Glutamate hypothesis of schizophrenia

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https://en.wikipedia.org/wiki/Glutamate_hypothesis_of_schizophrenia 

 

The glutamate hypothesis of schizophrenia models the subset of pathologic mechanisms linked to glutamatergic signaling. The hypothesis was initially based on a set of clinical, neuropathological, and, later, genetic findings pointing at a hypofunction of glutamatergic signaling via NMDA receptors. While thought to be more proximal to the root causes of schizophrenia, it does not negate the dopamine hypothesis, and the two may be ultimately brought together by circuit-based models. The development of the hypothesis allowed for the integration of the GABAergic and oscillatory abnormalities into the converging disease model and made it possible to discover the causes of some disruptions.

Like the dopamine hypothesis, the development of the glutamate hypothesis developed from the observed effects of mind-altering drugs. However, where dopamine agonists can mimic positive symptoms with significant risks to brain structures during and after use, NMDA antagonists mimic some positive and negative symptoms with less brain harm, when combined with a GABA_A activating drug. Likely, both dopaminergic and glutaminergic abnormalities are implicated in schizophrenia, from a profound alteration in the function of the chemical synapses, as well as electrical synaptic irregularities. These form a portion of the complex constellation of factors, neurochemically, psychologically, psychosocially, and structurally, which result in schizophrenia.

The role of heteromer formation

Alteration in the expression, distribution, autoregulation, and prevalence of specific glutamate heterodimers alters relative levels of paired G proteins to the heterodimer-forming glutamate receptor in question. 

Namely: 5HT2A and mGlu2 form a dimer which mediates psychotomimetic and entheogenic effects of psychedelics; as such this receptor is of interest in schizophrenia. Agonists at either constituent receptor may modulate the other receptor allosterically; e.g. glutamate-dependent signaling via mGlu2 may modulate 5HT2A-ergic activity. Equilibrium between mGlu2/5HT2A is altered against tendency towards of psychosis by neuroleptic-pattern 5HT2A antagonists and mGlu2 agonists; both display antipsychotic activity. AMPA, the most widely distributed receptor in the brain, is a tetrameric ionotropic receptor; alterations in equilibrium between constituent subunits are seen in mGlu2/5HT2A antagonist (antipsychotic) administration GluR2 is seen to be upregulated in the PFC while GluR1 downregulates in response to antipsychotic administration. 

Reelin abnormalities may also be involved in the pathogenesis of schizophrenia via a glutamate-dependent mechanism. Reelin expression deficits are seen in schizophrenia, and reelin enhances expression of AMPA and NMDA alike. As such deficits in these two ionotropic glutamate receptors may be partially explained by altered reelin cascades. Neuregulin 1 deficits may also be involved in glutaminergic hypofunction as NRG1 hypofunction leads to schizophrenia-pattern behavior in mice; likely due in part to reduced NMDA signaling via Src suppression.

The role of synaptic pruning

Various neurotrophic factors dysregulate in schizophrenia and other mental illnesses, namely BDNF; expression of which is lowered in schizophrenia as well as in major depression and bipolar disorder. BDNF regulates in an AMPA-dependent mechanism - AMPA and BDNF alike are critical mediators of growth cone survival. NGF, another neurotrophin involved in maintenance of synaptic plasticity is similarly seen in deficit.

Dopaminergic excess, classically understood to result in schizophrenia, puts oxidative load on neurons; leading to inflammatory response and microglia activation. Similarly, toxoplasmosis infection in the CNS (positively correlated to schizophrenia) activates inflammatory cascades, also leading to microglion activation. The lipoxygenase-5 inhibitor minocycline has been seen to be marginally effective in halting schizophrenia progression. One of such inflammatory cascades' downstream transcriptional target, NF-κB, is observed to have altered expression in schizophrenia.

In addition, CB2 is one of the most widely distributed glial cell-expressed receptors, downregulation of this inhibitory receptor may increase global synaptic pruning activity. While difference in expression or distribution is observed, when the CB2 receptor is knocked out in mice, schizophreniform behaviors manifest. This may deregulate synaptic pruning processes in a tachyphlaxis mechanism wherein immediate excess CB2 activity leads to phosphorylation of the receptor via GIRK, resultant in b-arrestin-dependent internalization and subsequent trafficking to the proteasome for degradation.

The role of endogenous antagonists

Alterations in production of endogenous NMDA antagonists such as agmatine and kyenurenic acid have been shown in schizophrenia. Deficit in NMDA activity produces psychotomimetic effects, though it remains to be seen if the blockade of NMDA via these agents is causative or actually mimetic of patterns resultant from monoaminergic disruption.

AMPA, the most widely distributed receptor in the brain, mediates long term potentiation via activity-dependent modulation of AMPA density. GluR1 subunit-containing AMPA receptors are Ca2+ permeable while GluR2/3 subunit-positive receptors are nearly impermeable to calcium ions. In the regulated pathway, GluR1 dimers populate the synapse at a rate proportional to NMDA-ergic Ca2+ influx. In the constitutative pathway, GluR2/3 dimers populate the synapse at a steady state.

This forms a positive feedback loop, where a small trigger impulse degating NMDA from Mg2+ pore blockade results in calcium influx, this calcium influx then triggers trafficking of GluR1-containing(Ca2+ permeable) subunits to the PSD, such trafficking of GluR1-positive AMPA to the postsynaptic neuron allows for upmodulation of the postsynaptic neuron's calcium influx in response to presynaptic calcium influx. Robust negative feedback at NMDA from kyenurenic acid, magnesium, zinc, and agmatine prevents runaway feedback.

Misregulation of this pathway would sympathetically dysregulate LTP via disruption of NMDA. Such alteration in LTP may play a role, specifically in negative symptoms of schizophrenia, in creation of more broad disruptions such as loss of brain volume; an effect of the disease which antidopaminergics actually worsen, rather than treat.

The role of a7 nicotinic

Anandamide, an endocannabinoid, is an a7 nicotinic antagonist. Cigarettes, consumed far out of proportion by schizophrenics, contain nornitrosonicotine; a potent a7 antagonist. This may indicate a7 pentameter excess as a causative factor, or possibly as a method of self-medication to combat antipsychotic side effects. Cannabidiol, a FAAH inhibitor, increases levels in anandamide and may have antipsychotic effect; though results are mixed here as anandamide also is a cannabinoid and as such displays some psychotomimetic effect. However, a7 nicotinic agonists have been indicated as potential treatments for schizophrenia, though evidence is somewhat contradictory there is indication a7 nAChR is somehow involved in the pathogenesis of schizophrenia.

