such as depression, Alzheimer's, autism spectrum disorder, schizophrenia, ADHD and bipolar disorder.

Core networks

An example that identified 10 large-scale brain networks from resting state fMRI activity through independent component analysis.

Because brain networks can be identified at various different resolutions and with various different neurobiological properties, there is currently no universal atlas of brain networks that fits all circumstances. The Organization for Human Brain Mapping has the Workgroup for HArmonized Taxonomy of NETworks (WHATNET) group to work towards a consensus regarding network nomenclature. While the work continues, Uddin, Yeo, and Spreng proposed in 2019 that the following six networks should be defined as core networks based on converging evidences from multiple studies to facilitate communication between researchers.

Default Mode (Medial frontoparietal)

  • The default mode network is active when an individual is awake and at rest. It preferentially activates when individuals focus on internally-oriented tasks such as daydreaming, envisioning the future, retrieving memories, and theory of mind. It is negatively correlated with brain systems that focus on external visual signals. It is the most widely researched network.

Salience (Midcingulo-Insular)

  • The salience network consists of several structures, including the anterior (bilateral) insula, dorsal anterior cingulate cortex, and three subcortical structures which are the ventral striatum, substantia nigra/ventral tegmental region. It plays the key role of monitoring the salience of external inputs and internal brain events. Specifically, it aids in directing attention by identifying important biological and cognitive events.
  • This network includes the ventral attention network, which primarily includes the temporoparietal junction and the ventral frontal cortex of the right hemisphere. These areas respond when behaviorally relevant stimuli occur unexpectedly. The ventral attention network is inhibited during focused attention in which top-down processing is being used, such as when visually searching for something. This response may prevent goal-driven attention from being distracted by non-relevant stimuli. It becomes active again when the target or relevant information about the target is found.

Attention (Dorsal frontoparietal)

  • This network is involved in the voluntary, top-down deployment of attention. Within the dorsal attention network, the intraparietal sulcus and frontal eye fields influence the visual areas of the brain. These influencing factors allow for the orientation of attention.

Control (Lateral frontoparietal)

  • This network initiates and modulates cognitive control and comprises 18 sub-regions of the brain. There is a strong correlation between fluid intelligence and the involvement of the fronto-parietal network with other networks.
  • Versions of this network have also been called the central executive (or executive control) network and the cognitive control network.

Sensorimotor or Somatomotor (Pericentral)

  • This network processes somatosensory information and coordinates motion. The auditory cortex may be included.

Visual (Occipital)

  • This network handles visual information processing.

Other networks

Different methods and data have identified several other brain networks, many of which greatly overlap or are subsets of more well-characterized core networks.

  • Limbic
  • Auditory
  • Right/left executive
  • Cerebellar
  • Spatial attention
  • Language
  • Lateral visual
  • Temporal
  • Visual perception/imagery

Biology of depression

From Wikipedia, the free encyclopedia

Scientific studies have found that different brain areas show altered activity in humans with major depressive disorder (MDD), and this has encouraged advocates of various theories that seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. Factors spanning these causative groups include nutritional deficiencies in magnesium, vitamin D, and tryptophan with situational origin but biological impact. Several theories concerning the biologically based cause of depression have been suggested over the years, including theories revolving around monoamine neurotransmitters, neuroplasticity, neurogenesis, inflammation and the circadian rhythm. Physical illnesses, including hypothyroidism and mitochondrial disease, can also trigger depressive symptoms.

Neural circuits implicated in depression include those involved in the generation and regulation of emotion, as well as in reward. Abnormalities are commonly found in the lateral prefrontal cortex whose putative function is generally considered to involve regulation of emotion. Regions involved in the generation of emotion and reward such as the amygdala, anterior cingulate cortex (ACC), orbitofrontal cortex (OFC), and striatum are frequently implicated as well. These regions are innervated by a monoaminergic nuclei, and tentative evidence suggests a potential role for abnormal monoaminergic activity.

Genetic factors

Difficulty of gene studies

Historically, candidate gene studies have been a major focus of study. However, as the number of genes reduces the likelihood of choosing a correct candidate gene, Type I errors (false positives) are highly likely. Candidate genes studies frequently possess a number of flaws, including frequent genotyping errors and being statistically underpowered. These effects are compounded by the usual assessment of genes without regard for gene-gene interactions. These limitations are reflected in the fact that no candidate gene has reached genome-wide significance.

Gene candidates

5-HTTLPR

The 5-HTTLPR, or serotonin transporter promoter gene's short allele, has been associated with increased risk of depression; since the 1990s, however, results have been inconsistent. Other genes that have been linked to a gene–environment interaction include CRHR1, FKBP5 and BDNF, the first two of which are related to the stress reaction of the HPA axis, and the latter of which is involved in neurogenesis. Candidate gene analysis of 5-HTTLPR on depression was inconclusive on its effect, either alone or in combination with life stress.

A 2003 study proposed that a gene-environment interaction (GxE) may explain why life stress is a predictor for depressive episodes in some individuals, but not in others, depending on an allelic variation of the serotonin-transporter-linked promoter region (5-HTTLPR). This hypothesis was widely discussed in both the scientific literature and popular media, where it was dubbed the "Orchid gene", but has conclusively failed to replicate in much larger samples, and the observed effect sizes in earlier work are not consistent with the observed polygenicity of depression.

BDNF

BDNF polymorphisms have also been hypothesized to have a genetic influence, but early findings and research failed to replicate in larger samples, and the effect sizes found by earlier estimates are inconsistent with the observed polygenicity of depression.

SIRT1 and LHPP

A 2015 GWAS study in Han Chinese women positively identified two variants in intronic regions near SIRT1 and LHPP with a genome-wide significant association.

Norepinephrine transporter polymorphisms

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results.

