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What is the biochemical reason for mental fatigue?

What is the biochemical reason for mental fatigue?


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Is it known exactly why the brain needs sleep? What's dropping low / going high when we experience mental fatigue? I can see why low glucose could result in mental fatigue, are other reasons known?


This is not the biochemistry, but the brain regions involved are described in this article about an fMRI study: http://www.sciencedaily.com/releases/2012/12/121210101630.htm

EDIT:

From what I can tell, mental fatigue is attributed to low oxygenation levels. Here's a study that examines the effect of creatine in preventing mental fatigue: http://jtoomim.org/brain-training/watanabe2001-creatine-reduces-mentalfatigue.pdf


Fatigue

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Fatigue, specific form of human inadequacy in which the individual experiences an aversion to exertion and feels unable to carry on. Such feelings may be generated by muscular effort exhaustion of the energy supply to the muscles of the body, however, is not an invariable precursor. Feelings of fatigue may also stem from pain, anxiety, fear, or boredom. In the latter cases, muscle function commonly is unimpaired.

The once-held belief that work was the cause of fatigue led to efforts to use the work output of factory workers, for example, as direct measures of fatigue. Early studies by industrial psychologists and engineers failed to show a close connection between how an individual worker said he felt and the amount of work he accomplished production-oriented investigators were even led to attribute no significance at all to inner feelings of fatigue, and their attention shifted from the inner condition of the worker to external phenomena not related to the worker at all. In the process it was forgotten that work output is a product of, rather than a description of, the worker.

For other researchers who retained an interest in the worker himself, study was typically directed to observable body processes rather than to the overall internal state of the worker as manifested in how he said he felt. Such studies disclosed, among other things, that oxygen and glucose were consumed during work and that waste products such as carbon dioxide and uric acid were produced. Hence, for some investigators fatigue came to mean a bodily state in which waste products were present in high concentration.

All such studies clearly revealed specific results of exertion and disclosed evidence for the burning of food materials (metabolites) taken by themselves, the data provided a picture of the human organism as an energy-converting system and showed a definite relation of this process to energetic (work) performance. Such studies are a part of basic physiological research and apply most closely to what may be expected of people under heavy exertion in the workaday world and in sports and athletics.

Feelings and other signs of fatigue can arise suddenly and disappear suddenly, and the onset, duration, and termination of fatigue symptoms may appear to bear little relation to exertion or work. When fatigue arises in nonexertional situations, there is a temptation simply to say that the fatigue is “psychological” or “ motivational.” Relatively little research has been devoted to fatigue as descriptive of the person himself and of the full range of demands he has to meet, although many of these demands lie outside the simple energy requirements of more-or-less arduous work.

Man is able to—and may—respond to any situation in more than one way and at more than one level of behavioral complexity. The most readily observable ways are grossly physical and chemical but these, in turn, underlie other levels of response such as primitive sensory activity (becoming aware of stimuli), and still higher levels such as perceiving (e.g., evaluating the nature and objectives of work activity). At the highest level of activity the relationship often is spoken of as existing between the whole person and the environment.

Since most investigative attention in industrial or other production situations has been directed toward what man can do in terms of his being only a machine that converts food energy into useful work, an understanding of the fine details of the relation between fatigue and physiological body processes has preceded experimental efforts to specify the role of personal attitudes (such as the individual’s own evaluation of his abilities). Such self-evaluations (e.g., a worker’s judgment that he cannot continue activity) rather than any exhaustion of the energy available within the body result in the termination of activity. Often when such changes in performance are attributed to motivation, or to any of a number of factors called psychological, one’s allegiance to ancient views of the nature of man may tempt him to think of mental factors disjoined and unrelated to any physical, energistic description of the organism. Yet, a fully useful definition of fatigue would require that all relevant factors be considered. Indeed, modern efforts to achieve a unified, integrated definition of fatigue rest on studies in which higher-order mental processes (such as thinking, perceiving, and emoting) are investigated to find whether they seem to stem from physical body processes.

Fatigue as it is applied to the whole person involves an individual’s feelings of discomfort and aversion, his inner awareness of making mistakes, and any changes in observable signs of effort required to carry on the performance involved. These aspects are found to be related in various ways to measurable variations in work output. Investigators who typically focus primarily on work output are apt to be concerned with the applied, practical view of the person as a productive worker interest is more likely to be concentrated upon the worker himself by those scientists who wish to study fatigue even if their findings are not directly productive of work output. The worker himself is interested in how he feels and what makes him feel as he does.

At any rate, in accounting for fatigue, it is useful to make distinctions between what pertains to the individual as a whole and what pertains only to some part or organ of the individual. That the total behaviour is spoken of as personalistic, or psychological, is not simply because self-awareness (inner feeling of fatigue) is involved but because, at this level, resources are directed toward ends that go beyond the limited function of any one body part. This situation is illustrated by a simple example in muscular activity. When muscle activity is described in itself (at a given subpersonalistic level), it is simply called muscle contraction. Muscle contraction occurring as an integrated part of more complex personalistic behaviour may be called reaching this action is an integral part of grasping a pencil, which is part of the more personalistic act of writing to one’s friends.

While fatigue is one consequence of grossly observable activity, it can occur in the absence of manifest muscular exertion. It can develop, for example, as a rather immediate response to a socially exercised demand (such as that of a nagging supervisor), of which the person suddenly becomes aware but may not like. The feeling of fatigue produced in the absence of productive work seems to be essentially the same as that produced by goal-directed labour. Some components nevertheless are different, such as aching muscles in the one case and not in the other, but the factors that give fatigue its identity and differentiate it from other states of inadequacy are present in both. In each case conditions exist that can even result in one’s total inability to carry on, whether his muscles contain high concentrations of waste products or not.

Muscular exertion does, however, produce biochemical changes in the body that are quite complex and that differ in various tissues and organs such as the heart or the brain. The consequence almost invariably is to produce secondary effects, perhaps muscular stiffness, and these in turn give rise to higher level effects such as one’s sensory awareness of pain and discomfort. At a more personalistic level, the individual may develop a change in attitude with regard to the task or activity in progress e.g., he may begin to feel aversion for the work. The whole process, in effect, yields the individual’s self-generated assessment of his own ability to carry on. If he continues his exertions under his personal assessment that such activity will produce more pain or will become more nearly intolerable or even impossible, the anticipated consequences include less efficient work performance. As the worker becomes preoccupied with his discomfort and with his waning production, the effect typically is to produce still more inefficient work. Thus fatigue defined as muscular inability to carry on and fatigue defined as a kind of felt aversion for exertion and as feelings of inability to carry on are all produced.

Performance may be observed to deteriorate (among factory workers, for example) even when there are no signs of the feeling state and of the aversive, pessimistic self-assessment defined here as personalistic fatigue. Indeed, often enough one may be “fatigued” without knowing it, indicating the predominance of relatively subpersonalistic factors at work. Such factors can be lumped under the term impairment, mentioned originally as one of the major forms of human inadequacy. While transient impairment and personalistic fatigue generally have not been distinguished from each other by many psychologists, in numerous studies impairment, rather than the feeling of fatigue, has been the point of interest.

Impairment of this sort reflects alterations in the chemical processes that occur within the cells of the body. That the alterations are reversible is illustrated in alcohol intoxication and oxygen lack (hypoxia). When such transient impairment incapacitates the individual for energetic activities without greatly affecting his brain processes, he is likely to feel tired and weak. Thus, it can be said that transient physiological impairment and personalistic fatigue are closely related, one being a basis for the other. When brain processes are so sharply affected as to reduce perceptual or attitudinal awareness, impairment may produce marked behavioral consequences without associated feelings of fatigue. In such cases, feelings of weakness and tiredness may not be reported by the individual since his abilities for self-evaluation have been dulled.

The failure of people to have feelings of fatigue as a consequence of physiological impairment is characteristic of some forms of hypoxia, which can be brought on in several ways. One of these is by a fairly abrupt reduction in atmospheric oxygen pressure, as would occur in one’s being deposited atop a mountain by helicopter. Feelings of fatigue are much more likely to set in when oxygen reduction is gradual and associated with exertion (as in mountain climbing). Along with lack of oxygen, other factors of the climber’s task play their roles, and the climber’s own awareness of the negative factors that are developing produces the full syndrome of fatigue, including both the inability to carry on and the aversive attitude.