The role of 5-HT

This deficit in activation also results in a decrease in activity of 5-HT1A receptors in the raphe nucleus. This serves to increase global serotonin levels, as 5-HT1A serves as an autoreceptor. The 5-HT1B receptor, also acting as an autoreceptor, specifically within the striatum, but also parts of basal ganglia then will inhibit serotonin release. This disinhibits frontal dopamine release. The local deficit of 5-HT within the striatum, basal ganglia, and prefrontal cortex causes a deficit of excitatory 5-HT6 signalling. This could possibly be the reason antipsychotics sometimes are reported to aggravate negative symptoms as antipsychotics are 5HT6 antagonists This receptor is primarily GABAergic, as such, it causes an excess of glutamatergic, noradrenergic, dopaminergic, and cholinergic activity within the prefrontal cortex and the striatum. An excess of 5-HT7 signaling within the thalamus also creates too much excitatory transmission to the prefrontal cortex. Combined with another critical abnormality observed in schizoid patients: 5-HT2A dysfunction, this altered signalling cascade creates cortical, thus cognitive abnormalities. 5-HT2A allows a link between cortical, thus conscious, and the basal ganglia, unconscious. Axons from 5-HT2A neurons in layer V of the cerebral cortex reach the basal ganglia, forming a feedback loop. Signalling from layer V of the cerebral cortex to the basal ganglia alters 5-HT2C signalling. This feedback loop with 5-HT2A/5-HT2C is how the outer cortex layers can exert some control over our neuropeptides, specifically opioid peptides, oxytocin and vasopressin. This alteration in this limbic-layer V axis may create the profound change in social cognition (and sometimes cognition as a whole) that is observed in schizoid patients. However, genesis of the actual alterations is a much more complex phenomena.

The role of inhibitory transmission

The cortico-basal ganglia-thalamo-cortical loop is the source of the ordered input necessary for a higher level upper cortical loop. Feedback is controlled by the inhibitory potential of the cortices via the striatum. Through 5-HT2A efferents from layer V of the cortex transmission proceeds through the striatum into the globulus pallidus internal and substantia nigra pars compacta. This core input to the basal ganglia is combined with input from the subthalamic nucleus. The only primarily dopaminergic pathway in this loop is a reciprocal connection from the substantia nigra pars reticulata to the striatum. 

Dopaminergic drugs such as dopamine releasing agents and direct dopamine receptor agonists create alterations in this primarily GABAergic pathway via increased dopaminergic feedback from the substantia nigra pars compacta to the striatum. However, dopamine also modulates other cortical areas, namely the VTA; with efferents to the amygdala and locus coeruleus, likely modulating anxiety and paranoid aspects of psychotic experience. As such, the glutamate hypothesis is probably not an explanation of primary causative factors in positive psychosis, but rather might possibly be an explanation for negative symptoms. 

Dopamine hypothesis of schizophrenia elaborates upon the nature of abnormal lateral structures found in someone with a high risk for psychosis.

Altered signalling cascades

Again, thalamic input from layer V is a crucial factor in the functionality of the human brain. It allows the two sides to receive similar inputs, thus be able to perceive the same world. In psychosis, thalamic input loses much of its integrated character: hyperactive core feedback loops overwhelm the ordered output. This is due to excessive D2 and 5-HT2A activity. This alteration in input to the top and bottom of the cortex. The altered 5-HT signal cascade enhances the strength of excitatory thalamic input from layer V. This abnormality, enhancing the thalamic-cortical transmission cascade versus the corticostriatal control, creates a feedback loop, resulting in abnormally strong basal ganglia output.

The root of psychosis (experiences that cannot be explained, even within their own mind) is when basal ganglia input to layer V overwhelms the inhibitory potential of the higher cortexies resulting from striatal transmission. When combined with the excess prefrontal, specifically orbitofrontal transmission, from the hippocampus, this creates a brain prone to falling into self reinforcing belief.

However, given a specific environment, a person with this kind of brain (a human) can create a self-reinforcing pattern of maladaptive behavior, from the altered the layer II/III and III/I axises, from the disinhibited thalamic output. Rationality is impaired, primarily as response to the deficit of oxytocin and excess of vasopressin from the abnormal 5HT2C activity.

Frontal cortex activity will be impaired, when combined with excess DA activity: the basis for the advancement of schizophrenia, but it is also the neurologic mechanism behind many other psychotic diseases as well.. Heredation of schizophrenia may even be a result of conspecific "refrigerator parenting" techniques passed on though generations. However, the genetic component is the primary source of the neurological abnormalities which leave one prone to psychological disorders. Specifically, there is much overlap between bipolar disorder and schizophrenia, and other psychotic disorders.

Psychotic disorder is linked to excessive drug use, specifically dissociatives, psychedelics, stimulants, and marijuana.

Current state of schizophrenia treatment

Alterations in serine racemase indicate that the endogenous NDMA agonist D-serine may be produced abnormally in schizophrenia and that d-serine may be an effective treatment for schizophrenia. 

Schizophrenia is now treated by medications known as antipsychotics (or neuroleptics) that typically reduce dopaminergic activity because too much activity has been most strongly linked to positive symptoms, specifically persecutory delusions. Dopaminergic drugs do not induce the characteristic auditory hallucinations of schizophrenia. Dopaminergic drug abuse such as abuse of methamphetamine may result in a short lasting psychosis or provokation of a longer psychotic episode that may include symptoms of auditory hallucinations. The typical antipsychotics are known to have significant risks of side effects that can increase over time, and only show clinical effectiveness in reducing positive symptoms. Additionally, although newer atypical antipsychotics can have less affinity for dopamine receptors and still reduce positive symptoms, do not significantly reduce negative symptoms. A 2006 systematic review investigated the efficacy of glutamatergic drugs as add-on: 

Adding glutamatergic drug to antipsychotics compared to the same antipsychotic plus a placebo for schizophrenia

Summary
In general, all glutamatergic drugs appeared to be ineffective in further reducing 'positive symptoms' of the illness when added to the existing antipsychotic treatment. Glycine and D-serine may somewhat improve 'negative symptoms' when added to regular antipsychotic medication, but the results were not fully consistent and data are too few to allow any firm conclusions.