One review identified multiple frequently studied candidate genes. The genes encoding for the 5-HTT and 5-HT2A receptor were inconsistently associated with depression and treatment response. Mixed results were found for brain-derived neurotrophic factor (BDNF) Val66Met polymorphisms. Polymorphisms in the tryptophan hydroxylase gene was found to be tentatively associated with suicidal behavior. A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E epsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk.

Circadian rhythm

Depression may be related to the same brain mechanisms that control the cycles of sleep and wakefulness.

Depression may be related to abnormalities in the circadian rhythm, or biological clock.

A well synchronized circadian rhythm is critical for maintaining optimal health. Adverse changes and alterations in the circadian rhythm have been associated various neurological disorders and mood disorders including depression.

Sleep

Sleep disturbance is the most prominent symptom in depressive patients. Studies about sleep electroencephalograms have shown characteristic changes in depression such as reductions in non-rapid eye movement sleep production, disruptions of sleep continuity and disinhibition of rapid eye movement (REM) sleep. Rapid eye movement (REM) sleep—the stage in which dreaming occurs—may be quick to arrive and intense in depressed people. REM sleep depends on decreased serotonin levels in the brain stem, and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation activates serotonergic neurons, leading to processes similar to the therapeutic effect of antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs). Depressed individuals can exhibit a significant lift in mood after a night of sleep deprivation. SSRIs may directly depend on the increase of central serotonergic neurotransmission for their therapeutic effect, the same system that impacts cycles of sleep and wakefulness.

Light therapy

Research on the effects of light therapy on seasonal affective disorder suggests that light deprivation is related to decreased activity in the serotonergic system and to abnormalities in the sleep cycle, particularly insomnia. Exposure to light also targets the serotonergic system, providing more support for the important role this system may play in depression. Sleep deprivation and light therapy both target the same brain neurotransmitter system and brain areas as antidepressant drugs, and are now used clinically to treat depression. Light therapy, sleep deprivation and sleep time displacement (sleep phase advance therapy) are being used in combination quickly to interrupt a deep depression in people who are hospitalized for MDD (Major Depressive Disorder).

Increased and decreased sleep length appears to be a risk factor for depression. People with MDD sometimes show diurnal and seasonal variation of symptom severity, even in non-seasonal depression. Diurnal mood improvement was associated with activity of dorsal neural networks. Increased mean core temperature was also observed. One hypothesis proposed that depression was a result of a phase shift.

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression.

Monoamines

Illustration of the major elements in a prototypical synapse. Synapses are gaps between nerve cells. These cells convert their electrical impulses into bursts of chemical relayers, called neurotransmitters, which travel across the synapses to receptors on adjacent cells, triggering electrical impulses to travel down the latter cells.

Monoamines are neurotransmitters that include serotonin, dopamine, norepinephrine, and epinephrine.

Monoamine hypothesis of depression

Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and dopamine. The observation of this efficacy led to the monoamine hypothesis of depression, which postulates that the deficit of certain neurotransmitters is responsible for depression, and even that certain neurotransmitters are linked to specific symptoms. Normal serotonin levels have been linked to mood and behaviour regulation, sleep, and digestion; norepinephrine to the fight-or-flight response; and dopamine to movement, pleasure, and motivation. Some have also proposed the relationship between monoamines and phenotypes such as serotonin in sleep and suicide, norepinephrine in dysphoria, fatigue, apathy, cognitive dysfunction, and dopamine in loss of motivation and psychomotor symptoms. The main limitation for the monoamine hypothesis of depression is the therapeutic lag between initiation of antidepressant treatment and perceived improvement of symptoms. One explanation for this therapeutic lag is that the initial increase in synaptic serotonin is only temporary, as firing of serotonergic neurons in the dorsal raphe adapt via the activity of 5-HT1A autoreceptors. The therapeutic effect of antidepressants is thought to arise from autoreceptor desensitization over a period of time, eventually elevating firing of serotonergic neurons.

Monoamine receptors affect phospholipase C and adenylyl cyclase inside of the cell. Green arrows means stimulation and red arrows inhibition. Serotonin receptors are blue, norepinephrine orange, and dopamine yellow. Phospholipase C and adenylyl cyclase start a signaling cascade which turn on or off genes in the cell. Sufficient ATP from mitochondria is required for these downstream signalling events. The 5HT-3 receptor is associated with gastrointestinal adverse effects and has no relationship to the other monoamine receptors.

Serotonin

The serotonin "chemical imbalance" theory of depression, proposed in the 1960s,  is not supported by the available scientific evidence. SSRIs alter the balance of serotonin inside and outside of neurons: their clinical antidepressant effect (which is robust in severe depression) is likely due to more complex changes in neuronal functioning which occur as a downstream consequence of this.

Initial studies of serotonin in depression examined peripheral measures such as the serotonin metabolite 5-Hydroxyindoleacetic acid (5-HIAA) and platelet binding. The results were generally inconsistent, and may not generalize to the central nervous system. However evidence from receptor binding studies and pharmacological challenges provide some evidence for dysfunction of serotonin neurotransmission in depression. Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioral and neural level. Pharmacologically reducing serotonin synthesis, and pharmacologically enhancing synaptic serotonin can produce and attenuate negative affective biases, respectively. These emotional processing biases may explain the therapeutic gap.

Dopamine

While various abnormalities have been observed in dopaminergic systems, results have been inconsistent. People with MDD have an increased reward response to dextroamphetamine compared to controls, and it has been suggested that this results from hypersensitivity of dopaminergic pathways due to natural hypoactivity. While polymorphisms of the D4 and D3 receptor have been implicated in depression, associations have not been consistently replicated. Similar inconsistency has been found in postmortem studies, but various dopamine receptor agonists show promise in treating MDD. There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems.

Catecholamines

A number of lines of evidence indicative of decreased adrenergic activity in depression have been reported. Findings include the decreased activity of tyrosine hydroxylase, decreased size of the locus coeruleus, increased alpha 2 adrenergic receptor density, and decreased alpha 1 adrenergic receptor density. Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression.