In contrast to this, oxygen lack can be produced much more quickly in a decompression chamber in a laboratory, without any associated muscular exertion. It is possible to reach levels of hypoxia that abruptly reduce the subject’s efficiency in exercising self-assessment, and personalistic fatigue in such cases fails to develop.

This article was most recently revised and updated by Michele Metych, Product Coordinator.


The biology of trauma: implications for treatment

During the past 20 years, the development of brain imaging techniques and new biochemical approaches has led to increased understanding of the biological effects of psychological trauma. New hypotheses have been generated about brain development and the roots of antisocial behavior. We now understand that psychological trauma disrupts homeostasis and can cause both short and long-term effects on many organs and systems of the body. Our expanding knowledge of the effects of trauma on the body has inspired new approaches to treating trauma survivors. Biologically informed therapy addresses the physiological effects of trauma, as well as cognitive distortions and maladaptive behaviors. The authors suggest that the most effective therapeutic innovation during the past 20 years for treating trauma survivors has been Eye Movement Desensitization and Reprocessing (EMDR), a therapeutic approach that focuses on resolving trauma using a combination of top-down (cognitive) and bottom-up (affect/body) processing.


Contents

Difficulty of gene studies Edit

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. [5]

Gene candidates Edit

5-HTTLPR Edit

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). [6] 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. [7]

BDNF Edit

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. [8]

SIRT1 and LHPP Edit

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. [9] [10]

Norepinephrine transporter polymorphisms Edit

Attempts to find a correlation between norepinephrine transporter polymorphisms and depression have yielded negative results. [11]

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. [12] A meta analysis of 182 case controlled genetic studies published in 2008 found Apolipoprotein E verepsilon 2 to be protective, and GNB3 825T, MTHFR 677T, SLC6A4 44bp insertion or deletions, and SLC6A3 40 bpVNTR 9/10 genotype to confer risk. [13]

Sleep Edit

Depression may be related to abnormalities in the circadian rhythm, [14] or biological clock. For example, 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, [15] and is impaired by compounds, such as antidepressants, that increase serotonergic tone in brain stem structures. [15] Overall, the serotonergic system is least active during sleep and most active during wakefulness. Prolonged wakefulness due to sleep deprivation [14] 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. [15]

Light therapy Edit

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. [16] 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. [17] 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). [16]

Increased and decreased sleep length appears to be a risk factor for depression. [18] 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. [19]

Daytime light exposure correlates with decreased serotonin transporter activity, which may underlie the seasonality of some depression. [20]

Monoamine hypothesis of depression Edit

Many antidepressant drugs acutely increase synaptic levels of the monoamine neurotransmitter, serotonin, but they may also enhance the levels of norepinephrine and serotonin. 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. [22] 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. [23]

Serotonin Edit

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. [24] Serotonin may indirectly influence mood by altering emotional processing biases that are seen at both the cognitive/behavioral and neural level. [25] [24] 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. [25]

Dopamine Edit

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. [26] There is some evidence that there is decreased nigrostriatal pathway activity in people with melancholic depression (psychomotor retardation). [27] Further supporting the role of dopamine in depression is the consistent finding of decreased cerebrospinal fluid and jugular metabolites of dopamine, [28] as well as post mortem findings of altered Dopamine receptor D3 and dopamine transporter expression. [29] Studies in rodents have supported a potential mechanism involving stress-induced dysfunction of dopaminergic systems. [30]

Catecholamines Edit

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. [28] Furthermore, norepinephrine transporter knockout in mice models increases their tolerance to stress, implicating norepinephrine in depression. [31]

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. [32]

Monoamine oxidase Edit

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. [33] In genetic studies, the alterations of MAO-A-related genes have not been consistently associated with depression. [34] [35] 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. [36] In addition, some evidence indicates that disrupted information processing within neural networks, rather than changes in chemical balance, might underlie depression. [37]

Limitations Edit

Since the 1990s, research has uncovered multiple limitations of the monoamine hypothesis, and its inadequacy has been criticized within the psychiatric community. [38] 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. [39] 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. [40] Experiments with pharmacological agents that cause depletion of monoamines have shown that this depletion does not cause depression in healthy people. [41] [42] 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. [43] Already limited, the monoamine hypothesis has been further oversimplified when presented to the general public. [44]

Receptor binding Edit

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. [45]

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. [46] 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. [47] 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. [48] Dopamine transporter binding is not changed in depression. [49]

Emotional Bias Edit

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. [50] Depressed people also have impaired recognition of happy, angry, disgusted, fearful and surprised, but not sad faces. [51] 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. [52] 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. [53] 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. [54] 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. [55] 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. [56]

Neural circuits Edit

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. [57]

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. [59] [60] 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). [61]

Reward Edit

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. [62] 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. [63] [64] 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. [65] 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. [66] 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. [65] 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. [67]

Elevated response in the sgACC is a consistent finding in neuroimaging studies using a number of paradigms including reward related tasks. [65] [68] [69] Treatment is also associated with attenuated activity in the sgACC, [70] and inhibition of neurons in the rodent homologue of the sgACC, the infralimbic cortex (IL), produces an antidepressant effect. [71] Hyperactivity of the sgACC has been hypothesized to lead to depression via attenuating the somatic response to reward or positive stimuli. [72] 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. [73] 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. [74]

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. [75] Due to these issues and others, including the longitudinal consistency of depression, most neural models are likely inapplicable to all depression. [61]

Structural neuroimaging Edit

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). [77] 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. [78] 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. [79] A meta analysis performed using "activation likelihood estimate" reported reductions in the paracingulate cortex, dACC and amygdala. [80]

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. [81]

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. [82] Subcortical abnormalities, including reductions in hippocampus and amygdala volumes, which were especially pronounced in early onset depression. [83]

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, [85] [86] and general major depressive populations. [84] [87] 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 [85] and only in the genu of the CC. [86] On the other hand, general MDD samples have been reported to have reductions in the body of the CC, [86] the body and genu of the CC, [84] and only the genu of the CC. [87] Reductions of FA have also been reported in the anterior limb of the internal capsule (ALIC) [85] [84] and superior longitudinal fasciculus. [85] [86]

Functional neuroimaging Edit

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. [88] 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 [89] 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. [90] 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. [91] 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. [57]

Brain regions Edit

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 Edit

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. [92] : 576–578 [93]

Prefrontal cortex Edit

One review reported hypoactivity in the prefrontal cortex of those with depression compared to controls. [94] 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. [95] One meta analysis published in 2012 found that areas of the prefrontal cortex were hypoactive in response to negative stimuli in people with MDD. [57] 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. [91]

Amygdala Edit

The amygdala, a structure involved in emotional processing appears to be hyperactive in those with major depressive disorder. [93] 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. [96] 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. [97] One study, however, found no difference in amygdala activity during emotional processing tasks. [98]

Hippocampus Edit

Atrophy of the hippocampus has been observed during depression, consistent with animal models of stress and neurogenesis. [99] [100]

Stress can cause depression and depression-like symptoms through monoaminergic changes in several key brain regions as well as suppression in hippocampal neurogenesis. [101] 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. [102]

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 the often shows increased activation in depressed people, but the mechanism behind this is not yet known. [103] Increased basal cortisol levels and abnormal response to dexamethasone challenges have been observed in people with MDD. [104] Early life stress has been hypothesized as a potential cause of HPA dysfunction. [105] [106] 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. [107] HPA axis changes by 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. [108]

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. [109] Depression without familial risk or childhood trauma has been linked to a normal hippocampal volume but localised dysfunction. [110]

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 [111] and the biological plausibility. [112] [113]

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 [111] models involving environmental manipulation associated with depression in humans, including chronic mild stress, early life stress and learned helplessness. [114] 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. [113] 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. [111] 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. [115]

Neurocircuits Edit

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. [116] 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. [117] Learned helplessness induced potentiation of LHb synapses are reversed by antidepressant treatment, providing predictive validity. [116] 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. [116] Tentative in vivo evidence from people with MDD suggests abnormalities in dopamine signalling. [118] 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. [119] 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. [119] 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. [71] 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. [120]

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. [121]

Blood levels of BDNF in people with MDD increase significantly with antidepressant treatment and correlate with decrease in symptoms. [122] 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. [123]