Outcome	Findings in words	Findings in numbers	Quality of evidence
Global outcome
Relapse (add-on glycine)	At present it is not possible to be confident about the effect of adding the glutamatergic drug to standard antipsychotic treatment. Data supporting this finding are very limited.	RR 0.39 (0.02 to 8.73)	Very low
Service outcome
Hospital admission (add-on glycine)	There is no clarity about the benefits or otherwise of adding a glutamatergic drug to antipsychotics for outcomes about how much hospital/community care is used. Data supporting this finding are based on low quality evidence.	RR 2.63 (0.12 to 59.40)	Low
Mental state
No clinically significant improvement (add-on glycine)	There is no evidence of clear advantage of using add-on glutamatergic to standard antipsychotic medication. These findings are based on data of low quality.	RR 0.92 (0.79 to 1.08)	Low
Adverse effects
Constipation (add-on glycine or D-serine)	There is no clarity from very limited data. Additional glutamatergic could cause constipation or help avoid it. Data are very limited.	RR 0.61 (0.06 to 6.02)	Very low
Insomnia (add-on glycine or D-serine)	Additional glutamatergic may help or cause insomnia - it is not clear from the very limited data.	RR 0.61 (0.13 to 2.84)	Very low
Missing outcomes
Quality of life	This outcome was not reported in any studies

Psychotomimetic glutamate antagonists

Ketamine and PCP were observed to produce significant similarities to schizophrenia. Ketamine produces more similar symptoms (hallucinations, withdrawal) without observed permanent effects (other than ketamine tolerance). Both arylcyclohexamines have some(uM) affinity to D2 and as triple reuptake inhibitors. PCP is representative symptomatically, but does appear to cause brain structure changes seen in schizophrenia. Although unconfirmed, Dizocilpine discovered by a team at Merck seems to model both the positive and negative effects in a manner very similar to schizophreniform disorders.

Possible glutamate based treatment

An early clinical trial by Eli Lilly of the drug LY2140023 has shown potential for treating schizophrenia without the weight gain and other side-effects associated with conventional anti-psychotics. A trial in 2009 failed to prove superiority over placebo or Olanzapine, but Lilly explained this as being due to an exceptionally high placebo response. However, Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials. This drug acts as a selective agonist at metabotropic mGluR2 and mGluR3 glutamate receptors (the mGluR3 gene has previously been associated with schizophrenia.).

Studies of glycine (and related co-agonists at the NMDA receptor) added to conventional anti-psychotics have also found some evidence that these may improve symptoms in schizophrenia.

Animal models

Research done on mice in early 2009 has shown that when the neuregulin-1\ErbB post-synaptic receptor genes are deleted, the dendritic spines of glutamate neurons initially grow, but break down during later development. This led to symptoms (such as disturbed social function, inability to adapt to predictable future stressors) that overlap with schizophrenia. This parallels the time delay for symptoms setting in with schizophrenic humans who usually appear to show normal development until early adulthood.

Disrupted in schizophrenia 1 is a gene that is disrupted in schizophrenia.

Dopamine hypothesis of schizophrenia

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Dopamine_hypothesis_of_schizophrenia 

 

The dopamine hypothesis of schizophrenia or the dopamine hypothesis of psychosis is a model that attributes the positive symptoms of schizophrenia to a disturbed and hyperactive dopaminergic signal transduction. The model draws evidence from the observation that a large number of antipsychotics have dopamine-receptor antagonistic effects. The theory, however, does not posit dopamine overabundance as a complete explanation for schizophrenia. Rather, the overactivation of D2 receptors, specifically, is one effect of the global chemical synaptic dysregulation observed in this disorder.

Introduction

Some researchers have suggested that dopamine systems in the mesolimbic pathway may contribute to the 'positive symptoms' of schizophrenia (whereas problems with dopamine function in the mesocortical pathway may be responsible for the 'negative symptoms', such as avolition and alogia). Abnormal expression, thus distribution of the D₂ receptor between these areas and the rest of the brain may also be implicated in schizophrenia, specifically in the acute phase. A relative excess of these receptors within the limbic system means Broca's area, which can produce illogical language, has an abnormal connection to Wernicke's area, which comprehends language but does not create it. Note that variation in distribution is observed within individuals, so abnormalities of this characteristic likely play a significant role in all psychological illnesses. Individual alterations are produced by differences within glutamatergic pathways within the limbic system, which are also implicated in other psychotic syndromes. Among the alterations of both synaptic and global structure, the most significant abnormalities are observed in the uncinate fasciculus and the cingulate cortex. The combination of these creates a profound dissymmetry of prefrontal inhibitory signaling, shifted positively towards the dominant side. Eventually, the cingulate gyrus becomes atrophied towards the anterior, due to long-term depression (LTD) and long-term potentiation (LTP) from the abnormally strong signals transversely across the brain. This, combined with a relative deficit in GABAergic input to Wernicke's area, shifts the balance of bilateral communication across the corpus callosum posteriorly. Through this mechanism, hemispherical communication becomes highly shifted towards the left/dominant posterior. As such, spontaneous language from Broca's can propagate through the limbic system to the tertiary auditory cortex. This retrograde signaling to the temporal lobes that results in the parietal lobes not recognizing it as internal results in the auditory hallucinations typical of chronic schizophrenia.

In addition, significant cortical grey matter volume reductions are observed in this disorder. Specifically, the right hemisphere atrophies more, while both sides show a marked decrease in frontal and posterior volume. This indicates that abnormal synaptic plasticity occurs, where certain feedback loops become so potentiated, others receive little glutaminergic transmission. This is a direct result of the abnormal dopaminergic input to the striatum, thus (indirectly) disinhibition of thalamic activity. The excitatory nature of dopaminergic transmission means the glutamate hypothesis of schizophrenia is inextricably intertwined with this altered functioning. 5-HT also regulates monoamine neurotransmitters, including dopaminergic transmission. Specifically, the 5-HT2A receptor regulates cortical input to the basal ganglia and many typical and atypical antipsychotics are antagonists at this receptor. Several antipsychotics are also antagonists at the 5-HT2C receptor, leading to dopamine release in the structures where 5-HT2C is expressed; striatum, prefrontal cortex, nucleus accumbens, amygdala, hippocampus (all structures indicated in this disease), and currently thought to be a reason why antipsychotics with 5HT2C antagonistic properties improves negative symptoms. More research is needed to explain the exact nature of the altered chemical transmission in this disorder.