One method used to study the role of monoamines is monoamine depletion. Depletion of tryptophan (the precursor of serotonin), tyrosine and phenylalanine (precursors to dopamine) does result in decreased mood in those with a predisposition to depression, but not in persons lacking the predisposition. On the other hand, inhibition of dopamine and norepinephrine synthesis with alpha-methyl-para-tyrosine does not consistently result in decreased mood.

Monoamine oxidase

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. This would, in turn, cause the lowered levels of monoamines. This hypothesis received support from a PET study, which found significantly elevated activity of MAO-A in the brain of some depressed people. In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. Contrary to the assumptions of the monoamine hypothesis, lowered but not heightened activity of MAO-A was associated with depressive symptoms in adolescents. This association was observed only in maltreated youth, indicating that both biological (MAO genes) and psychological (maltreatment) factors are important in the development of depressive disorders. In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression.

Limitations

Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. For one thing, serotonin system dysfunction cannot be the sole cause of depression. Not all patients treated with antidepressants show improvements despite the usually rapid increase in synaptic serotonin. If significant mood improvements do occur, this is often not for at least two to four weeks. One possible explanation for this lag is that the neurotransmitter activity enhancement is the result of auto receptor desensitization, which can take weeks. Intensive investigation has failed to find convincing evidence of a primary dysfunction of a specific monoamine system in people with MDD. The antidepressants that do not act through the monoamine system, such as tianeptine and opipramol, have been known for a long time. There have also been inconsistent findings with regard to levels of serum 5-HIAA, a metabolite of serotonin. Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. Another problem that presents is that drugs that deplete monoamines may actually have antidepressants properties. Further, some have argued that depression may be marked by a hyperserotonergic state. Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public.

Receptor binding

As of 2012, efforts to determine differences in neurotransmitter receptor expression or for function in the brains of people with MDD using positron emission tomography (PET) had shown inconsistent results. Using the PET imaging technology and reagents available as of 2012, it appeared that the D1 receptor may be underexpressed in the striatum of people with MDD. 5-HT1A receptor binding literature is inconsistent; however, it leans towards a general decrease in the mesiotemporal cortex. 5-HT2A receptor binding appears to be unregulated in people with MDD. Results from studies on 5-HTT binding are variable, but tend to indicate higher levels in people with MDD. Results with D2/D3 receptor binding studies are too inconsistent to draw any conclusions. Evidence supports increased MAO activity in people with MDD, and it may even be a trait marker (not changed by response to treatment). Muscarinic receptor binding appears to be increased in depression, and, given ligand binding dynamics, suggests increased cholinergic activity.

Four meta analyses on receptor binding in depression have been performed, two on serotonin transporter (5-HTT), one on 5-HT1A, and another on dopamine transporter (DAT). One meta analysis on 5-HTT reported that binding was reduced in the midbrain and amygdala, with the former correlating with greater age, and the latter correlating with depression severity. Another meta-analysis on 5-HTT including both post-mortem and in vivo receptor binding studies reported that while in vivo studies found reduced 5-HTT in the striatum, amygdala and midbrain, post mortem studies found no significant associations. 5-HT1A was found to be reduced in the anterior cingulate cortex, mesiotemporal lobe, insula, and hippocampus, but not in the amygdala or occipital lobe. The most commonly used 5-HT1A ligands are not displaced by endogenous serotonin, indicating that receptor density or affinity is reduced. Dopamine transporter binding is not changed in depression.

Emotional processing and neural circuits

Emotional Bias

People with MDD show a number of biases in emotional processing, such as a tendency to rate happy faces more negatively, and a tendency to allocate more attentional resources to sad expressions. Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. Functional neuroimaging has demonstrated hyperactivity of various brain regions in response to negative emotional stimuli, and hypoactivity in response to positive stimuli. One meta analysis reported that depressed subjects showed decreased activity in the left dorsolateral prefrontal cortex and increased activity in the amygdala in response to negative stimuli. Another meta analysis reported elevated hippocampus and thalamus activity in a subgroup of depressed subjects who were medication naive, not elderly, and had no comorbidities. The therapeutic lag of antidepressants has been suggested to be a result of antidepressants modifying emotional processing leading to mood changes. This is supported by the observation that both acute and subchronic SSRI administration increases response to positive faces. Antidepressant treatment appears to reverse mood congruent biases in limbic, prefrontal, and fusiform areas. dlPFC response is enhanced and amygdala response is attenuated during processing of negative emotions, the former or which is thought to reflect increased top down regulation. 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. These effects do not appear to be unique to serotonergic or noradrenergic antidepressants, but also occur in other forms of treatment such as deep brain stimulation.

Neural circuits

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, people with MDD 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.

Rendition of the Limbic-cortical-striatal-pallidal-thalamic circuit as described by Drevets et al. 2008

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. This model and another termed "the cortical striatal model", which focused more on abnormalities in the cortico-basal ganglia-thalamo-cortical loop, have been supported by recent literature. 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.e.,. dependent upon mood), while subcortical abnormalities are trait markers (i.e., reflect a susceptibility).

Reward

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. The study of reward in depression is limited by heterogeneity in the definition and conceptualizations of reward and anhedonia. 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. As anhedonia is a prominent symptom of depression, direct comparison of depressed with healthy subjects reveals increased activation of the subgenual anterior cingulate cortex (sgACC), and reduced activation of the ventral striatum, and in particular the nucleus accumbens (NAcc) in response to positive stimuli. Although the finding of reduced NAcc activity during reward paradigms is fairly consistent, the NAcc is made up of a functionally diverse range of neurons, and reduced blood-oxygen-level dependent (BOLD) signal in this region could indicate a variety of things including reduced afferent activity or reduced inhibitory output. Nevertheless, these regions are important in reward processing, and dysfunction of them in depression is thought to underlie anhedonia. 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 response to reward in the medial orbitofrontal cortex (OFC) is attenuated in depression, while lateral OFC response is enhanced to punishment. 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. Treatment is also associated with attenuated activity in the sgACC, and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. Contrary to studies of functional magnetic resonance imaging response in the sgACC during tasks, resting metabolism is reduced in the sgACC. 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. suggests that reduced sgACC activity results in enhanced sympathetic nervous system activity and blunted HPA axis feedback. Activity in the sgACC may also not be causal in depression, as the authors of one review that examined neuroimaging in depressed subjects during emotional regulation hypothesized that the pattern of elevated sgACC activity reflected increased need to modulate automatic emotional responses in depression. 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.