Various review have found that general inflammation may play a role in depression. [124] [125] One meta analysis of cytokines in people with MDD found increased levels of pro-inflammatory IL-6 and TNF-a levels relative to controls. [126] The first theories came about when it was noticed that interferon therapy caused depression in a large number of people receiving it. [127] 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. [128] [129] Increased numbers of T-Cells presenting activation markers, levels of neopterin, IFN gamma, sTNFR, and IL-2 receptors have been observed in depression. [130] Various sources of inflammation in depressive illness have been hypothesized and include trauma, sleep problems, diet, smoking and obesity. [131] 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. [132] One review found normalization of cytokine levels after successful treatment of depression. [133] A meta analysis published in 2014 found the use of anti-inflammatory drugs such as NSAIDs and investigational cytokine inhibitors reduced depressive symptoms. [134] 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. [135]

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. [136] 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. [137]

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. [138] Another meta-analysis found similar results with regards to oxidative damage products as well as decreased oxidative capacity. [139] Oxidative DNA damage may play a role in MDD. [140]

Mitochondrial Dysfunction:

Increased markers of oxidative stress relative to controls have been found in people with MDD. [141] 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. [142] 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. [143]

Instead of studying one brain region, studying large scale brain networks is another approach to understanding psychiatric and neurological disorders, [144] 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: [144]

Central executive network Edit

The central executive network is made up of fronto-parietal regions, including dorsolateral prefrontal cortex and lateral posterior parietal cortex. [145] [146] This network is involved in high level cognitive functions such as maintaining and using information in working memory, problem solving, and decision making. [144] [147] Deficiencies in this network are common in most major psychiatric and neurological disorders, including depression. [148] [149] 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. [150]

Default mode network Edit

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. [144] 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. [151] [152] 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. [153] 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. [154] 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. [155] However, further research is needed to gain a precise understanding of how these network interactions map to specific symptoms of depression.

Salience network Edit

The salience network is a cingulate-frontal operculum network that includes core nodes in the anterior cingulate and anterior insula. [145] 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. [144] 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. [156] This atypically high activity in the right anterior insula is thought to contribute to the experience of negative and worrisome feelings. [157] In major depressive disorder, anxiety is often a part of the emotional state that characterizes depression. [158]


Calculation task

A representative time course of the performance in the calculation task in one subject is shown in Fig. 1. Average performance significantly increased on the second UKT (P<0.001) in both groups. Mental fatigue before and after administration of creatine was assessed using linear regression analysis of the second 15-min standardized performance (Fig. 2). The regression coefficient (a, where y=ax+b) of the creatine group significantly increased from −0.0115 to −0.0055 (P<0.02, paired t-test),


The Biological Evidence for “Mental Illness”

On January 2, 2017, I published a short post titled Carrie Fisher Dead at Age 60 on Behaviorism and Mental Health. The article was published simultaneously on Mad in America.

On January 4, a response from Carolina Partners was entered into the comments string on both sites.

Carolina Partners in Mental Healthcare, PLLC, is a large psychiatric group practice based in North Carolina. According to their website, they comprise 14 psychiatrists, 7 psychologists, 34 Advanced Practice Nurse Practitioners/Physicians Assistants, and 43 Therapists and Counselors. They have 27 North Carolina locations.

Partners’ comment consists essentially of unsubstantiated assertions, non sequiturs, and appeals to psychiatric authority. As such, it is fairly typical of the kind of “rebuttals” that psychiatry’s adherents routinely direct towards those of us on this side of the issue. For this reason, and also because it comes from, and presumably represents the views of, an extremely large psychiatric practice, it warrants a close look.

I will discuss each paragraph in turn.

“We strongly disagree with this article, which neglects a lot of important information and uses selective hearing to distort what Carrie Fisher was about and also to distort the evidence for mental illness as a real disorder.”

My Carrie Fisher article was brief (566 words), and was intended as a counterpoint to the very widespread obituaries that lionized her as a champion of “bipolar disorder”. The essential point of my article was that Ms. Fisher had been a victim of psychiatry, and like a great many such victims, died prematurely. Obviously I neglected a lot of important information. I could have gone into great length as to the recklessness of psychiatry assigning the bipolar label, with all its implications of helplessness, disempowerment, and “chemical imbalance” to a young woman who by her own account was, at the time, using any drugs she could get her hands on. But I felt that a brief and respectful statement of the facts was all that was needed.

“Mental illnesses have a long history of biological evidence. For example, researchers have demonstrated that people with depression have an overactive area of the brain, called Brodmann area 25. Schizophrenia has been linked to specific genes, as PTSD and autism have been linked to specific brain abnormalities. Suicide has been linked to a decreased concentration of serotonin in the brain. OCD has been linked to increased activity in the basal ganglia region of the brain.”

Brodmann area 25 (BA25)
Partners did not provide a specific reference in support of this contention, but my best guess is that the reference is Mayberg, HS, et al (1999) Reciprocal Limbic-Cortical Function and Negative Mood: Converging PET Findings in Depression and Normal Sadness (Am J Psychiatry 1999 156:675–682). Here’s the study’s primary conclusion:

“Reciprocal changes involving subgenual cingulate [which includes Brodmann area 25] and right prefrontal cortex occur with both transient and chronic changes in negative mood.”

What this means essentially is that negative mood, whether transient or enduring, is correlated with changes in both the subgenual cingulate (Brodmann area 25) and the right pre-frontal cortex, and that when the depression is relieved, the changes are reversed.

This, of course, is an interesting finding, but provides no evidence that depression, mild or severe, transient or enduring, is caused by a biological pathology.

The reality is that all human activity is triggered by brain activity. Every thought, every feeling, every action has its origins in the brain. I cannot lift a finger, blink an eye, scratch my head, or recall my childhood home without a characteristic brain function initiating and maintaining the action in question. Without stimuli from the brain, my heart will stop beating, my respiratory apparatus will shut down, and I will die, unless these functions are maintained by machines.

So there is absolutely no surprise in the discovery that sadness and despondency have similar neural triggers and maintainers. It would be amazing if they didn’t. But – and this is the critical point – this does not warrant the conclusion that sadness which crosses arbitrary and vaguely-defined thresholds of severity, duration, and frequency is best conceptualized as an illness caused by pathological or excessive activity in BA 25.

Depression is a normal state. It is the normal human reaction to significant loss and/or living in sub-optimal conditions/circumstances. It is also an adaptive mechanism, the purpose of which is to encourage us to take action to restore the loss and/or improve the conditions.

All consciously-felt human drives stem from unpleasant feelings. Thirst drives us to seek water hunger, food hypothermia, warmth hyperthermia, coolness danger, safety, etc. Sadness and despondency are no exceptions. They drive us to seek change, and have been serving the species well since prehistoric times.

But – as is the case with all the above examples – when a drive is not acted upon, for whatever reason, the unpleasant feelings worsen. Just as unrequited hunger and thirst increase in strength, so the depression drive when not requited deepens.

The reality is that most people deal with depression in appropriate, naturalistic, and time-honored ways. If the source of the depression is the loss of a job, they start job-hunting. If the source is an abusive relationship, they seek ways to exit or remediate the situation. If the source is a shortage of money, they seek ways to budget more sensibly, or increase their earnings etc.

Depression, either mild or severe, transient or lasting, is not a pathological condition. It is the natural, appropriate, and adaptive response when a feeling-capable organism confronts an adverse event or circumstance. And the only sensible and effective way to ameliorate depression is to deal appropriately and constructively with the depressing situation. Misguided tampering with the person’s feeling apparatus is analogous to deliberately damaging a person’s hearing because he is upset by the noise pollution in his neighborhood, or damaging his eyesight because of complaints about litter in the street.

Our feeling apparatus is as valuable and adaptive as our other senses. But psychiatry routinely numbs, and in many cases permanently damages, this apparatus to sell drugs and to promote the fiction that they are real doctors. Their justification for this blatantly destructive activity hinges on the false notion that depression becomes a diagnosable illness when its severity crosses arbitrary and vaguely-defined thresholds. But deep despondency is no more an illness than mild despondency. The latter is the appropriate and adaptive response to minor losses and adversity. The former is the appropriate and natural response to more profound or more enduring adversity. Though, of course, what constitutes profound adversity will vary enormously from person to person. An individual, for instance, raised to the expectation of stable and permanent employment may be truly heartbroken at the loss of a job. Another individual, raised to the notion that there’s always another job “around the corner” will, other things being equal, be less affected. And so on.

