User:Petergstrom/sandbox

Shortcuts =Stats=
 * Mechanisms of schizophrenia
 * Biology of bipolar disorder
 * Biology of depression
 * Causes of mental disorders
 * Cause of obsessive-compulsive disorder
 * Biology of obsessive-compulsive disorder

Factor Analysis
Factor analytic techniques in the most general form seek to model p observed variables as a linear combination of k usually $$\ll p$$ latent or unobserved variables plus orthogonal error variance:

$$x=z\Lambda+\epsilon; \quad E[zz']=\Phi;\quad E[\epsilon\epsilon']=\Psi=\text{diag}(\psi_{1}, \psi_{2} \dots \psi_{p}); \quad E[xx']=\Lambda\Phi\Lambda'+\Psi$$

This can be formulated as the modeling of the observed sample covariance, denoted $$S$$ with the covariance implied by the factor analytic model $$\Sigma=\Lambda\Phi\Lambda'+\Psi$$. The model can be specified with a general class of fitting functions, the GLS functions of the general form $$F_{GLS}=(s-\sigma)'V^{-1}(s-\sigma)$$ for $$\sigma=\text{vech}(\Sigma)$$ and $$ s=\text{vech}(S)$$ which provided it provided V is a consistent estimator of the asymptotic covariance of the sample covariance(i.e. $$E[X^{2}X^{2}]$$), is asymptotically equivalent to estimation by maximum likelihood under normality assumptions, with the fitting function being

$$F_{ML}=\ln\vert\Sigma\vert+\text{tr}\left(S\Sigma^{-1}\right) $$

A common constraint, usually imposed under the name of Exploratory Factor Analysis(EFA), is $$\Phi=I_{k} \rightarrow \Sigma=\Lambda\Lambda'+\Psi$$ The model without this constraint is usually called Confirmatory Factor Analysis(CFA)

Due to orthogonality constraints, EFA solutions are not unique, and $$\Lambda$$ is invariant under rotation by an orthogonal matrix. These rotations may be used to obtain a loadings matrices that has desirable properties for the given application(i.e. loadings forced towards zero or one).

Factor analysis is frequently confused with principal component analysis, but it differs as it is a probabilistic rather than a deterministic model, as PCA does not have an underlying generative model.

Fitting of the model by newton-raphson algorithms or MM algorithms(e.g. Expectation Maximization, or EMCM) usually require at least first order derivatives. These are, for a parameter vector $$\theta=\left[\text{vec}(\Lambda), \text{vech}(\Psi), \text{vech}(\Psi)\right]$$

$$\frac{\partial F_{ML}(\theta)}{\partial\theta'}=\Delta=\begin{bmatrix}2\text{vec}\left(\Sigma^{-1}(S-\Sigma)\Sigma^{-1}\Lambda\Phi\right) \\ \text{vech}\left(\Lambda'\Sigma^{-1}(S-\Sigma)\Sigma^{-1}\Lambda\right) \\ 2\text{vech}\left(\Sigma^{-1}(S-\Sigma)\Sigma^{-1}\right)\end{bmatrix}$$

$$\frac{\partial^{2} F_{ML}(\theta)}{(\partial\theta')(\partial\theta)}=\Delta'(\Sigma^{-1}\otimes\Sigma^{-1}(S-\Sigma)\Sigma^{-1})\Delta$$

The inverse of the second matrix represents the observed fisher information matrix, $$\mathcal{I}_{obs}$$, while the expected information can be expressed as $$\mathcal{I}_{exp}=\left[\Delta'(\Sigma^{-1}\otimes\Sigma^{-1})\Delta\right]^{-1}$$

Popular methods of estimation include Lawley and Maxwell's maximum likelihood algorithm, Rubin and Thayer's Expectation Maximization Algorithm, or generalized least squares.

=Pathophysiology of Depression=

Structural Neuroimaging

 * https://www.ncbi.nlm.nih.gov/pubmed/21727252
 * MDD > Ctrl : Ventricles, CSF
 * Ctrl > MDD : Thalamus, hippocampus, frontal lobe, orbitofrontal gyrus, basal ganglia, gyrus rectus
 * Current MDD Ctrl : mPFC

Functional Neuroimaging

 * https://www.ncbi.nlm.nih.gov/pubmed/23890584
 * Altered patterns of activity were observed in the prefrontal and limbic regions, in support of the cortico-limib model


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3384264/
 * Hyper-responsiveness in the amygdala, insula, and parahippocampal gyrus to negative facial stimuli
 * Inconsistent magnitude of difference in the dlPFC, OFC and Cingulate gyrus, but a difference from control was consistently observed.