Neuroanatomy

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 subjects. Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression.

Structural neuroimaging

GMV reductions in MDD and BD

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). One meta analysis on first episode depression observed distinct patterns of grey matter reductions in medication free, and combined populations; medication free depression was associated with reductions in the right dorsolateral prefrontal cortex, right amygdala, and right inferior temporal gyrus; analysis on a combination of medication free and medicated depression found reductions in the left insula, right supplementary motor area, and right middle temporal gyrus. Another review distinguishing medicated and medication free populations, albeit not restricted to people with their first episode of MDD, found reductions in the combined population in the bilateral superior, right middle, and left inferior frontal gyrus, along with the bilateral parahippocampus. Increases in thalamic and ACC grey matter was reported in the medication free and medicated populations respectively. A meta analysis performed using "activation likelihood estimate" reported reductions in the paracingulate cortex, dACC and amygdala.

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. Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression.

MDD is associated with reduced FA in the ALIC and genu/body of the CC

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. The extent of CC reductions differs from study to study. People with MDD who have not taken antidepressants before have been reported to have reductions only in the body of the CC and only in the genu of the CC. On the other hand, general MDD samples have been reported to have reductions in the body of the CC, the body and genu of the CC, and only the genu of the CC. Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) and superior longitudinal fasciculus.

Functional neuroimaging

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.

Studies using ALFF and fALFF have reported elevations in ACC activity, with the former primarily reporting more ventral findings, and the latter more dorsal findings. A conjunction analysis of ALFF and CBF studies converged on the left insula, with previously untreated people having increased insula activity. Elevated caudate CBF was also reported A meta analysis combining multiple indicators of resting activity reported elevated anterior cingulate, striatal, and thalamic activity and reduced left insula, post-central gyrus and fusiform gyrus activity. An activation likelihood estimate (ALE) meta analysis of PET/SPECT resting state studies reported reduced activity in the left insula, pregenual and dorsal anterior cingulate cortex and elevated activity in the thalamus, caudate, anterior hippocampus and amygdala. Compared to the ALE meta analysis of PET/SPECT studies, a study using multi-kernel density analysis reported hyperactivity only in the pulvinar nuclei of the thalamus.

Brain regions

Research on the brains of people with MDD 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:

Subgenual cingulate

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.

Prefrontal cortex

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. The prefrontal cortex is involved in emotional processing and regulation, and dysfunction of this process may be involved in the etiology of depression. One study on antidepressant treatment found an increase in PFC activity in response to administration of antidepressants. One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. One study suggested that areas of the prefrontal cortex are part of a network of regions including dorsal and pregenual cingulate, bilateral middle frontal gyrus, insula and superior temporal gyrus that appear to be hypoactive in people with MDD. However the authors cautioned that the exclusion criteria, lack of consistency and small samples limit results.

Amygdala

The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. The amygdala in unmedicated depressed persons tended to be smaller than in those that were medicated, however aggregate data shows no difference between depressed and healthy persons. During emotional processing tasks right amygdala is more active than the left, however there is no differences during cognitive tasks, and at rest only the left amygdala appears to be more hyperactive. One study, however, found no difference in amygdala activity during emotional processing tasks.

Hippocampus

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. This leads to alteration in emotion and cognition related brain regions as well as HPA axis dysfunction. 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. The HPA axis involves three structure, the hypothalamus which release CRH that stimulates the pituitary gland to release ACTH which stimulates the adrenal glands to release cortisol. Cortisol has a negative feedback effect on the pituitary gland and hypothalamus. In people with MDD this often shows increased activation in depressed people, but the mechanism behind this is not yet known. Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. Early life stress has been hypothesized as a potential cause of HPA dysfunction. HPA axis regulation may be examined through a dexamethasone suppression tests, which tests the feedback mechanisms. Non-suppression of dexamethasone is a common finding in depression, but is not consistent enough to be used as a diagnostic tool. HPA axis changes may be responsible for some of the changes such as decreased bone mineral density and increased weight found in people with MDD. One drug, ketoconazole, currently under development has shown promise in treating MDD.

Hippocampal Neurogenesis

Reduced hippocampal neurogenesis leads to a reduction in hippocampal volume. A genetically smaller hippocampus has been linked to a reduced ability to process psychological trauma and external stress, and subsequent predisposition to psychological illness. Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction.

Animal Models

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. The validity of these models in producing depressive behaviors may be assessed with a number of behavioral tests. Anhedonia and motivational deficits may, for example, be assessed via examining an animal's 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. From an evolutionary standpoint, the behavior correlates of defeats of loss are thought to be an adaptive response to prevent further loss. Therefore, attempts to model depression that seeks 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. Pharmacological assessment of validity is frequently disconnected from clinical pharmacotherapeutics in that most screening tests assess acute effects, while antidepressants normally take a few weeks to work in humans.