Recent evidence on a variety of animal models of psychosis, such as sensitization of animal behaviour by amphetamine, or phencyclidine (PCP, Angel Dust), or excess steroids, or by removing various genes (COMT, DBH, GPRK6, RGS9, RIIbeta), or making brain lesions in newborn animals, or delivering animals abnormally by Caesarian section, all induce a marked behavioural supersensitivity to dopamine and a marked rise in the number of dopamine D₂ receptors in the high-affinity state for dopamine. This latter work implies that there are multiple genes and neuronal pathways that can lead to psychosis and that all these multiple psychosis pathways converge via the high-affinity state of the D2 receptor, the common target for all antipsychotics, typical or atypical. Combined with less inhibitory signalling from the thalamus and other basal ganglic structures, from hyoptrophy the abnormal activation of the cingulate cortex, specifically around Broca's and Wernicke's areas, abnormal D₂ agonism can facilitate the self-reinforcing, illogical patterns of language found in such patients. In schizophrenia, this feedback loop has progressed, which produced the widespread neural atrophy characteristic of this disease. Patients on neuroleptic or antipsychotic medication have significantly less atrophy within these crucial areas. As such, early medical intervention is crucial in preventing the advancement of these profound deficits in bilateral communication at the root of all psychotic disorders. Advanced, chronic schizophrenia can not respond even to clozapine, regarded as the most potent antipsychotic, as such, a cure for highly advanced schizophrenia is likely impossible through the use of any modern antipsychotics, so the value of early intervention cannot be stressed enough.

Discussion

Evidence for the dopamine hypothesis

Amphetamine, cocaine and similar drugs increase levels of dopamine in the brain and can cause symptoms which resemble those present in psychosis, particularly after large doses or prolonged use. This is often referred to as "amphetamine psychosis" or "cocaine psychosis," but may produce experiences virtually indistinguishable from the positive symptoms associated with schizophrenia. Similarly, those treated with dopamine enhancing levodopa for Parkinson's disease can experience psychotic side effects mimicking the symptoms of schizophrenia. Up to 75% of patients with schizophrenia have increased signs and symptoms of their psychosis upon challenge with moderate doses of methylphenidate or amphetamine or other dopamine-like compounds, all given at doses at which control normal volunteers do not have any psychologically disturbing effects.

Some functional neuroimaging studies have also shown that, after taking amphetamine, patients diagnosed with schizophrenia show greater levels of dopamine release (particularly in the striatum) than non-psychotic individuals. However, the acute effects of dopamine stimulants include euphoria, alertness and over-confidence; these symptoms are more reminiscent of mania than schizophrenia. Since the 2000s, several PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.

A group of drugs called the phenothiazines, including antipsychotics such as chlorpromazine, has been found to antagonize dopamine binding (particularly at receptors known as D₂ dopamine receptors) and reduce positive psychotic symptoms. This observation was subsequently extended to other antipsychotic drug classes, such as butyrophenones including haloperidol. The link was strengthened by experiments in the 1970s which suggested that the binding affinity of antipsychotic drugs for D₂ dopamine receptors seemed to be inversely proportional to their therapeutic dose. This correlation, suggesting that receptor binding is causally related to therapeutic potency, was reported by two laboratories in 1976.

Genetic evidence has suggested that there may be genes, or specific variants of genes, that code for mechanisms involved in dopamine function, which may be more prevalent in people experiencing psychosis or diagnosed with schizophrenia. Dopamine-related genes linked to psychosis in this way include COMT, DRD4, and AKT1.

People with Schizophrenia appear to have a high rate of self-medication with nicotine; the therapeutic effect likely occurs through dopamine modulation by nicotinic acetylcholine receptors.

However, there was controversy and conflicting findings over whether postmortem findings resulted from drug tolerance to chronic antipsychotic treatment. Compared to the success of postmortem studies in finding profound changes of dopamine receptors, imaging studies using SPET and PET methods in drug naive patients have generally failed to find any difference in dopamine D₂ receptor density compared to controls. Comparable findings in longitudinal studies show: " Particular emphasis is given to methodological limitations in the existing literature, including lack of reliability data, clinical heterogeneity among studies, and inadequate study designs and statistic," suggestions are made for improving future longitudinal neuroimaging studies of treatment effects in schizophrenia A recent review of imaging studies in schizophrenia shows confidence in the techniques, while discussing such operator error. In 2007 one report said, "During the last decade, results of brain imaging studies by use of PET and SPET in schizophrenic patients showed a clear dysregulation of the dopaminergic system." 

Recent findings from meta-analyses suggest that there may be a small elevation in dopamine D₂ receptors in drug-free patients with schizophrenia, but the degree of overlap between patients and controls makes it unlikely that this is clinically meaningful. While the review by Laruelle acknowledged more sites were found using methylspiperone, it discussed the theoretical reasons behind such an increase (including the monomer-dimer equilibrium) and called for more work to be done to 'characterise' the differences. In addition, newer antipsychotic medication (called atypical antipsychotic medication) can be as potent as older medication (called typical antipsychotic medication) while also affecting serotonin function and having somewhat less of a dopamine blocking effect. In addition, dopamine pathway dysfunction has not been reliably shown to correlate with symptom onset or severity. HVA levels correlate trendwise to symptoms severity. During the application of debrisoquin, this correlation becomes significant.

Giving a more precise explanation of this discrepancy in D₂ receptor has been attempted by a significant minority. Radioligand imaging measurements involve the monomer and dimer ratio, and the 'cooperativity' model. Cooperativitiy is a chemical function in the study of enzymes. Dopamine receptors interact with their own kind, or other receptors to form higher order receptors such as dimers, via the mechanism of cooperativity. Philip Seeman has said: "In schizophrenia, therefore, the density of [11C] methylspiperone sites rises, reflecting an increase in monomers, while the density of [11C] raclopride sites remains the same, indicating that the total population of D₂ monomers and dimers does not change." (In another place Seeman has said methylspiperone possibly binds with dimers) With this difference in measurement technique in mind, the above-mentioned meta-analysis uses results from 10 different ligands. Exaggerated ligand binding results such as SDZ GLC 756 (as used in the figure) were explained by reference to this monomer-dimer equilibrium.