 * https://www.ncbi.nlm.nih.gov/pubmed/25785575
 * Hypoconnectivity within the frontoparietal system, as well as between the frontoparietal system and the dorsal attention network.
 * Hyperconnectivity within the default network.


 * https://www.ncbi.nlm.nih.gov/pubmed/23206667
 * Depressed> Ctrl in response to negative stimuli, and Ctrl>Depressed in response to positive stimuli in Anterior Cingulate Cortex, Hippocampus, Amygdala, Striatum


 * https://www.ncbi.nlm.nih.gov/pubmed/22521254
 * Altered activations of the striatum, insula, anterior cingulate in response to emotional stimuli.


 * https://www.ncbi.nlm.nih.gov/pubmed/26332700
 * Hyperactivation in the anterior cingulate cortex, ventrolateral prefronta cortex, and hypoactivity in the caudate across all cognitive and emotional tasks


 * https://www.ncbi.nlm.nih.gov/pubmed/22535198
 * Increased activity in the pulivnar nuclei, amygdala, insular, and anterior cingulate cortex in response to negative stimuli
 * Decreased activity in the striatum in response to positive stimuli.

Monoamines

 * https://www.ncbi.nlm.nih.gov/pubmed/27623971
 * Reduced 5-HT1A receptor binding in the mesiotemporal cortex, the raphe nucleus, the insula and the anterior cingulate cortex.


 * https://www.ncbi.nlm.nih.gov/pubmed/24802331
 * Reduced 5-HTT binding in the thalamus, amygdala, midbrain, striatum and brainstem.


 * https://www.ncbi.nlm.nih.gov/pubmed/25497470
 * No altered striatal DAT availability


 * https://www.ncbi.nlm.nih.gov/pubmed/22218074
 * 5-HT1A: Most literature points towards reduced BP in the mesiotemporal cortex, possible related with elevated cortisol
 * 5-HT2A: PET examinations have found decreased BP, but post-mortem research suggests elevation in some depressed populations.
 * 5-HTT: Moderate evidence for elevated 5-HTT activity in depression
 * D1 receptor: Decreased in the striatum
 * D2 receptor: Unclear
 * Muscarinic Receptors: Evidence for elevation in depression


 * https://www.ncbi.nlm.nih.gov/pubmed/25625874
 * The 5-HT/5-HIAA ratio, antidepressant efficacy gap, and failure of tryptophan depletion to elicit depression in health persons suggests elevated synaptic concentrations of serotonin in at least some subtypes of depression.

Inflammation

 * https://www.ncbi.nlm.nih.gov/pubmed/24228900
 * Depression is associated with mild inflammation, and increased oxidative and nitrosative stress.


 * https://www.ncbi.nlm.nih.gov/pubmed/24417575
 * Psychosocial stress is thought to contribute to depression by elevating inflammatory factors such as IL-1B, and TNF-alpha.
 * These inflammatory factors alter processing in the anterior cingulate cortex, striatum, and cerebellum.


 * https://www.ncbi.nlm.nih.gov/pubmed/23995180
 * Cytokines concentrations are elevated in depression, and trials with cytokine based treatments so far have been successful.


 * https://www.ncbi.nlm.nih.gov/pubmed/22553073
 * A subset of depressed patients exhibit decreased cellular immunity, and elevated pro-inflammatory cytokines, which can alter neurotransmitter metabolis.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3002174/
 * The structural changes in the hippocampus and prefrontal cortex may be a result of chronic low grade inflammation, leading to altered kynurenine metabolism and the production of neurotoxic metabolites.

Genetics

 * https://www.ncbi.nlm.nih.gov/pubmed/25709105
 * Shortened Telomere lengths in depression


 * https://www.ncbi.nlm.nih.gov/pubmed/11007705
 * The heritability of depression is estimated at 31-42%.