Neurocircuits

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). Tentative fMRI studies in humans demonstrate elevated LHb activity in depression. The lateral habenula projects to the RMTg to drive inhibition of dopamine neurons in the VTA during omission of reward. 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. Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. A number of inputs to the LHb have been implicated in producing depressive behaviors. Silencing GABAergic projections from the NAc to the LHb reduces conditioned place preference induced in social aggression, and activation of these terminals induces CPP. 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. Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. This led to early studies investigating VTA activity and manipulations in animal models 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. Stress and social defeat induced depressive symptoms, including anhedonia, are associated with potentiation of excitatory inputs to Dopamine D2 receptor-expressing medium spiny neurons (D2-MSNs) and depression of excitatory inputs to Dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs). Optogenetic excitation of D1-MSNs alleviates depressive symptoms and is rewarding, while the same with D2-MSNs enhances depressive symptoms. Excitation of glutaminergic inputs from the ventral hippocampus reduces social interactions, and enhancing these projections produces susceptibility to stress-induced depression. Manipulations of different regions of the mPFC can produce and attenuate depressive behaviors. 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. mPFC projections to the raphe nuclei are largely GABAergic and inhibit the firing of serotonergic neurons. 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.

Altered neuroplasticity

Recent studies have called attention to the role of altered neuroplasticity in depression. A review found a convergence of three phenomena:

  1. Chronic stress reduces synaptic and dendritic plasticity
  2. Depressed subjects show evidence of impaired neuroplasticity (e.g. shortening and reduced complexity of dendritic trees)
  3. Anti-depressant medications may enhance neuroplasticity at both a molecular and dendritic level.

The conclusion is that disrupted neuroplasticity is an underlying feature of depression, and is reversed by antidepressants.

Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. Post mortem studies and rat models demonstrate decreased neuronal density in the prefrontal cortex thickness in people with MDD. Rat models demonstrate histological changes consistent with MRI findings in humans, however studies on neurogenesis in humans are limited. Antidepressants appear to reverse the changes in neurogenesis in both animal models and humans.

Inflammation

Various reviews have found that general inflammation may play a role in depression. One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. Meta analysis on cytokine levels in people with MDD have demonstrated increased levels of IL-1, IL-6, C-reactive protein, but not IL-10. Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. Cytokines, by manipulating neurotransmitters, are involved in the generation of sickness behavior, which shares some overlap with the symptoms of depression. Neurotransmitters hypothesized to be affected include dopamine and serotonin, which are common targets for antidepressant drugs. Induction of indolamine-2,3 dioxygenease by cytokines has been proposed as a mechanism by which immune dysfunction causes depression. One review found normalization of cytokine levels after successful treatment of depression. A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. Exercise can act as a stressor, decreasing the levels of IL-6 and TNF-a and increasing those of IL-10, an anti-inflammatory cytokine.

Inflammation is also intimately linked with metabolic processes in humans. For example, low levels of Vitamin D have been associated with greater risk for depression. The role of metabolic biomarkers in depression is an active research area. Recent work has explored the potential relationship between plasma sterols and depressive symptom severity.

Oxidative stress

A marker of DNA oxidation, 8-Oxo-2'-deoxyguanosine, has been found to be increased in both the plasma and urine of people with MDD. This along with the finding of increased F2-isoprostanes levels found in blood, urine and cerebrospinal fluid indicate increased damage to lipids and DNA in people with MDD. Studies with 8-Oxo-2' Deoxyguanosine varied by methods of measurement and type of depression, but F2-Isoprostane level was consistent across depression types. Authors suggested lifestyle factors, dysregulation of the HPA axis, immune system and autonomics nervous system as possible causes. Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. Oxidative DNA damage may play a role in MDD.

Mitochondrial Dysfunction:

Increased markers of oxidative stress relative to controls have been found in people with MDD. These markers include high levels of RNS and ROS which have been shown to influence chronic inflammation, damaging the electron transport chain and biochemical cascades in mitochondria. This lowers the activity of enzymes in the respiratory chain resulting in mitochondrial dysfunction. The brain is a highly energy-consuming and has little capacity to store glucose as glycogen and so depends greatly on mitochondria. Mitochondrial dysfunction has been linked to the dampened neuroplasticity observed in depressed brains.

Large-scale brain network theory

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, supported by recent research that has shown that multiple brain regions are involved in these disorders. Understanding the disruptions in these networks may provide important insights into interventions for treating these disorders. Recent work suggests that at least three large-scale brain networks are important in psychopathology:

Central executive network

The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. Because this network is crucial for everyday life activities, those who are depressed can show impairment in basic activities like test taking and being decisive.

Default mode network

The default mode network includes hubs in the prefrontal cortex and posterior cingulate, with other prominent regions of the network in the medial temporal lobe and angular gyrus. The default mode network is usually active during mind-wandering and thinking about social situations. In contrast, during specific tasks probed in cognitive science (for example, simple attention tasks), the default network is often deactivated. Research has shown that regions in the default mode network (including medial prefrontal cortex and posterior cingulate) show greater activity when depressed participants ruminate (that is, when they engage in repetitive self-focused thinking) than when typical, healthy participants ruminate. People with MDD also show increased connectivity between the default mode network and the subgenual cingulate and the adjoining ventromedial prefrontal cortex in comparison to healthy individuals, individuals with dementia or with autism. Numerous studies suggest that the subgenual cingulate plays an important role in the dysfunction that characterizes major depression. The increased activation in the default mode network during rumination and the atypical connectivity between core default mode regions and the subgenual cingulate may underlie the tendency for depressed individual to get "stuck" in the negative, self-focused thoughts that often characterize depression. However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience network

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. A salience network is a large-scale brain network involved in detecting and orienting the most pertinent of the external stimuli and internal events being presented. Individuals who have a tendency to experience negative emotional states (scoring high on measures of neuroticism) show an increase in the right anterior insula during decision-making, even if the decision has already been made. This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. In major depressive disorder, anxiety is often a part of the emotional state that characterizes depression.

Evolutionary approaches to depression

Evolutionary approaches to depression are attempts by evolutionary psychologists to use the theory of evolution to shed light on the problem of mood disorders within the perspective of evolutionary psychiatry. Depression is generally thought of as dysfunction or a mental disorder, but its prevalence does not increase with age the way dementia and other organic dysfunction commonly does. Some researchers have surmised that the disorder may have evolutionary roots, in the same way that others suggest evolutionary contributions to schizophrenia, sickle cell anemia, psychopathy and other disorders. Psychology and psychiatry have not generally embraced evolutionary explanations for behaviors, and the proposed explanations for the evolution of depression remain controversial.