In this regard, it’s noteworthy that Partners’ comment refers to overactivity in BA 25. The use of the prefix over implies pathology, but in reality there is no yardstick to determine what would be a correct amount of activity for BA 25. All that can be said, on the basis of Mayberg et al’s findings, and subsequent BA 25 research, is that when a person is sad, there is more activity than when he is happy. So the use of the term “overactivity” is deceptive – sneaking in the notion of pathology without any genuine or valid reasons to consider it so. The “reasoning” here is:

– depression is an illness
– depression is correlated with high activity in BA 25
– therefore high activity in BA 25 is pathological

In other words, the contention of pathology rests on the assumption that depression is an illness. To turn around and use this falsely inferred pathology to prove that depression is an illness is obviously fallacious. It is also typical of the kind of circular reasoning that permeates psychiatric contentions. In reality, there is nothing in Mayberg et al or in subsequent research that warrants the conclusion that the increased activity in BA 25 is pathological or excessive.

Schizophrenia linked to specific genes
This assertion, that schizophrenia is linked to specific genes, is frequently adduced in these debates, as evidence that “schizophrenia” is a real illness with a biological pathology. Here again, Partners do not provide any references in support of this assertion, but there have been a number of studies in the past fifteen years or so that have found links of this kind. However, in all cases, the correlations have been small. In other words, there are always a great many individuals who have been assigned the “schizophrenia” label, but who do not have the gene variant in question and there are a great many who have the gene variant, but who do not acquire the label “schizophrenia”. To date, no genetic test has been found helpful in confirming or refuting a “diagnosis of schizophrenia”.

An additional problem arises here, in that the assertion that “schizophrenia has been linked to specific genes” is often interpreted as meaning that “schizophrenia” is a genetic disease, which it emphatically is not. To illustrate this, let’s look briefly at a real genetic illness: polycystic kidney disease (PKD). This is a well established genetic illness caused by cysts in the kidneys. The cysts progressively block the flow of blood through the kidneys, causing tissue death.

Most cases of PKD are caused by the defective gene (PKD-1). In polycystic kidney disease, the pathology occurs because the PKD-1 gene causes the nephrons to be made from cyst wall epithelium rather than nephron epithelium. And cyst wall epithelium produces fluid which accumulates in, and ultimately destroys, the nephrons and the kidney.

So the gene determines the structure of the nephron wall. This is the primary genetic effect. This structure causes the wall to produce fluid. As the nephrons become increasingly blocked, the kidneys produce less urine. So, reduced urination is a secondary effect of the gene PKD-1. Symptoms of PKD don’t usually emerge until adulthood, but about 25% of children with PKD1 experience pain and other symptoms. So a child growing up with polycystic kidney disease may feel sick much of the time. Such a child, other things being equal, is likely to be fussier and more distressed than other children, and it is entirely possible that one could find a weak correlational link between gene PKD-1 and childhood fussiness, though, of course, any search for such a correlation will be confounded by the obvious fact that children can be habitually fussy for other reasons. The fussiness would be a tertiary effect of the gene PKD1.

And from there the causal chain could continue in various ever-weakening directions. For instance, the child might become somewhat sad and despondent. Or it could be that the child received extra attention and comforting from his parents and was fairly content, and so on. Ultimately the outcome is impossible to predict with any kind of precision, and the best we can expect from genes vs. subsequent behavior studies are weak, tenuous correlations.

Cleft palate is another example of a pathology that is caused by a gene defect actually a gene deletion. This condition results in a characteristically strained and nasal speech quality which can be quite stigmatizing. The nasal speech is a secondary effect of the gene deletion.

Children with this kind of speech are sometimes mocked and bullied by their peers. The child might react to this kind of stigmatizing by speaking as little as possible, by withdrawing socially, or in various other ways. These reactions would be considered tertiary effects of the defect. And so on. As with the PKD, each step in the chain takes us further from the genetic defect, and the statistical associations grow proportionally weaker, and it would be stretching the matter to say that the lack of speech was caused by the gene deletion. Nor would one conclude that the child’s social withdrawal was a symptom of a genetic disease. And this is true even though the link between the deletion and the cleft palate is clear-cut and direct.

In the same way, it is simply not tenable to claim that “schizophrenic” behaviors (e.g. disorganized speech) are symptoms of a genetic disease. This is particularly the case in that correlations between the “diagnosis” and genetic anomalies are typically very small. The effects of any minor genetic anomalies that might exist have had ample opportunity to be shaped by social and environmental factors, and these are more credible causal constructs.

“Schizophrenia” is not a unified condition. Rather, it is a loose collection of vaguely defined behaviors. For this reason, any genetic research done on this condition will inevitably result in conflicting and confusing results. It’s like looking for genetic similarities in all the people who play bridge, or read romance novels, visit libraries, play football, or whatever. If the sample sizes are large enough, and in genetic research sample sizes are often enormous, one could probably find small effects in all or most of these areas, but no one would conclude from this that these are genetically determined activities, much less illnesses.

A person’s ability to learn depends on two general factors: a) the structure of his brain, as determined by his DNA, and b) his experiences since birth.

One can’t learn to play the piano, for instance, unless one has appropriate neural apparatus, and fingers, both of which require appropriate DNA. But even a person with good genetic endowment in these regards, will never learn to play unless he is exposed to certain environmental factors. He must, at the very least, encounter a piano. In the same way, a person whose genetic endowment might be relatively marginal might become an excellent pianist, if he were to receive persistent environmental encouragement and support.

Similar reasoning can be applied to the behavior of not-being-“schizophrenic.” This behavior involves navigating the pitfalls of late adolescence/early adulthood, and establishing functional habits in interpersonal, occupational, and other important life areas. Obviously it requires appropriate neural apparatus, hence the weak correlations with genetic material, but equally clearly it calls for a nurturing childhood environment, with opportunities for emotional growth and acquisition of social, occupational, and other skills.

Given all of this, it’s not surprising that researchers are finding correlations between DNA variations and a “diagnosis” of schizophrenia, but given the number of links in the causal chain and the multiplicity of possible pathways at each link, it is also not surprising that the correlations are always found to be weak, and of little or no practical consequence.

Nor is it surprising that the correlations between being labeled “schizophrenic” and various psychosocial factors are by contrast generally strong. Having a schizophrenia label is correlated with childhood social adversity, childhood abuse and maltreatment, poverty, and a family history of migration.

Generally similar considerations apply to Partners contentions with regards to “PTSD”, “autism”, suicide, and “OCD”, but space precludes a detailed discussion here.

“Eric Kandel, MD, a Nobel Prize laureate and professor of brain science at Columbia University, says, ‘All mental processes are brain processes, and therefore all disorders of mental functioning are biological diseases…The brain is the organ of the mind. Where else could [mental illness] be if not in the brain?'”

Dr. Kandel (now 87 years old) is an eminent neuroscience researcher at Columbia University. There’s an extensive biography in Wikipedia. His early research focused on the neurophysiology of memory. He has received numerous awards, including the Nobel Prize in Physiology/Medicine (2000), and is widely published. His record of research achievements is enormous, and his knowledge and expertise are vast, but in the statement quoted by Partners, and, incidentally, by other psychiatry adherents, he is simply wrong.

Let’s take a closer look. Logically, the Kandel quote can be stated symbolically as: A is identical to B therefore malfunctions or aberrations in A are malfunctions or aberrations in B.

On the face of it, this seems sound, and indeed, it is a valid inference in some situations. For instance, the furnace in a person’s home is the primary heating appliance therefore, malfunctions in the furnace are malfunctions in the primary heating appliance. Indeed, in a simple example of this sort, the statement is tautological. We are simply substituting the synonyms furnace and primary heating appliance, and the inference contains no new information or insights. But the inference is fallacious in more complex matters.

Let’s concede, for the sake of discussion, that the premise of the Kandel quote is true, i.e., that all mental processes are brain processes. The term mental processes embraces a wide range of activities, including sensations, perceptions, thoughts, choices, positive feelings, negative feelings, hopes, beliefs, speaking, singing, general behavior, etc.

The term “disorders of mental functioning” is harder to define, but, again for the purposes of discussion, let’s accept the APA’s catalog as definitive in this regard. Let’s accept that anything listed in the DSM is a “disorder of mental functioning”.

It’s immediately obvious that some of the DSM entries are indeed the result of brain malfunctioning. In the text these are referred to as disorders due to a general medical condition or to the effects of a substance. But in the great majority of DSM labels, no such biological cause is identified, and so the conclusion in the Kandel quote would appear to call for some kind of evidence or proof. However, in the Kandel quote, the conclusion is not presented as something that has been, or even needs to be, proven. Rather, it is presented as a logical conclusion inherent in, and stemming directly from, the premise. And it is from this perspective that the Kandel quote needs to be evaluated.