 * https://www.ncbi.nlm.nih.gov/pubmed/24433458
 * The BDNF Val66Met allele modulates the relationship between stress and depression


 * https://www.ncbi.nlm.nih.gov/pubmed/21199959
 * The 5-HTT promotor region was associated with increased risk of depression, especially in association with stress and childhood maltreatment


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837431/
 * A meta analysis observed no significant SNPs, probably due to the complex and heterogenous nature of depression


 * https://www.ncbi.nlm.nih.gov/pubmed/20038947/
 * Significant SNPs included Metabotropic glutamate receptor 7 and ATP6V1B2


 * https://www.ncbi.nlm.nih.gov/pubmed/21042317/
 * No significant SNPs

Endocrine

 * https://www.ncbi.nlm.nih.gov/pubmed/24495607
 * Dysregulated cortisol observed in the elderly with depression


 * https://www.ncbi.nlm.nih.gov/pubmed/21257974
 * Increased cortisol but no increase in CRH


 * https://www.ncbi.nlm.nih.gov/pubmed/20447770
 * Increased morning and evening cortisol in depression
 * https://www.ncbi.nlm.nih.gov/pubmed/15961250
 * Depressed patients exhibited elavated recovery levels of cortisol after psychological stressors.

Neurogenesis

 * https://www.ncbi.nlm.nih.gov/pubmed/23958957
 * Decreased peripheral measures of BDNF


 * https://www.ncbi.nlm.nih.gov/pubmed/25934030
 * The decreased hippocampal volume appears in post mortem studies to be a result of altered neuroplasticity.


 * https://www.ncbi.nlm.nih.gov/pubmed/22525700
 * Inflammatory factors in depression may lead to altered neuroplasticity through modulating neural stem cell survival, neurogenesis, dendritic branching and long term potentiation


 * https://www.ncbi.nlm.nih.gov/pubmed/22054117
 * Decreased BDNF and decreased neuroplasticity in depression.

Antidepressants

 * https://www.ncbi.nlm.nih.gov/pubmed/28178949
 * While antidepressants statistically significantly reduced hamilton depresson rating scale, this effect did not reach clinical significance, according to a predefined threshold set according to NICE standards. Overall, the risk outweighed the rewards.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3133866/
 * The monoaminergic activity of antidepressants correlated with long term risk of relapse, probably due to monoaminergic dys-homeostasis.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4172306/
 * The lack of a unified mechanism of antidepressants, and high placebo rates negate the small statistical difference between placebo and antidepressants. Supports the above studies finding that ADs may predispose to future relapse


 * http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)30385-3/abstract
 * In adolescence and children, only fluoxetine was statistically more effective than placebo.


 * http://www.cochrane.org/CD007954/DEPRESSN_antidepressants-versus-placebo-for-depression-in-primary-care
 * Depression is effectively treated by TCAs and SSRIs, but most studies were of short duration and funded by pharmaceutical companies.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3712503/
 * Antidepressants are only better than placebo for patients with very severe depression(Hamilton>23)


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4592645/
 * While antidepressants are statistically better than placebo, poor design quality and low effect sizes are characteristic of most studies.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3280655/
 * Moderate effect size for ADs, but over the years placebo efficacy has been increasing and response rates have been decreasing.

=Pathophysiology of OCD=


 * Cortico-Basal Ganglia-Thalamocortical circuits
 * Orbitofrontal cortex, anterior cingulate cortex
 * Anxiety/Impulse control disorder
 * Treated with
 * CBT
 * TCAs>SSRIs

Functional

 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3079445/
 * Functional neuroimaging studies usually report abnormalities in the OFC and ACC, although the direction is inconsistent
 * https://www.ncbi.nlm.nih.gov/pubmed/15546704
 * Meta analysis observed significant elevation of activity in the OFC and head of the caudate


 * https://www.ncbi.nlm.nih.gov/pubmed/18787662
 * During provocation of symptoms, significant activation likelihood was observed in the dorsolateral prefrontal cortex, precuneus, orbitofrontal cortex and ACC
 * https://www.ncbi.nlm.nih.gov/pubmed/27276220
 * OCD and ADHD share reduced ventromedial PFC GMV and functionality

Structural

 * https://www.ncbi.nlm.nih.gov/pubmed/18718575
 * The left ACC and right OFC demonstrated decreased volume in OCD.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4023155/
 * Decreased FA observed in anterior midline tracts


 * https://www.ncbi.nlm.nih.gov/pubmed/26733823
 * OCD involve aberrant connectivity between the OFC and striatum
 * https://www.ncbi.nlm.nih.gov/pubmed/20603451
 * OCD demonstrates increased bilateral lenticular and caudate volumes relative to other anxiety disorders

Structural/Functional Reviews

 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681810/
 * Affective dysfunction appears to underly and link obsessions and compulsions.
 * Amygdala hyperactivity in response to fearful stimuli, and, along with the ventral striatum, hypoactivity in response to positive stimuli.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889493/
 * Structural and functional imaging suggests the involvement of the OFC-Striatal circuit, which involved the OFC/ACC, and basolateral amygdala/hippocampus projecting to the ventral striatum, which in turn projects to the globus padillus and returns to the OFC/ACC/amygdala/hippocampus through the thalamus.