Background

Major depression (also called "major depressive disorder", "clinical depression" or often simply "depression") is a leading cause of disability worldwide, and in 2000 was the fourth leading contributor to the global burden of disease (measured in DALYs); it is also an important risk factor for suicide. It is understandable, then, that clinical depression is thought to be a pathology—a major dysfunction of the brain.

In most cases, rates of organ dysfunction increase with age, with low rates in adolescents and young adults, and the highest rates in the elderly. These patterns are consistent with evolutionary theories of aging which posit that selection against dysfunctional traits decreases with age (because there is a decreasing probability of surviving to later ages).

In contrast to these patterns, prevalence of clinical depression is high in all age categories, including otherwise healthy adolescents and young adults. In one study of the US population, for example, the 12 month prevalence for a major depression episode was highest in the youngest age category (15- to 24-year-olds). The high prevalence of unipolar depression (excluding depression associated bipolar disorder) is also an outlier when compared to the prevalence of other mental disorders such as major intellectual disability, autism, schizophrenia and even the aforementioned bipolar disorder, all with prevalence rates about one tenth that of depression, or less. As of 2017, the only mental disorders with a higher prevalence than depression are anxiety disorders.

The common occurrence and persistence of a trait like clinical depression with such negative effects early in life is difficult to explain. (Rates of infectious disease are high in young people, of course, but clinical depression is not thought to be caused by an infection.) Evolutionary psychology and its application in evolutionary medicine suggest how behaviour and mental states, including seemingly harmful states such as depression, may have been beneficial adaptations of human ancestors which improved the fitness of individuals or their relatives. It has been argued, for example, that Abraham Lincoln's lifelong depression was a source of insight and strength. Some even suggest that "we aren't designed to have happiness as our natural default" and so a state of depression is the evolutionary norm.

The following hypotheses attempt to identify a benefit of depression that outweighs its obvious costs.

Such hypotheses are not necessarily incompatible with one another and may explain different aspects, causes, and symptoms of depression.

Psychic pain hypothesis

One reason depression is thought to be a pathology is that it causes so much psychic pain and distress. However, physical pain is also very distressful, yet it has an evolved function: to inform the organism that it is being damaged, to motivate it to withdraw from the source of damage, and to learn to avoid such damage-causing circumstances in the future. Sadness is also distressing, yet is widely believed to be an evolved adaptation. In fact, perhaps the most influential evolutionary view is that most cases of depression are simply particularly intense cases of sadness in response to adversity, such as the loss of a loved one.

According to the psychic pain hypothesis, depression is analogous to physical pain in that it informs them that current circumstances, such as the loss of a friend, are imposing a threat to biological fitness. It motivates them to cease activities that led to the costly situation, if possible, and it causes him or her to learn to avoid similar circumstances in the future. Proponents of this view tend to focus on low mood, and regard clinical depression as a dysfunctional extreme of low mood—and not as a unique set of characteristics that are physiologically distanced from regular depressed mood.

Alongside the absence of pleasure, other noticeable changes include psychomotor retardation, disrupted patterns of sleeping and feeding, a loss of sex drive and motivation—which are all also characteristics of the body's reaction to actual physical pain. In depressed people there is an increased activity in the regions of the cortex involved with the perception of pain, such as the anterior cingulate cortex and the left prefrontal cortex. This activity allows the cortex to manifest an abstract negative thought as a true physical stressor to the rest of the brain.

Behavioral shutdown model

The behavioral shutdown model states that if an organism faces more risk or expenditure than reward from activities, the best evolutionary strategy may be to withdraw from them. This model proposes that emotional pain, like physical pain, serves a useful adaptive purpose. Negative emotions like disappointment, sadness, grief, fear, anxiety, anger, and guilt are described as "evolved strategies that allow for the identification and avoidance of specific problems, especially in the social domain." Depression is characteristically associated with anhedonia and lack of energy, and those experiencing it are risk-aversive and perceive more negative and pessimistic outcomes because they are focused on preventing further loss. Although the model views depression as an adaptive response, it does not suggest that it is beneficial by the standards of current society; but it does suggest that many approaches to depression treat symptoms rather than causes, and underlying social problems need to be addressed.

A related phenomenon to the behavioral shutdown model is learned helplessness. In animal subjects, a loss of control or predictability in the subject's experiences results in a condition similar to clinical depression in humans. That is to say, if uncontrollable and unstoppable stressors are repeated for long enough, a rat subject will adopt a learned helplessness, which shares a number of behavioral and psychological features with human depression. The subject will not attempt to cope with problems, even when placed in a stressor-free novel environment. Should their rare attempts at coping prove successful in a new environment, a long lasting cognitive block prevents them from perceiving their action as useful and their coping strategy does not last long. From an evolutionary perspective, learned helplessness also allows a conservation of energy for an extended period of time should people find themselves in a predicament that is outside of their control, such as an illness or a dry season. However, for today's humans whose depression resembles learned helplessness, this phenomenon usually manifests as a loss of motivation and the distortion of one uncontrollable aspect of a person's life being viewed as representative of all aspects of their life – suggesting a mismatch between ultimate cause and modern manifestation.

Analytical rumination hypothesis

This hypothesis suggests that depression is an adaptation that causes the affected individual to concentrate his or her attention and focus on a complex problem in order to analyze and solve it.

One way depression increases the individual's focus on a problem is by inducing rumination. Depression activates the left ventrolateral prefrontal cortex, which increases attention control and maintains problem-related information in an "active, accessible state" referred to as "working memory", or WM. As a result, depressed individuals have been shown to ruminate, reflecting on the reasons for their current problems. Feelings of regret associated with depression also cause individuals to reflect and analyze past events in order to determine why they happened and how they could have been prevented. The rumination hypothesis has come under criticism. Evolutionary fitness is increased by ruminating before rather than after bad outcomes. A situation that resulted in a child being in danger but unharmed should lead the parent to ruminate on how to avoid the dangerous situation in the future. Waiting until the child dies and then ruminating in a state of depression is too late.