According to Seeman, "...Numerous postmortem studies have consistently revealed D₂ receptors to be elevated in the striata of patients with schizophrenia". However, the authors were concerned the effect of medication may not have been fully accounted for. The study introduced an experiment by Abi-Dargham et al. in which it was shown medication-free live schizophrenics had more D₂ receptors involved in the schizophrenic process and more dopamine. Since then another study has shown such elevated percentages in D₂ receptors is brain-wide (using a different ligand, which did not need dopamine depletion). In a 2009 study, Annisa Abi-Dagham et al. confirmed the findings of her previous study regarding increased baseline D₂ receptors in schizophrenics and showing a correlation between this magnitude and the result of amphetamine stimulation experiments.

Some animal models of psychosis are similar to those for addiction – displaying increased locomotor activity. For those female animals with previous sexual experience, amphetamine stimulation happens faster than for virgins. There is no study on male equivalent because the studies are meant to explain why females experience addiction earlier than males.

Even in 1986 the effect of antipsychotics on receptor measurement was controversial. An article in Science sought to clarify whether the increase was solely due to medication by using drug-naive schizophrenics: "The finding that D₂ dopamine receptors are substantially increased in schizophrenic patients who have never been treated with neuroleptic drugs raises the possibility that dopamine receptors are involved in the schizophrenic disease process itself. Alternatively, the increased D₂ receptor number may reflect presynaptic factors such as increased endogenous dopamine levels (16). In either case, our findings support the hypothesis that dopamine receptor abnormalities are present in untreated schizophrenic patients."  (The experiment used 3-N-[11C]methylspiperone – the same as mentioned by Seeman detects D₂ monomers and binding was double that of controls.)

It is still thought that dopamine mesolimbic pathways may be hyperactive, resulting in hyperstimulation of D₂ receptors and positive symptoms. There is also growing evidence that, conversely, mesocortical pathway dopamine projections to the prefrontal cortex might be hypoactive (underactive), resulting in hypostimulation of D₁ receptors, which may be related to negative symptoms and cognitive impairment. The overactivity and underactivity in these different regions may be linked, and may not be due to a primary dysfunction of dopamine systems but to more general neurodevelopmental issues that precede them. Increased dopamine sensitivity may be a common final pathway.

Another finding is a six-fold excess of binding sites insensitive to the testing agent, raclopride; Seeman said this increase was probably due to the increase in D₂ monomers. Such an increase in monomers may occur via the cooperativity mechanism which is responsible for D₂^High and D₂^Low, the supersensitive and lowsensitivity states of the D₂ dopamine receptor. More specifically, "an increase in monomers, may be one basis for dopamine supersensitivity".

Evidence against the dopamine hypothesis

Further experiments, conducted as new methods were developed (particularly the ability to use PET scanning to examine drug action in the brain of living patients) challenged the view that the amount of dopamine blocking was correlated with clinical benefit. These studies showed that some patients had over 90% of their D₂ receptors blocked by antipsychotic drugs, but showed little reduction in their psychoses. This primarily occurs in patients who have had the psychosis for ten to thirty years. At least 90-95% of first-episode patients, however, respond to antipsychotics at low doses and do so with D₂ occupancy of 60-70%. The antipsychotic aripiprazole occupies over 90% of D₂ receptors, but this drug is both an agonist and an antagonist at D₂ receptors.

Furthermore, although dopamine-inhibiting medications modify dopamine levels within minutes, the associated improvement in patient symptoms is usually not visible for at least several days, suggesting that dopamine may be indirectly responsible for the illness.

Similarly, the second generation of antipsychotic drugs – the atypical antipsychotics) were found to be just as effective as older typical antipsychotics in controlling psychosis, but more effective in controlling the negative symptoms, despite the fact that they have lower affinity for dopamine receptors than for various other neurotransmitter receptors. More recent work, however, has shown that atypical antipsychotic drugs such as clozapine and quetiapine bind and unbind rapidly and repeatedly to the dopamine D₂ receptor. All of these drugs exhibit inverse agonistic effects at the 5-HT_2A/2C receptors, meaning serotonin abnormalities are also involved in the complex constellation of neurologic factors predisposing one to the self reinforcing language-based psychological deficits found in all forms of psychosis.

The excitatory neurotransmitter glutamate is now also thought to be associated with schizophrenia. Phencyclidine (also known as PCP or "Angel Dust") and ketamine, both of which block glutamate (NMDA) receptors, are known to cause psychosis at least somewhat resembling schizophrenia, further suggesting that psychosis and perhaps schizophrenia cannot fully be explained in terms of dopamine function, but may also involve other neurotransmitters.

Similarly, there is now evidence to suggest there may be a number of functional and structural anomalies in the brains of some people diagnosed with schizophrenia, such as changes in grey matter density in the frontal and temporal lobes. It appears, therefore, that there are multiple causes for psychosis and schizophrenia, including gene mutations and anatomical lesions.

Psychiatrist David Healy has argued that drug companies have inappropriately promoted the dopamine hypothesis of schizophrenia as a deliberate and calculated simplification for the benefit of drug marketing.

Relationship with glutamate

Research has shown the importance of glutamate receptors, specifically N-methyl-D-aspartate receptors (NMDARs), in addition to dopamine in the etiology of schizophrenia. Mice with only 5% of the normal levels of NMDAR's expressed schizophrenic like behaviors seen in animal models of schizophrenia while mice with 100% of NMDAR's behaved normally. Schizophrenic behavior in low NMDAR mice has been effectively treated with antipsychotics that lower dopamine. NMDAR's and dopamine receptors in the prefrontal cortex are associated with the cognitive impairments and working memory deficits commonly seen in schizophrenia. Rats that have been given a NMDAR antagonist exhibit a significant decrease in performance on cognitive tasks. Rats given a dopamine antagonist (antipsychotic) experience a reversal of the negative effects of the NMDAR antagonist. Glutamate imbalances appear to cause abnormal functioning in dopamine. When levels of glutamate are low dopamine is overactive and results in the expression schizophrenic symptoms.

Criticisms

Dr Ronald Pies, the current editor in Chief Emeritus of Psychiatric Times with a circulation of about 50,000 psychiatrists monthly, wrote on July 11, 2011 " In truth, the “chemical imbalance” notion was always a kind of urban legend- - never a theory seriously propounded by well-informed psychiatrists."

Combined networks of dopamine, serotonin, and glutamate

PsychopharmacologistStephen M. Stahl suggested in a review of 2018 that in many cases of psychosis, including schizophrenia, three interconnected networks based on dopamine, serotonin, and glutamate - each on its own or in various combinations - contributed to an overexcitation of dopamine D2 receptors in the ventral striatum.