 * https://www.ncbi.nlm.nih.gov/pubmed/25766413
 * Structural alterations were observed in the cerebellar, frontal, striatal and thalamic regions, implicating dysfunction of the corticobasal ganglia thalamocortical loop in OCD. Furthermore, deficits in functionality localized to these regions such as inference, inhibition and task switching were observed.


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3972003/
 * OCD appears to have five different subtypes, of which the hoarding subtype appears to have a different underlying neurobiological mechanism


 * https://www.ncbi.nlm.nih.gov/pubmed/26635696
 * The altered corticolimbic circuitry likely results in an excessive reliance in habit based learning and deficits in goal directed behavior


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4148591/
 * OCD and ADHD demonstrate similar deficits in executive function, and involve dysfunction in overlaping corticostriatal circuits


 * https://www.ncbi.nlm.nih.gov/pubmed/22678698
 * There is a significant association altered functionality cortico-basal ganglia-thalamocortical circuits and OCD, despite inconsistencies in the direction of changes
 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4476073/
 * Theoretical SEC model suggests that various behavioral patterns represented in the cortex are executed with the help of motivational signals.
 * In OCD, the ACC generates aberrant SEC error signals, and anxiety arises from limbic systems. The basal ganglia then generates "compensatory" SECs in the form of compulsions.


 * https://www.ncbi.nlm.nih.gov/pubmed/16242823
 * OCD models defined by two neuropsychological facets, executive function and modulatory control. The first model involves dysfunction in the dlPFC, striatum, and thalamus, and the second of which involves dysfunction in the OFC and ACC


 * https://www.ncbi.nlm.nih.gov/pubmed/25150566
 * OCD involves inflexibility of internal cognition, and supporting this notion is the observation of altered DMN activity

Genetic

 * https://www.ncbi.nlm.nih.gov/pubmed/25896187
 * The 5-HTTPR S type was associated with OCD, but only in females


 * https://www.ncbi.nlm.nih.gov/pubmed/23606572
 * Moderate association between OCD and SNPs of the glutamate transporter


 * https://www.ncbi.nlm.nih.gov/pubmed/22665263
 * OCD was associated with 5-HTTPLR and 5-HT2A gene polymorphisms, and in males only, the COMT and MAO-A genes


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4218751/
 * OCD was associated with https://www.ncbi.nlm.nih.gov/gene/79154, https://www.ncbi.nlm.nih.gov/gene/140862, and DLGAP1


 * https://www.ncbi.nlm.nih.gov/pubmed/18186076
 * While no overall association between the 5-HTTPLR S or L gene with OCD, family based studies found an association between the L type and OCD in caucasians


 * https://www.ncbi.nlm.nih.gov/pubmed/24177038
 * Microstructure abnormalities were observed in the ACC and OFC pathways to the basal ganglia, and hyperconnectivity in the genu of the corpus callosum.


 * https://www.ncbi.nlm.nih.gov/pubmed/17264842
 * Association between OCD and COMT polymoprhism, but only in men.


 * https://www.ncbi.nlm.nih.gov/pubmed/14582147
 * No association between COMT and OCD


 * https://www.ncbi.nlm.nih.gov/pubmed/17291658
 * OCD was associated with 5-HTTPLR SS allele, but inversely with the LS allele

Neurochemical

 * https://www.ncbi.nlm.nih.gov/pubmed/24986387
 * 5-Fold increase in risk of anti-basal ganglia antibodies in OCD, supporting the theory that a subset of OCD involve basal ganglia auto-immunity


 * https://www.ncbi.nlm.nih.gov/pubmed/22892718
 * Reduced N-Acetylaspartate in the medial PFC in OCD


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681810/
 * While some evidence suggests "elevated" dopamine in OCD, however this is contradicted by much evidence, including the fact that antipsychotics can exacerbate OCD, and the observation of contradictory molecular imaging findings with regard to DAT


 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205262/
 * Elevated CSF glutamate
 * Inconsistent molecular imaging studies about glutamate, although abnormalities have been frequently observed
 * Significant association between glutamate regulating genes and OCD

=Dopaminergic Modulation of the PFC=


 * Phasic dopamine release in the prefrontal cortex is capable of mediating cognitive flexibility. Activation of D1 receptors on a neuron increases the influence of strong signals and inhibits the weaker signals, effectively strengthening the representation of information in the PFC.  D2 receptors on the other hand increase sensitivity to external noise, resulting in increased cognitive flexibility.  This dynamic enables a switch in focus due to a salient stimulus.  Given that D2 receptors tend to be synaptic, and D1 receptors tend to be extrasynaptic, phasic transmission is characterized first by preferential D2 activation, followed by tonic D1 activation.  A salient stimulis can then trigger a transition state, followed by restrengthening.