To pursue this, let’s consider the example of “oppositional defiant disorder”. This is a disorder of mental functioning as defined above, because it is listed in the DSM. And according to Dr. Kandel’s “logic”, it is also therefore a “biological disease”. The “symptoms” of oppositional defiant disorder as listed in DSM-5 are:

  1. Often loses temper.
  2. Is often touchy or easily annoyed.
  3. Is often angry and resentful.
  4. Often argues with authority figures or, for children and adolescents, with adults.
  5. Often actively defies or refuses to comply with requests from authority figures or with rules.
  6. Often deliberately annoys others.
  7. Often blames others for his or her mistakes or misbehavior.
  8. Has been spiteful or vindictive at least twice within the past 6 months. (p 462)

Obviously for any of these behaviors to occur, there has to be corresponding neural activity. But there is no necessity that the neural activity is diseased or malfunctioning in any way. A child learning from his environment, developing his behavioral repertoire in accordance with the ordinary principles or learning, could acquire any or all of these behavioral habits without any malfunctioning in his neural apparatus. We acquire counterproductive habits as readily, and by essentially the same processes, as we acquire productive ones. In general, if a child discovers that he can acquire power and control in his environment by throwing temper tantrums, he will, other things being equal, acquire the habit of throwing temper tantrums. Similarly, if arguing with parents and other authority figures yields positive results, there is a good chance that this also will become habitual. And this is not because there is anything wrong with the child’s brain. Rather, it’s because his brain is functioning correctly. He is internalizing as habits those decisions and actions that pay off. It is often observed in child-raising practice that if you’re not training your children, they’re training you.

Similar observations can be made about the other seven “symptoms” of oppositional defiant disorder, and indeed all the DSM labels. A person with a perfectly normal-functioning brain can acquire the habits in question if the circumstances are conducive to this learning.

So to return to the question in the Kandel quote: “Where else could [mental illness] be if not in the brain?”, the answer is clear: In the self-serving and unwarranted perception of psychiatrists. Mental illness is the distorting lens through which psychiatrists view all problems of thinking, feeling, and behaving. It is the device they use to legitimize their drug-pushing and to maintain the fiction that they are practicing medicine.

“You’re right that mental illness is also affected by social and environmental conditions–by a person’s disposition, or upbringing, or current environment. It’s also true that mental illness is affected by drug use (both prescribed and not prescribed). So are other medical conditions, such as heart disease and cancer.”

I’m not sure where Partners are coming from here, because I never made any such statement. In my view, which I have stated clearly on numerous occasions, “mental illness” is a psychiatric invention, self-servingly created to promote the spurious notion that all problematic thoughts, feelings, and/or behaviors are illnesses. And not just illnesses in some vague allegorical sense, but real illnesses “just like diabetes”, which need to be treated by medically trained psychiatrists with mood-altering drugs and high voltage electric shocks to the brain.

Partners’ vague concessions concerning environment, child-rearing, and drug effects is a fairly standard psychiatric sop, but doesn’t mitigate their earlier contentions on the “long history of biological evidence” and their uncritical endorsement of the logically spurious Kandel quote.

“And it’s true that mental illness is often difficult to diagnose because of
1) the current limitations of the field of research. Thomas R. Insel, MD, director of the National Institute of Mental Health, for example, talks about how the diagnosis and treatment of mental illness today is where cardiology was 100 years ago, concluding that we need to continue scientific research of mental illnesses. (There’s a longer quote on this below.)”

And (from later in the comment)

“Longer aforementioned quote:
Take cardiology, Insel says. A century ago, doctors had little knowledge of the biological basis of heart disease. They could merely observe a patient’s physical presentation and listen to the patient’s subjective complaints. Today they can measure cholesterol levels, examine the heart’s electrical impulses with EKG, and take detailed CT images of blood vessels and arteries to deliver a precise diagnosis. As a result, Insel says, mortality from heart attacks has dropped dramatically in recent decades. ‘In most areas of medicine, we now have a whole toolkit to help us know what’s going on, from the behavioral level to the molecular level. That has really led to enormous changes in most areas of medicine,’ he says.

Insel believes the diagnosis and treatment of mental illness is today where cardiology was 100 years ago. And like cardiology of yesteryear, the field is poised for dramatic transformation, he says. ‘We are really at the cusp of a revolution in the way we think about the brain and behavior, partly because of technological breakthroughs. We’re finally able to answer some of the fundamental questions.'”

It is at least forty years since I started hearing about psychiatry’s great biological breakthroughs that were just around the proverbial corner, and the promise, if my readers will pardon the pun, is getting a little old.

What’s noteworthy, however, is that in other disciplines, where there is hope or expectation of breakthroughs, the proponents of these endeavors generally wait until the evidence is in, before implementing practices based on these hopes. In fact, to the best of my knowledge, psychiatry is the only profession whose entire work, indeed, whose entire conceptual framework, is based on “evidence” and “breakthroughs” that are not yet to hand.

Note also the truly exquisite contrast between Partners’ earlier and confident contention that “mental illnesses have a long history of biological evidence” with the assertion here that the “diagnosis” and “treatment” of “mental illness” today is where cardiology was 100 year ago.

Incidentally, Dr. Insel, former Director of the NIMH, also said:

“While DSM has been described as a ‘Bible’ for the field, it is, at best, a dictionary, creating a set of labels and defining each. The strength of each of the editions of DSM has been ‘reliability’ – each edition has ensured that clinicians use the same terms in the same ways. The weakness is its lack of validity. Unlike our definitions of ischemic heart disease, lymphoma, or AIDS, the DSM diagnoses are based on a consensus about clusters of clinical symptoms, not any objective laboratory measure. In the rest of medicine, this would be equivalent to creating diagnostic systems based on the nature of chest pain or the quality of fever. Indeed, symptom-based diagnosis, once common in other areas of medicine, has been largely replaced in the past half century as we have understood that symptoms alone rarely indicate the best choice of treatment.” (Transforming Diagnosis, 2013)

And let us be quite clear. “Lack of validity” in this context means that the “diagnoses” don’t actually correspond to any disease entities in the real world. Note also that Dr. Insel didn’t say poor validity, or low validity. He said lack of validity – meaning none.

Back to the Carolina Partners comment:

𔄚) mental illness symptoms often overlap with symptoms caused by other illnesses, for example, someone with cancer may also become depressed after diagnosis. Or someone’s fatigue may be caused by a vitamin deficiency, rather than by depression.

While considering all these factors, it is still completely inaccurate to state that there is no biological foundation for mental illnesses. They are not ‘make-believe’ diseases, but rather are caused by a variety of factors, including biological ones. As we understand more about mental illness through research we will (as we have with cardiology, for example) gain more precise vehicles for measuring and understanding the biological implications of these disorders.”

This is a little rambling, but let’s see if we can unravel it.

“… someone with cancer may also become depressed after diagnosis.”

This is true. In fact, I would say that most people who contract serious illness become somewhat sad and despondent. But this in no way establishes the notion that the sadness should be considered an additional illness.

“…someone’s fatigue may be caused by a vitamin deficiency, rather than by depression.”

This quote contains one of psychiatry’s core fallacies: that the various “mental illnesses” are the causes of their respective symptoms (as is the case in real illness). To illustrate the fallacy, consider the hypothetical conversation:

Client’s wife: Why is my husband so tired all the time?
Psychiatrist: Because he has an illness called major depressive disorder.
Client’s wife: How do you know he has this illness?
Psychiatrist: Because he is tired all the time.

Psychiatry defines major depression (the so-called illness) by the presence of five “symptoms” from a list of nine, one of which is fatigue, and then routinely adduces the “illness” to explain the symptoms. In reality, the “symptoms” are entailed in the definition of the “illness”, and the explanation is entirely spurious. There are many valid reasons why a person might feel fatigued, but none of these is because he “has a mental illness”. Mental illnesses are merely labels with no explanatory significance. And because of the inherent vagueness in the criteria, they’re not even good labels.

“…it is still completely inaccurate to state that there is no biological foundation for mental illnesses.”

As stressed above, there is a biological foundation to everything we do – every thought, every feeling, every eye blink, every action. But – and this is the point that seems to evade psychiatry – there is no good reason to believe that the various problems catalogued in the DSM are underlain by pathological biological processes. And there are lots of very good reasons to believe that they are not.