Salience (neuroscience)

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Salience_(neuroscience) 

The salience (also called saliency) of an item is the state or quality by which it stands out from its neighbors. Saliency detection is considered to be a key attentional mechanism that facilitates learning and survival by enabling organisms to focus their limited perceptual and cognitive resources on the most pertinent subset of the available sensory data.

Saliency typically arises from contrasts between items and their neighborhood, such as a red dot surrounded by white dots, a flickering message indicator of an answering machine, or a loud noise in an otherwise quiet environment. Saliency detection is often studied in the context of the visual system, but similar mechanisms operate in other sensory systems. What is salient can be influenced by training: for example, for human subjects particular letters can become salient by training.

When attention deployment is driven by salient stimuli, it is considered to be bottom-up, memory-free, and reactive. Conversely, attention can also be guided by top-down, memory-dependent, or anticipatory mechanisms, such as when looking ahead of moving objects or sideways before crossing streets. Humans and other animals have difficulty paying attention to more than one item simultaneously, so they are faced with the challenge of continuously integrating and prioritizing different bottom-up and top-down influences.

Neuroanatomy

The brain component named the hippocampus helps with the assessment of salience and context by using past memories to filter new incoming stimuli, and placing those that are most important into long term memory. The entorhinal cortex is the pathway into and out of the hippocampus, and is an important part of the brain's memory network; research shows that it is a brain region that suffers damage early on in Alzheimer's disease, one of the effects of which is altered (diminished) salience.

The pulvinar nuclei (in the thalamus) modulates physical/perceptual salience in attentional selection.

One group of neurons (i.e., D1-type medium spiny neurons) within the nucleus accumbens shell (NAcc shell) assigns appetitive motivational salience ("want" and "desire", which includes a motivational component), aka incentive salience, to rewarding stimuli, while another group of neurons (i.e., D2-type medium spiny neurons) within the NAcc shell assigns aversive motivational salience to aversive stimuli.

The primary visual cortex (V1) generates a bottom-up saliency map from visual inputs to guide reflexive attentional shifts or gaze shifts. The saliency of a location is higher when V1 neurons give higher responses to that location relative to V1 neurons' responses to other visual locations. For example, a unique red item among green items, or a unique vertical bar among horizontal bars, is salient since it evokes higher V1 responses and attracts attention or gaze. The V1 neural responses are sent to the superior colluculus to guide gaze shifts to the salient locations. A fingerprint of the saliency map in V1 is that attention or gaze can be captured by the location of an eye-of-origin singleton in visual inputs, e.g., a bar uniquely shown to the left eye in a background of many other bars shown to the right eye, even when observers cannot tell the difference between the singleton and the background bars.

In psychology

The term is widely used in the study of perception and cognition to refer to any aspect of a stimulus that, for any of many reasons, stands out from the rest. Salience may be the result of emotional, motivational or cognitive factors and is not necessarily associated with physical factors such as intensity, clarity or size. Although salience is thought to determine attentional selection, salience associated with physical factors does not necessarily influence selection of a stimulus.

Salience bias

Salience bias (also known as perceptual salience) is the cognitive bias that predisposes individuals to focus on items that are more prominent or emotionally striking and ignore those that are unremarkable, even though this difference is often irrelevant by objective standards. Salience bias is closely related to the concept of availability in behavioral economics:

Accessibility and salience are closely related to availability, and they are important as well. If you have personally experienced a serious earthquake, you’re more likely to believe that an earthquake is likely than if you read about it in a weekly magazine. Thus, vivid and easily imagined causes of death (for example, tornadoes) often receive inflated estimates of probability, and less-vivid causes (for example, asthma attacks) receive low estimates, even if they occur with a far greater frequency (here, by a factor of twenty). Timing counts too: more recent events have a greater impact on our behavior, and on our fears, than earlier ones.

— Richard H. Thaler, Nudge: Improving Decisions about Health, Wealth, and Happiness (2008-04-08)

Aberrant salience hypothesis of schizophrenia

Kapur (2003) proposed that a hyperdopaminergic state, at a "brain" level of description, leads to an aberrant assignment of salience to the elements of one's experience, at a "mind" level. These aberrant salience attributions have been associated with altered activities in the mesolimbic system, including the striatum, the amygdala, the hippocampus, and the parahippocampal gyrus. Dopamine mediates the conversion of the neural representation of an external stimulus from a neutral bit of information into an attractive or aversive entity, i.e. a salient event. Symptoms of schizophrenia may arise out of 'the aberrant assignment of salience to external objects and internal representations', and antipsychotic medications reduce positive symptoms by attenuating aberrant motivational salience via blockade of the dopamine D2 receptors (Kapur, 2003).

Alternative areas of investigation include supplementary motor areas, frontal eye fields and parietal eye fields. These areas of the brain are involved with calculating predictions and visual salience. Changing expectations on where to look restructures these areas of the brain. This cognitive repatterning can result in some of the symptoms found in such disorders.

Visual saliency modeling

In the domain of psychology, efforts have been made in modeling the mechanism of human attention, including the learning of prioritizing the different bottom-up and top-down influences.

In the domain of computer vision, efforts have been made in modeling the mechanism of human attention, especially the bottom-up attentional mechanism, including both spatial and temporal attention. Such a process is also called visual saliency detection.

Generally speaking, there are two kinds of models to mimic the bottom-up saliency mechanism. One way is based on the spatial contrast analysis: for example, a center-surround mechanism is used to define saliency across scales, which is inspired by the putative neural mechanism.  The other way is based on the frequency domain analysis. While they used the amplitude spectrum to assign saliency to rarely occurring magnitudes, Guo et al. use the phase spectrum instead. Recently, Li et al. introduced a system that uses both the amplitude and the phase information.

A key limitation in many such approaches is their computational complexity leading to less than real-time performance, even on modern computer hardware. Some recent work attempts to overcome these issues at the expense of saliency detection quality under some conditions. Other work suggests that saliency and associated speed-accuracy phenomena may be a fundamental mechanisms determined during recognition through gradient descent, needing not be spatial in nature.