 * The role of DA in modulating the PFC is conceptualized by two regimes. The D1 dominated regime is characterized by a "robust", "high energy barrier" that facilitates the maintenance of information.  The D2 dominated regime is in turn characterized by a low energy barrier that facilitates quick transition between representational states.

=Bipolar Disorder=

Etiology
The etiology of bipolar disorder is unknown. The overall heritability of bipolar is estimated at 79%-93%, and first degree relatives of bipolar probands have a relative risk of developing bipolar around 7-10. While the heritability is high, no specific genes have been conclusively associated with bipolar, and a number of hypothesis have been posited to explain this fact. The polygenic common rare variant hypothesis suggests that a large number of risk conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The multiple rare variant model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease.

A number of genome wide associations have been reported, including CACNA1C and ODZ4. Less consistently reported loci include ANK3 and NCAN, ITIH1, ITIH3 and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa. In light of associations between bipolar and circadian abnormalities(such as decreased need for sleep and increased sleep latency), polymorphisms in the CLOCK gene have been tested for association, although findings have been inconsistent. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL, RORB, and DEC1.

Pathophysiology
Structural neuroimaging studies consistently report increased frequency of white matter hyperintensities in people with bipolar. However, whether or not the lesions play a causative role is unknown. It is possible that they are a result of secondary factors, such as in increased risk of cardiovascular disease in bipolar. On the other hand, the observation of reduced white matter integrity in frontal-subcortical regions makes it possible that these hyperintensities play a role dysfunction between limbic and cortical regions. Global brain volume and morphology are normal in bipolar. Regional deficits in volume have been reported in ventrolateral and dorsolateral prefrontal regions. Based on this, it has been suggested that reduced limbic regulation by prefrontal regions plays a role in bipolar. Findings related to the volume of the basal ganglia have been inconsistent.

Functional neuroimaging studies, contrary to structural studies, consistently find hyperactivation of the basal ganglia, amygdala, and thalamus. Prefrontal abnormalities are less consistently reported, although hyperactivation in the ventral prefrontal cortex is a fairly consistent finding. Mania is generally associated with frontal/ventral hypoactivation, while depression is generally associated with the opposite. A degree of lateralization with regard to abnormalities has been reported, with mania being associated with the right hemisphere, and depression the left. Trait abnormalities in euthymic patients have been observed, including hypoactivity in the ventral prefrontal cortex, and hyperactvity in the amygdala.

Cause

 * Precursors of bipolar disorders: a systematic literature review of prospective studies.
 * Juvenile onset; Mood lability.


 * Are there different genotypes in Bipolar II and Bipolar I disorder and if so, why then do we tend to observe Unipolar Depression converting to Bipolar II and then converting to Bipolar I?
 * Predicting bipolar disorder on the basis of phenomenology: implications for prevention and early intervention.
 * COMT/DRD3/DRD2/BDNF polymorphisms distinguish BPI from BPII


 * Interactions Between Variation in Candidate Genes and Environmental Factors in the Etiology of Schizophrenia and Bipolar Disorder: a Systematic Review.
 * Epidemiological and clinical variables related with the predominant polarity on bipolar disorder: A systematic review.
 * Predominately manic BP==pre onset drug use and earlier dx

Genetics

 * Exome Sequencing of Familial Bipolar Disorder.
 * A survey of genomic studies supports association of circadian clock genes with bipolar disorder spectrum illnesses and lithium response.
 * ARTNL, RORB, and DEC1 all associated with BP


 * Association at SYNE1 in both bipolar disorder and recurrent major depression.
 * Meta-analysis confirms a functional polymorphism (5-HTTLPR) in the serotonin transporter gene conferring risk of bipolar disorder in European populations.
 * TPH2 gene polymorphisms and bipolar disorder: A meta-analysis.
 * Association between brain-derived neurotrophic factor genetic polymorphism Val66Met and susceptibility to bipolar disorder: a meta-analysis.
 * Genetics of bipolar disorder.
 * Comparative Linkage Meta-Analysis Reveals Regionally-Distinct, Disparate Genetic Architectures: Application to Bipolar Disorder and Schizophrenia
 * Meta-analysis of genetic association studies on bipolar disorder.
 * The Genetics of Bipolar Disorder
 * Meta-analysis of genome-wide association data of bipolar disorder and major depressive disorder
 * Genomic View of Bipolar Disorder Revealed by Whole Genome Sequencing in a Genetic Isolate
 * Genetics of bipolar disorder