“They are not ‘make-believe’ diseases, but rather are caused by a variety of factors, including biological ones.”

I don’t think I’ve ever used the term “make-believe” to describe psychiatric “illnesses”, though I do routinely describe psychiatric labels as invented. The two terms are not synonymous. What psychiatry calls mental illnesses are actually nothing more than loose collections of vaguely-defined problems of thinking, feeling, and/or behaving. In most cases the “diagnosis” is polythetic (five out of nine, four out of six, etc.), so the labels aren’t coherent entities of any sort, let alone illnesses.

But the problems set out in the so-called symptom lists are real problems. That’s not the issue. I refer to these labels as inventions, because of psychiatry’s assertion that the loose clusters of problems are real diseases. In reality, they are not genuine diseases they are inventions. They are not discovered in nature, but rather are voted into existence by APA committees.

“As we understand more about mental illness through research we will (as we have with cardiology, for example) gain more precise vehicles for measuring and understanding the biological implications of these disorders.”

But meanwhile psychiatry has made up its mind. Within psychiatric dogma, all significant human problems of thinking, feeling, and behaving are illnesses that need to be “treated” with drugs and electric shocks.

All of this is interesting, and I suppose it’s important to refute the more or less steady stream of unsubstantiated assertions, fallacious reasoning, and spin that flows from the psychiatric strongholds.

But meanwhile the carnage continues. There is abundant prima facie evidence that psychiatric drugs are causally implicated in the suicide/murders that have become almost daily occurrences here in the US. My challenge to organized psychiatry is simple: call publicly for an independent, definitive study to explore this relationship. And my challenge to rank and file psychiatrists is equally simple: pressure the APA to call for such a study. If what you are doing is unqualifiedly wholesome, safe, and effective, then what do you have to fear?


Diabetes

Introduction

Diabetes mellitus is a condition in which the body is unable to control blood glucose levels adequately, resulting in high blood glucose levels (hyperglycaemia). Symptoms include frequent urination due to the osmotic effect of excess glucose in the urine, thirst due to loss of fluids and weight loss. Possible long-term complications of diabetes if blood glucose has been poorly controlled include cardiovascular disease (such as atherosclerosis and stroke) and damage to nerves, the kidney and eyes, which can potentially lead to blindness. Diabetes is a major health problem with an estimated 425 million people affected worldwide, and these numbers are predicted to rise. The rise in numbers is associated with an increase in obesity in the population and treating the complications is a major healthcare cost. In the U.K., some estimates predict the cost could reach 17% of the NHS budget.

Most people will be familiar with the classification of diabetes into the two main forms, Type 1 and Type 2 however, it is increasingly clear that there are in fact several different types of diabetes, some of which overlap to some extent. Recent research analysing nearly 15000 diabetics showed they could be clustered into five distinct groups based on specific biomarkers1 of the condition, which is significant because this better classification system may lead to improved treatment strategies in the future. Type 1 diabetes is an autoimmune disease in which cells of the body’s immune system cause destruction of insulin secreting β-cells in the pancreas, leading to a deficiency of insulin production. There are typically antibodies against key pancreatic proteins involved in insulin storage and secretion. It is a relatively rare form of the disease affecting 5–10% of diabetics, which is usually diagnosed in childhood and is not associated with excess body weight. Type 2 diabetes is the more common form of the disease, affecting 90–95% of diabetics, and is characterised by a loss of ability to respond to insulin (i.e. there is insulin resistance, also termed as insulin insensitivity). At diagnosis, individuals are typically over 30 years old, overweight, have high blood pressure and an unhealthy lipid profile (referred to as the metabolic syndrome). Established disease is associated with hypersecretion of insulin, but this is still inadequate to restore normal blood glucose levels, and the condition may progress towards insulin deficiency. The causes of diabetes are thought to be a combination of genetic and environmental factors, and it is recognised that being overweight is a strong risk factor for developing Type 2 diabetes.

Insulin action

In healthy individuals, blood glucose levels range between 3.5 and 5.5 mmol/l before meals. This range is maintained by the actions of hormones (primarily insulin and glucagon, but also adrenaline, cortisol and growth hormone) which control the production and uptake of glucose, levels of glycogen (the stored form of glucose), and fat and protein metabolism, as required following meals, during fasting and exercise. Both insulin and glucagon are polypeptides produced by the pancreas (β-cells – insulin α-cells – glucagon).

Insulin is secreted in response to an increase in blood glucose levels and its overall effect is to store chemical energy by enhancing the uptake and storage of glucose, amino acids and fats consequently reducing blood glucose levels, via actions on liver, muscle and adipose tissue (specifically adipocytes – fat cells). Glucagon, on the other hand, via a complex interplay with other hormones and the nervous system increases blood glucose by stimulating the breakdown of glycogen, fat and protein. When blood glucose is high, after a meal for example, insulin acts on the liver to decrease glucose synthesis (gluconeogenesis), increase glucose utilisation (glycolysis) and increases glycogen synthesis (glycogenesis). When the storage capacity for glycogen is reached, insulin increases synthesis of fatty acids (lipogenesis), via acetyl CoA as an intermediate, which is then exported for triglyceride synthesis in adipocytes. In muscle, insulin stimulates uptake of glucose, by recruiting the glucose uptake transporter type 4 (GLUT-4), and enhances glycogen synthesis and glycolysis. In adipose tissue, there is facilitated uptake of glucose which is metabolised to glycerol and subsequently used together with fatty acids to synthesise triglycerides. Insulin also inhibits pathways involved in lipolysis. In addition, insulin increases amino acid uptake and protein synthesis in muscle and is considered an anabolic hormone (i.e. one that builds up organs and tissues).

At the biochemical level, insulin produces its effects by binding to the insulin receptor – a cell surface glycoprotein composed of two extracellular α subunits and two β subunits that span the membrane (Figure 1). The receptor has tyrosine kinase activity (i.e. enzyme activity that catalyses the transfer of a phosphate group from ATP to a tyrosine amino acid within a protein, also known as tyrosine phosphorylation). Binding of insulin to the receptor initially causes tyrosine phosphorylation of the receptor itself, and then phosphorylation of intracellular proteins termed as insulin receptor substrate (IRS)-1 and IRS-2, followed by a complex series of intracellular signalling events involving many other kinases that lead to the physiological changes in carbohydrate, fat and protein metabolism discussed above via changes in gene expression and the activity of metabolic enzymes. The effects of insulin on glucose uptake are mediated via the glucose transporter GLUT-4, which is stored in intracellular vesicles in an inactive state, and insulin stimulates the movement of these vesicles to the plasma membrane where GLUT-4 becomes inserted into the membrane forming a pore that allows glucose uptake into the cell (Figure 1).

Insulin signalling in an adipocyte

Abbreviation: P, phosphorylation on tyrosine.

Abbreviation: P, phosphorylation on tyrosine.

Disease complications and ketoacidosis

Many of the longer term complications of diabetes involve effects on both large arteries (macrovascular) and small arteries and capillaries (microvascular). High blood glucose leads to proteins and lipids becoming modified in a non-enzymatic process by exposure to sugars, forming advanced glycation end products that have been implicated in the disease process. Oxidative stress and damage to the vascular endothelium lining blood vessels is also involved. One of the diagnostic tests for diabetes involves measuring levels of glycated haemoglobin (HbA1c) from red blood cells. This is a valuable test because it gives an assessment of the average plasma glucose concentration over months, because of the 120 days lifespan of a red blood cell, and it also gives an indication of how effective treatment has been.

An acute serious life-threatening condition associated with untreated Type 1 diabetes is diabetic ketoacidosis. It develops in the absence of insulin, during which there is increased glucose production by the liver but because of the absence of insulin cells in the periphery, such as muscle cells, are unable to take-up the glucose and use it. The consequent high blood glucose levels results in the kidneys filtering and removing it from the body in urine. This is associated with osmotic diuresis (loss of fluids and electrolytes) and dehydration. As an alternative energy source, triglycerides (fats) from adipose tissue are broken down to free fatty acids and taken up by the liver. Here they are converted into acetyl CoA which is the precursor for formation of ketones (acetoacetate, β-hydroxy-butyrate and acetone) within mitochondria. These are referred to as ketone bodies and released into the blood and are detectable in the breath giving a distinctive smell similar to that of acetone or pear drops. Release of ketones into the blood causes a drop in pH (acidosis) and the body tries to compensate by hyperventilating. If untreated, these events can lead to coma and death.