Some cognitive psychologists argue that ruminative tendency itself increases the likelihood of the onset of depression.

Another way depression increases an individual's ability to concentrate on a problem is by reducing distraction from the problem. For example, anhedonia, which is often associated with depression, decreases an individual's desire to participate in activities that provide short-term rewards, and instead, allows the individual to concentrate on long-term goals. In addition, "psychomotoric changes", such as solitariness, decreased appetite, and insomnia also reduce distractions. For instance, insomnia enables conscious analysis of the problem to be maintained by preventing sleep from disrupting such processes. Likewise, solitariness, lack of physical activity, and lack of appetite all eliminate sources of distraction, such as social interactions, navigation through the environment, and "oral activity", which disrupt stimuli from being processed.

Possibilities of depression as a dysregulated adaptation

Depression, especially in the modern context, may not necessarily be adaptive. The ability to feel pain and experience depression, are adaptive defense mechanisms, but when they are "too easily triggered, too intense, or long lasting", they can become "dysregulated". In such a case, defense mechanisms, too, can become diseases, such as "chronic pain or dehydration from diarrhea". Depression, which may be a similar kind of defense mechanism, may have become dysregulated as well.

Thus, unlike other evolutionary theories this one sees depression as a maladaptive extreme of something that is beneficial in smaller amounts. In particular, one theory focuses on the personality trait neuroticism. Low amounts of neuroticism may increase a person's fitness through various processes, but too much may reduce fitness by, for example, recurring depressions. Thus, evolution will select for an optimal amount and most people will have neuroticism near this amount. However, genetic variation continually occurs, and some people will have high neuroticism which increases the risk of depressions.

Rank theory

Rank theory is the hypothesis that, if an individual is involved in a lengthy fight for dominance in a social group and is clearly losing, then depression causes the individual to back down and accept the submissive role. In doing so, the individual is protected from unnecessary harm. In this way, depression helps maintain a social hierarchy. This theory is a special case of a more general theory derived from the psychic pain hypothesis: that the cognitive response that produces modern-day depression evolved as a mechanism that allows people to assess whether they are in pursuit of an unreachable goal, and if they are, to motivate them to desist.

Social risk hypothesis

This hypothesis is similar to the social rank hypothesis but focuses more on the importance of avoiding exclusion from social groups, rather than direct dominance contests. The fitness benefits of forming cooperative bonds with others have long been recognised—during the Pleistocene period, for instance, social ties were vital for food foraging and finding protection from predators.

As such, depression is seen to represent an adaptive, risk-averse response to the threat of exclusion from social relationships that would have had a critical impact on the survival and reproductive success of our ancestors. Multiple lines of evidence on the mechanisms and phenomenology of depression suggest that mild to moderate (or "normative") depressed states preserve an individual's inclusion in key social contexts via three intersecting features: a cognitive sensitivity to social risks and situations (e.g., "depressive realism"); it inhibits confident and competitive behaviours that are likely to put the individual at further risk of conflict or exclusion (as indicated by symptoms such as low self-esteem and social withdrawal); and it results in signalling behaviours directed toward significant others to elicit more of their support (e.g., the so-called "cry for help"). According to this view, the severe cases of depression captured by clinical diagnoses reflect the maladaptive, dysregulation of this mechanism, which may partly be due to the uncertainty and competitiveness of the modern, globalised world.

Honest signaling theory

Another reason depression is thought to be a pathology is that key symptoms, such as loss of interest in virtually all activities, are extremely costly to them. Biologists and economists have proposed, however, that signals with inherent costs can credibly signal information when there are conflicts of interest. In the wake of a serious negative life event, such as those that have been implicated in depression (e.g., death, divorce), "cheap" signals of need, such as crying, might not be believed when social partners have conflicts of interest. The symptoms of major depression, such as loss of interest in virtually all activities and suicidality, are inherently costly, but, as costly signaling theory requires, the costs differ for individuals in different states. For individuals who are not genuinely in need, the fitness cost of major depression is very high because it threatens the flow of fitness benefits. For individuals who are in genuine need, however, the fitness cost of major depression is low, because the individual is not generating many fitness benefits. Thus, only an individual in genuine need can afford to have major depression. Major depression therefore serves as an honest, or credible, signal of need.

For example, individuals suffering a severe loss such as the death of a spouse are often in need of help and assistance from others. Such individuals who have few conflicts with their social partners are predicted to experience grief—a means, in part, to signal need to others. Such individuals who have many conflicts with their social partners, in contrast, are predicted to experience depression—a means, in part, to credibly signal need to others who might be skeptical that the need is genuine.

Bargaining theory

Depression is not only costly to the affected person, it also imposes a significant burden on family, friends, and society at large—yet another reason it is thought to be pathological. Yet if people with depression have real but unmet needs, they might have to provide an incentive to others to address those needs.

The bargaining theory of depression is similar to the honest signaling, niche change, and social navigation theories of depression described below. It draws on theories of labor strikes developed by economists to basically add one additional element to honest signaling theory: The fitness of social partners is generally correlated. When a wife has depression and reduces her investment in offspring, for example, the husband's fitness is also put at risk. Thus, not only do the symptoms of major depression serve as costly and therefore honest signals of need, they also compel reluctant social partners to respond to that need in order to prevent their own fitness from being reduced. This explanation for depression has been challenged. Depression decreases the joint product of the family or group as the husband or helper only partially compensates for the loss of productivity by the depressed person. Instead of being depressed the person could break their own leg and gain help from the social group, but this obviously is a counterproductive strategy. And the lack of a sex drive certainly does not improve marital relations or fitness.