Analytical skill

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Analytical_skill 

 

The cerebral cortex is responsible for analytical thinking in the human brain

Analytical skill is the ability to deconstruct information into smaller categories in order to draw conclusions. Analytical skill consists of categories that include logical reasoning, critical thinking, communication, research, data analysis and creativity. Analytical skill is taught in contemporary education with the intention of fostering the appropriate practises for future professions. The professions that adopt analytical skill include educational institutions, public institutions, community organisations and industry. 

Richard J. Heuer Jr. explained that 'Thinking analytically is a skill like carpentry or driving a car. It can be taught, it can be learned, and it can improve with practice. But like many other skills, such as riding a bike, it is not learned by sitting in a classroom and being told how to do it. Analysts learn by doing.'. In the article by Freed, the need for programs within the educational system to help students develop these skills is demonstrated. According to scholars, workers 'will need more than elementary basic skills to maintain the standard of living of their parents. They will have to think for a living, analyse problems and solutions, and work cooperatively in teams'.

Logical Reasoning

Logical reasoning is a process comprising of inferences, where premises and hypotheses are formulated to arrive at a probable conclusion. It is a broad term comprising of three sub-classifications in deductive reasoning, inductive reasoning and abductive reasoning.

Deductive Reasoning

‘Deductive reasoning is a basic form of valid reasoning, commencing with a general statement or hypothesis, then examines the possibilities to reach a specific, logical conclusion’. This scientific method utilises deductions, to test hypotheses and theories, to predict if possible observations were correct. 

A logical deductive reasoning sequence can be executed by establishing: an assumption, followed by another assumption and finally, conducting an inference. For example, ‘All men are mortal. Harold is a man. Therefore, Harold is mortal.’

For deductive reasoning to be upheld, the hypothesis must be correct, therefore, reinforcing the notion that the conclusion is logical and true. It is possible for deductive reasoning conclusions to be inaccurate or incorrect entirely, but the reasoning and premise is logical. For example, ‘All bald men are grandfathers. Harold is bald. Therefore, Harold is a grandfather.’ is a valid and logical conclusion but it is not true as the original assumption is incorrect. Deductive reasoning is an analytical skill used in many professions such as management, as the management team delegates tasks for day-to-day business operations.

Inductive Reasoning

Inductive reasoning compiles information and data to establish a general assumption that is suitable to the situation. Inductive reasoning commences with an assumption based on faithful data, leading to a generalised conclusion. For example, ‘All the swans I have seen are white. (Premise) Therefore all swans are white. (Conclusion)’. It is clear that the conclusion is incorrect, therefore, it is a weak argument. To strengthen the conclusion, it is made more probable, for example, ‘All the swans I have seen are white. (Premise) Therefore most swans are probably white (Conclusion)’. Inductive reasoning is an analytical skill common in many professions such as the corporate environment, where statistics and data are constantly analysed.

Doctor using abductive reasoning to diagnose a man with diabetes

The 6 types of inductive reasoning

1. Generalised: This manner utilises a premise on a sample set to extract a conclusion about a population.
2. Statistical: This is a method that utilises statistics based on a large and viable random sample set that is quantifiable to strengthen conclusions and observations.
3. Bayesian: This form adapts statistical reasoning to account for additional or new data.
4. Analogical: This is a method that records on the foundations of shared properties between two groups, leading to a conclusion that they are also likely to share further properties.
5. Predictive: This form of reasoning extrapolates a conclusion about the future based on a current or past sample.
6. Casual inference: This method of reasoning is formed around a causal link between the premise and the conclusion.

Abductive reasoning

Abductive reasoning commences with layered hypotheses, which may be insufficient with evidence, leading to a conclusion that is most likely explanatory for the problem. It is a form of reasoning where the conductor chooses a hypothesis that would best suit the given data. For example, when a patient is ill, the doctor gathers a hypothesis from the patient’s symptoms, or other evidence, that they deem factual and appropriate. The doctor will then go through a list of possible illnesses and will attempt to assign the appropriate illness. Abductive reasoning is characterised by its lack of completeness, in evidence, explanation or both. This form of reasoning can be creative, intuitive and revolutionary due to its instinctive design.

Critical Thinking

Critical thinking is an analytical skill that involves clear, purposeful, and goal-directed thinking. It is used to interpret and explain the data given. It is the ability to think cautiously and rationally to resolve problems. This goal-directed thinking is achieved by supporting conclusions without biases, having reliable evidence and reasoning, and using appropriate data and information. Critical thinking is an imperative analytical skill as it underpins contemporary living in areas such as education and professional careers, but it is not restricted to a specific area.

Critical thinking is used to solve problems, calculate the likelihood, make decisions, and formulate inferences. Critical thinking requires examining information, reflective thinking, using appropriate skills, and confidence in the quality of the information given to come to a conclusion or plan. Critical thinking includes being willing to change if better information becomes available. As a critical thinker individuals do not accept assumptions without further questioning the reliability of it with further research and analysing the results found.

Developing Critical Thinking

Critical thinking can be developed through establishing personal beliefs and values. It is critical that individuals are able to query authoritative bodies: teachers, specialists, textbooks, books, newspapers, television etc. Querying these authorities allow critical thinking ability to be developed as the individual gains their own freedom and wisdom to think about reality and contemporary society, revering from autonomy.

Developing Critical Thinking through Probability Models

Critical thinking can be developed through probability models, where individuals adhere to a logical, conceptual understanding of mathematics and emphasise investigation, problem-solving, mathematical literacy and the use of mathematical discourse. The student actively constructs their knowledge and understanding, while teaching models function as a mediator by actively testing the student through querying, challenging and assigning investigation tasks, ultimately, allowing the student to think in deeper ways about various concepts, ideas and mathematical contexts.

Communication

Communication is a process where individuals transfer information from one another. It is a complex system comprising of a listener interpreting the information, understanding it and then transferring it. Communication as an analytical skill includes communicating with confidence, clarity, and sticking with the point you are trying to communicate. It comprises of verbal and non-verbal communication. Communication is an imperative component of analytical skill as it allows the individual to develop relationships, contribute to group decisions, organisational communication, and influence media and culture.

Dr. Martin Luther King Jr. providing a speech to 250,000 people during the Civil Rights March in Washington D.C. exemplifies verbal communication

Verbal Communication

Verbal communication is interaction through words in linguistic form. Verbal communication comprises of oral communication, written communication and sign language. It is an effective form of communication as the individuals sending and receiving the information are physically present, allowing immediate responses. In this form of communication, the sender uses words, spoken or written, to express the message to the individuals receiving the information.