Treatment

For treatment of Type 1 diabetes, insulin is essential. Human insulin is now produced by recombinant DNA technology, rather than via extraction from the pancreases of animals. Diet and exercise are key to treatment of Type 2 diabetes and this can be combined with drug treatment.


Can excessive athletic training make your brain tired? New study says yes

You'd expect excessive athletic training to make the body tired, but can it make the brain tired too? A new study reported in the journal Current Biology on September 26 suggests that the answer is "yes."

When researchers imposed an excessive training load on triathletes, they showed a form of mental fatigue. This fatigue included reduced activity in a portion of the brain important for making decisions. The athletes also acted more impulsively, opting for immediate rewards instead of bigger ones that would take longer to achieve.

"The lateral prefrontal region that was affected by sport-training overload was exactly the same that had been shown vulnerable to excessive cognitive work in our previous studies," says corresponding author Mathias Pessiglione of Hôpital de la Pitié-Salpêtrière in Paris. "This brain region therefore appeared as the weak spot of the brain network responsible for cognitive control."

Together, the studies suggest a connection between mental and physical effort: both require cognitive control. The reason such control is essential in demanding athletic training, they suggest, is that to maintain physical effort and reach a distant goal requires cognitive control.

"You need to control the automatic process that makes you stop when muscles or joints hurt," Pessiglione says.

The researchers, including Pessiglione and first author Bastien Blain, explain that the initial idea for the study came from the National Institute of Sport, Expertise, and Performance (INSEP) in France, which trains athletes for the Olympic games. Some athletes had suffered from "overtraining syndrome," in which their performance plummeted as they experienced an overwhelming sense of fatigue. The question was: Did this overtraining syndrome arise in part from neural fatigue in the brain -- the same kind of fatigue that also can be caused by excessive intellectual work?

To find out, Pessiglione and colleagues recruited 37 competitive male endurance athletes with an average age of 35. Participants were assigned to either continue their normal training or to increase that training by 40% per session over a three-week period. The researchers monitored their physical performance during cycling exercises performed on rest days and assessed their subjective experience of fatigue using questionnaires every two days. They also conducted behavioral testing and functional magnetic resonance imaging (fMRI) scanning experiments.

The evidence showed that physical training overload led the athletes to feel more fatigued. They also acted more impulsively in standard tests used to evaluate how they'd make economic choices. This tendency was shown as a bias in favoring immediate over delayed rewards. The brains of athletes who'd been overloaded physically also showed diminished activation of the lateral prefrontal cortex, a key region of the executive control system, as they made those economic choices.

The findings show that, while endurance sport is generally good for your health, overdoing it can have adverse effects on your brain, the researchers say.

"Our findings draw attention to the fact that neural states matter: you don't make the same decisions when your brain is in a fatigue state," Pessiglione say.

These findings may be important not just for producing the best athletes but also for economic choice theory, which typically ignores such fluctuations in the neural machinery responsible for decision-making, the researchers say. It suggests it may also be important to monitor fatigue level in order to prevent bad decisions from being made in the political, judicial, or economic domains.

In future studies, the researchers plan to explore why exerting control during sports training or intellectual work makes the cognitive control system harder to activate in subsequent tasks. Down the road, the hope is to find treatments or strategies that help to prevent such neural fatigue and its consequences.


Contents

Biological psychiatry is a branch of psychiatry where the focus is chiefly on researching and understanding the biological basis of major mental disorders such as unipolar and bipolar affective (mood) disorders, schizophrenia and organic mental disorders such as Alzheimer's disease. This knowledge has been gained using imaging techniques, psychopharmacology, neuroimmunochemistry and so on. Discovering the detailed interplay between neurotransmitters and the understanding of the neurotransmitter fingerprint of psychiatric drugs such as clozapine has been a helpful result of the research.

On a research level, it includes all possible biological bases of behavior — biochemical, genetic, physiological, neurological and anatomical. On a clinical level, it includes various therapies, such as drugs, diet, avoidance of environmental contaminants, exercise, and alleviation of the adverse effects of life stress, [9] all of which can cause measurable biochemical changes. [10] The biological psychiatrist views all of these as possible etiologies of or remedies for mental health disorders.

However, the biological psychiatrist typically does not discount talk therapies. Medical psychiatric training generally includes psychotherapy and biological approaches. [5] Accordingly, psychiatrists are usually comfortable with a dual approach: "psychotherapeutic methods […] are as indispensable as psychopharmacotherapy in a modern psychiatric clinic". [6]

Sigmund Freud developed psychotherapy in the early 1900s, and through the 1950s this technique was prominent in treating mental health disorders.

However, in the late 1950s, the first modern antipsychotic and antidepressant drugs were developed: chlorpromazine (also known as Thorazine), the first widely used antipsychotic, was synthesized in 1950, and iproniazid, one of the first antidepressants, was first synthesized in 1957. In 1959 imipramine, the first tricyclic antidepressant, was developed.

Based significantly on clinical observations of the above drug results, in 1965 the seminal paper "The catecholamine hypothesis of affective disorders" was published. [11] It articulated the "chemical imbalance" hypothesis of mental health disorders, especially depression. It formed much of the conceptual basis for the modern era in biological psychiatry. [12]

The hypothesis has been extensively revised since its advent in 1965. More recent research points to deeper underlying biological mechanisms as the possible basis for several mental health disorders. [13] [14] [ unreliable medical source? ]

Modern brain imaging techniques allow noninvasive examination of neural function in patients with mental health disorders, however this is currently experimental. With some disorders it appears the proper imaging equipment can reliably detect certain neurobiological problems associated with a specific disorder. [15] [16] If further studies corroborate these experimental results, future diagnosis of certain mental health disorders could be expedited using such methods.

Another source of data indicating a significant biological aspect of some mental health disorders is twin studies. Identical twins have the same nuclear DNA, so carefully constructed studies may indicate the relative importance of environmental and genetic factors on the development of a particular mental health disorder.

The results from this research and the associated hypotheses form the basis for biological psychiatry and the treatment approaches in a clinical setting.

Since various biological factors can affect mood and behavior, psychiatrists often evaluate these before initiating further treatment. For example, dysfunction of the thyroid gland may mimic a major depressive episode, or hypoglycemia (low blood sugar) may mimic psychosis. [ citation needed ]

While pharmacological treatments are used to treat many mental disorders, other non-drug biological treatments are used as well, ranging from changes in diet and exercise to transcranial magnetic stimulation and electroconvulsive therapy. Types of non-biological treatments such as cognitive therapy, behavioral therapy, and psychodynamic psychotherapy are often used in conjunction with biological therapies. Biopsychosocial models of mental illness are widely in use, and psychological and social factors play a large role in mental disorders, even those with an organic basis such as schizophrenia.

Correct diagnosis is important for mental health disorders, otherwise the condition could worsen, resulting in a negative impact on both the patient and the healthcare system. [17] Another problem with misdiagnosis is that a treatment for one condition smight exacerbate other conditions. [18] [19] In other cases apparent mental health disorders could be a side effect of a serious biological problem such as concussion, [20] brain tumor, [21] [22] or hormonal abnormality, [21] [23] [24] [25] which could require medical or surgical intervention.

Early 20th century Edit

Sigmund Freud was originally focused on the biological causes of mental illness. Freud's professor and mentor, Ernst Wilhelm von Brücke, strongly believed that thought and behavior were determined by purely biological factors. Freud initially accepted this and was convinced that certain drugs (particularly cocaine) functioned as antidepressants. He spent many years trying to "reduce" personality to neurology, a cause he later gave up on before developing his now well-known psychoanalytic theories. [26]

Nearly 100 years ago, Harvey Cushing, the father of neurosurgery, noted that pituitary gland problems often cause mental health disorders. He wondered whether the depression and anxiety he observed in patients with pituitary disorders were caused by hormonal abnormalities, the physical tumor itself, or both. [21]

Mid 20th century Edit

An important point in modern history of biological psychiatry was the discovery of modern antipsychotic and antidepressant drugs. Chlorpromazine (also known as Thorazine), an antipsychotic, was first synthesized in 1950. In 1952, iproniazid, a drug being trialed against tuberculosis, was serendipitously discovered to have anti-depressant effects, leading to the development of MAOIs as the first class of antidepressants. [27] In 1959 imipramine, the first tricyclic antidepressant, was developed. Research into the action of these drugs led to the first modern biological theory of mental health disorders called the catecholamine theory, later broadened to the monoamine theory, which included serotonin. These were popularly called the "chemical imbalance" theory of mental health disorders.