Social navigation or niche change theory

The social navigation or niche change hypothesis proposes that depression is a social navigation adaptation of last resort, designed especially to help individuals overcome costly, complex contractual constraints on their social niche. The hypothesis combines the analytical rumination and bargaining hypotheses and suggests that depression, operationally defined as a combination of prolonged anhedonia and psychomotor retardation or agitation, provides a focused sober perspective on socially imposed constraints hindering a person's pursuit of major fitness enhancing projects. Simultaneously, publicly displayed symptoms, which reduce the depressive's ability to conduct basic life activities, serve as a social signal of need; the signal's costliness for the depressive certifies its honesty. Finally, for social partners who find it uneconomical to respond helpfully to an honest signal of need, the same depressive symptoms also have the potential to extort relevant concessions and compromises. Depression's extortionary power comes from the fact that it slows the flow of just those goods and services such partners have come to expect from the depressive under status quo socioeconomic arrangements.

Thus depression may be a social adaptation especially useful in motivating a variety of social partners, all at once, to help the depressive initiate major fitness-enhancing changes in their socioeconomic life. There are diverse circumstances under which this may become necessary in human social life, ranging from loss of rank or a key social ally which makes the current social niche uneconomic to having a set of creative new ideas about how to make a livelihood which begs for a new niche. The social navigation hypothesis emphasizes that an individual can become tightly ensnared in an overly restrictive matrix of social exchange contracts, and that this situation sometimes necessitates a radical contractual upheaval that is beyond conventional methods of negotiation. Regarding the treatment of depression, this hypothesis calls into question any assumptions by the clinician that the typical cause of depression is related to maladaptive perverted thinking processes or other purely endogenous sources. The social navigation hypothesis calls instead for analysis of the depressive's talents and dreams, identification of relevant social constraints (especially those with a relatively diffuse non-point source within the social network of the depressive), and practical social problem-solving therapy designed to relax those constraints enough to allow the depressive to move forward with their life under an improved set of social contracts. This theory has been the subject of criticism.

Depression as an incentive device

This approach argues that being in a depressed state is not adaptive (indeed quite the opposite), but the threat of depression for bad outcomes and the promise of pleasure for good outcomes are adaptive because they motivate the individual toward undertaking effort that increase fitness. The reason for not relying on pleasure alone as an incentive device is because happiness is costly in terms of fitness as the individual becomes less cautious. This is most readily seen when an individual is manic and undertakes very risky behavior. The physiological manifestation of the incentives are most noticeable when an individual is bipolar with bouts of extreme elation and extreme depression as anxiety which is about the (possibly immediate) future is highly correlated with being bipolar. As noted earlier, bipolar disorder and clinical depression, as opposed to event depression, are viewed as dysregulation just as persistently high (or low) blood pressure are viewed as dysregulation even though at times high or low blood pressure is fitness enhancing.

Prevention of infection

It has been hypothesized that depression is an evolutionary adaptation because it helps prevent infection in both the affected individual and his/her kin.

First, the associated symptoms of depression, such as inactivity and lethargy, encourage the affected individual to rest. Energy conserved through such methods is highly crucial, as immune activation against infections is relatively costly; there must be, for instance, a 10% increase in metabolic activity for even a 1°C change in body temperature. Therefore, depression allows one to conserve and allocate energy to the immune system more efficiently.

Depression further prevents infection by discouraging social interactions and activities that may result in exchange of infections. For example, the loss of interest discourages one from engaging in sexual activity, which, in turn, prevents the exchange of sexually transmitted diseases. Similarly, depressed mothers may interact less with their children, reducing the probability of the mother infecting her kin. Lastly, the lack of appetite associated with depression may also reduce exposure to food-borne parasites.

However, it should also be noted that chronic illness itself may be involved in causing depression. In animal models, the prolonged overreaction of the immune system, in response to the strain of chronic disease, results in an increased production of cytokines (a diverse group of hormonal regulators and signaling molecules). Cytokines interact with neurotransmitter systems—mainly norepinephrine, dopamine, and serotonin, and induce depressive characteristics. The onset of depression may help an individual recover from their illness by allowing them a more reserved, safe and energetically efficient lifestyle. The overproduction of these cytokines, beyond optimal levels due to the repeated demands of dealing with a chronic disease, may result in clinical depression and its accompanying behavioral manifestations that promote extreme energy reservation.

The third ventricle hypothesis

Third ventricle

The third ventricle hypothesis of depression proposes that the behavioural cluster associated with depression (hunched posture, avoidance of eye contact, reduced appetites for food and sex plus social withdrawal and sleep disturbance) serves to reduce an individual's attack-provoking stimuli within the context of a chronically hostile social environment. It further proposes that this response is mediated by the acute release of an unknown inflammatory agent (probably cytokine) into the third ventricular space. In support of this suggestion, imaging studies reveal that the third ventricle is enlarged in depressives.

Reception

Clinical psychology and psychiatry have historically been relatively isolated from the field of evolutionary psychology. Some psychiatrists raise the concern that evolutionary psychologists seek to explain hidden adaptive advantages without engaging the rigorous empirical testing required to back up such claims. While there is strong research to suggest a genetic link to bipolar disorder and schizophrenia, there is significant debate within clinical psychology about the relative influence and the mediating role of cultural or environmental factors. For example, epidemiological research suggests that different cultural groups may have divergent rates of diagnosis, symptomatology, and expression of mental illnesses. There has also been increasing acknowledgment of culture-bound disorders, which may be viewed as an argument for an environmental versus genetic psychological adaptation. While certain mental disorders may have psychological traits that can be explained as 'adaptive' on an evolutionary scale, these disorders cause individuals significant emotional and psychological distress and negatively influence the stability of interpersonal relationships and day-to-day adaptive functioning.

Gene

From Wikipedia, the free encyclopedia https://en.wikipedia.org/wiki/Gene Chromosome ...