Verbal communication is an essential analytical skill as it allows for the development of positive relationships among individuals. This positive relationship is attributed to the notion that verbal communication between individuals fosters a depth of understanding, empathy and versatility among them, providing each other with more attention. Verbal communication is a skill that is commonly used in professions such as the health sector, where healthcare workers are desired to possess strong interpersonal skills. Verbal communication has been linked to patient satisfaction. An effective strategy to improve verbal communication ability is through debating as is it fosters communication and critical thinking.

Non-verbal Communication

Non-verbal communication is commonly known as unspoken dialogue between individuals. It is a significant analytical skill as it allows individuals to distinguish true feelings, opinions and behaviours, as individuals are more likely to believe nonverbal cues as opposed to verbal expressions. Non-verbal communication is able to transcend communicational barriers such as race, ethnicity and sexual orientation. This is a significant factor for international industries that require global communication or communication between other regions such as trade between China and The United States of America.

Dancing is a common expressionist form of human non-verbal communication

 

Statistical measures showcase that the true meaning behind all messages is 93% non-verbal and 7% verbal. Non-verbal communication is a critical analytical skill as it allows individuals to delve deeper into the meaning of messages. It allows individuals to analyse another person’s perceptions, expressions and social beliefs. Individuals who excel in communicating and understanding non-verbal communication are able to analyse the interconnectedness of mutualism, social beliefs and expectations.

Communication Theories

A communication theory is an abstract understanding of how information is transferred from individuals. Many communication theories have been developed to foster and build upon the ongoing dynamic nature of how people communicate. Early models of communication were simple, such as Aristotle’s model of communication, comprising of a speaker communicating a speech to an audience, leading to an effect. This is a basic form of communication that addresses communication as a linear concept where information is not being relayed back.

Modern theories for communication include Schramm’s model where there are multiple individuals, each individual is encoding, interpreting and decoding the message, and messages are being transferred between one another. Schramm has included another factor in his model in experience i.e. expressing that each individual’s experience influences their ability to interpret a message. Communication theories are constantly being developed to acclimatise to certain organisations or individuals. It is imperative for an individual to adopt a suitable communication theory for organisations to ensure that the organisation is able to function as desired. For example, traditional corporate hierarchy are commonly known to adopt a linear communicational model i.e. Aristotle’s model of communication.

Research

Research is the construct of utilising tools and techniques to deconstruct and solve problems. While researching, it is important to distinguish what information is relevant to the data and avoiding excess, irrelevant data. Research involves the collection and analysis of information and data with the intention of founding new knowledge and/or deciphering a new understanding of existing data. Research ability is an analytical skill as it allows individuals to comprehend social implications. Research ability is valuable as it fosters transferable employment related skills. Research is primarily employed in academia and higher education, it is a profession pursued by many graduates, individuals intending to supervise or teach research students or those in pursuit of a PhD.

Research in Academia

In higher education, new research provides the most desired quality of evidence, if this is not available, then existing forms of evidence should be used. It is accepted that research provides the greatest form of knowledge, in the form of quantitative or qualitative data.

Research students are highly desired by various industries due to their dynamic mental capacity. Research students are commonly sought after due to their analysis and problem-solving ability, interpersonal and leadership skills, project management and organisation, research and information management and written and oral communication.

Data Analysis

Data analysis is a systematic method of cleaning, transforming and modelling statistical or logical techniques to describe and evaluate data. Using data analysis as an analytical skill means being able to examine large volumes of data and then identifying trends within the data. It is critical to be able to look at the data and determine what information is important and should be kept and what information is irrelevant and can be discarded. Data analysis includes finding different patterns within the information which allows you to narrow your research and come to a better conclusion. It is a tool to discover and decipher useful information for business decision-making. It is imperative in inferring information from data and adhering to a conclusion or decision from that data. Data analysis can stem from past or future data. Data analysis is an analytical skill, commonly adopted in business, as it allows organisations to be come more efficient, internally and externally, solve complex problems and innovate.

Text Analysis

Text analysis is the discovery and understanding of valuable information in unstructured or large data. It is a method to transform raw data into business information, allowing for strategic business decisions by offering a method to extract and examine data, derive patterns and finally interpret the data.

Statistical Analysis

Statistical analysis involves the collection, analyses and presentation of data to decipher trends and patterns. It is common in research, industry and government to enhance the scientific aspects of the decision that needs to be made. It consists of descriptive analysis and inferential analysis.

Descriptive Analysis

Descriptive analysis provides information about a sample set that reflects the population by summarising relevant aspects of the dataset i.e. uncovering patterns. It displays the measures of central tendency and measures of spread, such as mean, deviation, proportion, frequency etc.

Inferential Analysis

Inferential analysis analyses a sample from complete data to compare the difference between treatment groups. Multiple conclusions are constructed by selecting different samples. Inferential analysis can provide evidence that, with a certain percentage of confidence, there is a relationship between two variables. It is adopted that the sample will be different to the population, thus, we further accept a degree of uncertainty.

Example of sales forecasting, a form of predictive analysis

Diagnostic Analysis

Diagnostic analysis showcases the origin of the problem by finding the cause from the insight found in statistical analysis. This form of analysis is useful to identify behavioural patterns of data.

Predictive Analysis

Predictive analysis is an advanced form of analytics that forecasts future activity, behaviour, trends and patterns from new and historical data. Its accuracy is based on how much faithful data is present and the degree of inference that can be exploited from it.

Prescriptive Analysis

Prescriptive analytics provide firms with optimal recommendations to solve complex decisions. It is used in many industries, such as aviation to optimise schedule selection for airline crew.

Creativity

Areas of the brain that stimulated during actions of creativity

Creativity is important when it comes to solving different problems when presented. Creative thinking works best for problems that can have multiple solutions to solve the problem. It is also used when there seems to be no correct answer that applies to every situation, and is instead based from situation to situation. It includes being able to put the pieces of a problem together, as well as figure out pieces that may be missing. Then it includes brainstorming with all the pieces and deciding what pieces are important and what pieces can be discarded. The next step would be now analysing the pieces found to be of worth and importance and using those to come to a logical conclusion on how to best solve the problem. There can be multiple answers you come across to solve this problem. Many times creative thinking is referred to as right brain thinking. Creativity is an analytical skill as it allows individuals to utilise innovative methods to solve problems. Individuals that adopt this analytical skill are able to perceive problems from varying perspectives. This analytical skill is highly transferrable among professions.