Late 20th century Edit

Starting with fluoxetine (marketed as Prozac) in 1988, a series of monoamine-based antidepressant medications belonging to the class of selective serotonin reuptake inhibitors were approved. These were no more effective than earlier antidepressants, but generally had fewer side effects. [28] Most operate on the same principle, which is modulation of monoamines (neurotransmitters) in the neuronal synapse. Some drugs modulate a single neurotransmitter (typically serotonin). Others affect multiple neurotransmitters, called dual action or multiple action drugs. They are no more effective clinically than single action versions. That most antidepressants invoke the same biochemical method of action may explain why they are each similarly effective in rough terms. Recent research indicates antidepressants often work but are less effective than previously thought. [29]

Problems with catecholamine/monoamine hypotheses Edit

The monoamine hypothesis was compelling, especially based on apparently successful clinical results with early antidepressant drugs, but even at the time there were discrepant findings. Only a minority of patients given the serotonin-depleting drug reserpine became depressed in fact reserpine even acted as an antidepressant in many cases. This was inconsistent with the initial monoamine theory which said depression was caused by neurotransmitter deficiency.

Another problem was the time lag between antidepressant biological action and therapeutic benefit. Studies showed the neurotransmitter changes occurred within hours, yet therapeutic benefit took weeks.

To explain these behaviors, more recent modifications of the monoamine theory describe a synaptic adaptation process which takes place over several weeks. Yet this alone does not appear to explain all of the therapeutic effects. [30]

New research indicates different biological mechanisms may underlie some mental health disorders, only indirectly related to neurotransmitters and the monoamine chemical imbalance hypothesis. [14] [ unreliable medical source? ]

Recent research indicates a biological "final common pathway" may exist which both electroconvulsive therapy [31] and most current antidepressant drugs have in common. These investigations show recurrent depression may be a neurodegenerative disorder, disrupting the structure and function of brain cells, destroying nerve cell connections, even killing certain brain cells, and precipitating a decline in overall cognitive function. [14] [ unreliable medical source? ]

In this new biological psychiatry viewpoint, neuronal plasticity is a key element. Increasing evidence points to various mental health disorders as a neurophysiological problem which inhibits neuronal plasticity. [32] [33] [34]

This is called the neurogenic hypothesis of depression. It promises to explain pharmacological antidepressant action, [13] [35] including the time lag from taking the drug to therapeutic onset, why downregulation (not just upregulation) of neurotransmitters can help depression, why stress often precipitates mood disorders, [36] and why selective modulation of different neurotransmitters can help depression. It may also explain the neurobiological mechanism of other non-drug effects on mood, including exercise, diet and metabolism. [37] By identifying the neurobiological "final common pathway" into which most antidepressants funnel, it may allow rational design of new medications which target only that pathway. This could yield drugs which have fewer side effects, are more effective and have quicker therapeutic onset. [14] [ unreliable medical source? ]

There is significant evidence that oxidative stress plays a role in schizophrenia. [38]

A number of patients, activists, and psychiatrists dispute biological psychiatry as a scientific concept or as having a proper empirical basis, for example arguing that there are no known biomarkers for recognized psychiatric conditions. This position has been represented in academic journals such as The Journal of Mind and Behavior [39] and Ethical Human Psychology and Psychiatry, which publishes material specifically countering "the idea that emotional distress is due to an underlying organic disease." [40] Alternative theories and models instead view mental disorders as non-biomedical and might explain it in terms of, for example, emotional reactions to negative life circumstances or to acute trauma. [41]

Fields such as social psychiatry, clinical psychology, and sociology may offer non-biomedical accounts of mental distress and disorder for certain ailments and are sometimes critical of biopsychiatry. Social critics believe biopsychiatry fails to satisfy the scientific method because they believe there is no testable biological evidence of mental disorders. Thus, these critics view biological psychiatry as a pseudoscience attempting to portray psychiatry as a biological science.

R.D. Laing argued that attributing mental disorders to biophysical factors was often flawed due to the diagnostic procedure. The "complaint" is often made by a family member, not the patient, the "history" provided by someone other than patient, and the "examination" consists of observing strange, incomprehensible behavior. Ancillary tests (EEG, PET) are often done after diagnosis, when treatment has begun, which makes the tests non-blind and incurs possible confirmation bias. The psychiatrist Thomas Szasz commented frequently on the limitations of the medical approach to psychiatry and argued that mental illnesses are medicalized problems in living.

Silvano Arieti, while approving of the use of medication in some cases of schizophrenia, preferred intensive psychotherapy without medication if possible. He was also known for approving the use of electroconvulsive therapy on those with disorganized schizophrenia in order to make them reachable by psychotherapy. The views he expressed in Interpretation of Schizophrenia are nowadays known as the trauma model of mental disorders, an alternative to the biopsychiatric model. [41]


On the Biology of Mental Disorders

“The notion that mental disorders are genetically encoded brain disorders is everywhere around us,” note several prominent researchers in the latest issue of Behavioral and Brain Sciences. The idea holds such currency that it “dominates the organization of research, it dominates teaching, and it dominates the media,” they conclude in a study that has generated robust debate and refocused attention on the many factors that influence mental health.

The idea that psychiatric conditions have clear neural correlates predates Emil Kraepelin’s classificatory system in the 1900s, but it intensified dramatically in recent decades, argue Denny Borsboom at the University of Amsterdam, Angélique Cramer at Tilburg University, and Annemarie Kalis at Utrecht University, authors of the study. As evidence, they cite Thomas Insel, who as director of the National Institute of Mental Health argued that “mental disorders are biological disorders.” His successor, current director Joshua Gordon, claimed more recently that “psychiatric disorders are disorders of the brain.”

Yet despite widespread acceptance of this argument, the search for the biological basis of mental disorders has not resulted in “conclusive reductionist explanations of psychopathology. We do not have biomarkers that are sufficiently reliable and predictive for diagnostic use.”

The researchers are not alone in highlighting this problem. “Despite decades of work,” David Adam noted in Nature in April 2013, “the genetic, metabolic and cellular signatures of almost all mental syndromes remain largely a mystery.”

According to the authors of the recent study, the assumptions of neuropsychiatry have become so widespread and engrained that they are often simply accepted as fact:

The central problem is dogma: The reductionist hypothesis is not treated as a scientific hypothesis, but as an almost trivial fact. It is not a fact but a hypothesis that mental disorders originate in the brain. It is not a fact but a hypothesis that there are genes “for” mental disorders and it is not a fact but a hypothesis that finding out “what goes wrong in the brain” is a necessary condition for progress in the science of mental disorders.

One of several respondents to the study, Kathryn Tabb at of Columbia University, wrote that the critique was “convincing,” but the charge of biological reductionism “in 2018, a bit of a straw man.” Apparently, today’s emphasis on biopsychosocial-spiritual dimensions is evenly spread, without preference or bias, leaving the charge of biological reductionism “misdirected.”

Yet as Borsboom and his colleagues point out in a detailed response, while the forum of respondents rejected biological reductionism as a practice and approach, their colleagues in the media continue largely unchallenged to claim that mental disorders are best seen as brain disorders.

The implications of that disconnect are far-reaching and profound: “If it makes sense to understand mental disorders as arising from the causal interplay of symptoms and other factors in a network structure, there may be no reductive biological explanation that awaits discovery. This is because, contrary to quite widely shared current opinion, mental disorders are not brain disorders at all” (emphasis mine).

Commenting in the same forum, the prominent Stanford scientist John Ioannidis observed: “If mental health problems are mostly not brain disorders, the dearth of useful neuroscience-derived biomarkers is only to be expected. There is enormous investment in basic neuroscience research and intensive searches for informative biomarkers of treatment response and toxicity,” he added, yet “the yield is close to nil.”

“To overcome this dead end,” he advises, “we should shift emphasis away from the research paradigm that considers mental health problems to be mostly brain disorders and move towards exploring other, potentially more fruitful paths,” such as environmental factors themselves impacting genes.

“Instead of being reducible to a biological basis,” Borsboom and colleagues conclude, “mental disorders feature biological and psychological factors that are deeply intertwined in feedback loops. This suggests that neither psychological nor biological levels can claim causal or explanatory priority.”

Adam D. (2013). Mental health: On the spectrum. [Editorial]. Nature 496:416-18.

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