Environmental

 * Gene environment interactions in bipolar disorder.
 * Beyond genetics: childhood affective trauma in bipolar disorder.
 * A Review of Bipolar Disorder in Adults
 * Prenatal Programming of Mental Illness: Current Understanding of Relationship and Mechanisms
 * A theoretical framework informing research about the role of stress in the pathophysiology of bipolar disorder.
 * The HPA axis in bipolar disorder: Systematic review and meta-analysis.
 * Predominately manic BO associated with drug use and earlier diagnosis

Mechanism

 * The bipolarity of light and dark: A review on Bipolar Disorder and circadian cycles.
 * Variation in CLOCK genes and circadian rhythm associated with BPD


 * Investigating the mechanism(s) underlying switching between states in bipolar disorder.
 * Season variation in BPD symptoms, with manic switches occurring during long photoperiods and depression episodes occurring during periods with less light. Furthermore, photoperiod induced variations in tyrosine hydroxylase expression support a role of catecholamine dysregulation in BPD.


 * The catecholaminergic-cholinergic balance hypothesis of bipolar disorder revisited.
 * Inconsistent evidence across D2 type receptors and DAT in both post-mortem studies but D1Rs BP is decreased/prbly due to increase synaptic conc
 * Pharmacological models of mania are generally DA release agents, and mood stabilizers reduce DA synthesis and release
 * Reduced in vivo BP of muscarinic receptors in BPD Dep, and decreased receptor expression in post-mortem studies-likely due to excessive synaptic conc
 * Pharmacological support^^


 * Integrated neurobiology of bipolar disorder.
 * Decreased vlPFC activity in both euthymic and manic bipolar disorder
 * Decreased activity(likely indicative of increased DA stimulation) in the striatum in mania, and increased activity in euthymia
 * Elavated dorsal ACC activity in mania
 * Thinning of the vmPFC and well as enlargement of ventricles correlates with manic episodes
 * More cells in the LC, slightly fewer cells in the RN
 * Hyperresponsiveness of the HPA axis correlated with longer duration of affective episodes
 * Delayed sleep phase in common in BPD, sleep efficiency is decreased, higher density of REM sleep
 * Nighttime correlates with symptom presentation, exaggerated melatonin reduction in response to light, and elevated afternoon cortisol.
 * Most anti-manic drugs alter intracellular GSK-3 signaling.


 * The underlying neurobiology of bipolar disorder
 * The Psychopathology and Treatment of Bipolar Disorder
 * Contributions from brain imaging to the elucidation of pathophysiology of bipolar disorder
 * New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings

Neurocircuits

 * A critical appraisal of neuroimaging studies of bipolar disorder: toward a new conceptualization of underlying neural circuitry and a road map for future research.
 * Dysfunction in emotional regulatory circuits characterized by reduced prefrontal-amygdala connectivity
 * Hypersensitivity to reward indicated by elevated ventral striatal, ventrolateral prefrontal, and orbitofrontal cortex response to positive emotional stimuli.
 * The functional neuroanatomy of bipolar disorder: a consensus model
 * Structural neuroimaging studies in the early stages of bipolar suggests that the progressive nature of bipolar disorder reflects dysregulated growth and connectivity in prefrontal-limbic circuits, especially in the amygdala


 * Neural circuits underlying the pathophysiology of mood disorders
 * Functional neuroanatomy of bipolar disorder: structure, function, and connectivity in an amygdala-anterior paralimbic neural system
 * Elevated reward-related neural activation as a unique biological marker of bipolar disorder: assessment and treatment implications/
 * Corticolimbic connectivity as a possible biomarker for bipolar disorder
 * Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: a review of functional neuroimaging studies
 * Brain network dysfunction in bipolar disorder.

Neurobiological

 * Dysregulation of the NF-κB pathway as a potential inducer of bipolar disorder.
 * Developmental meta-analyses of the functional neural correlates of bipolar disorder.
 * Could glutamate spectroscopy differentiate bipolar depression from unipolar?
 * Functional neuroanatomy of response inhibition in bipolar disorders--combined voxel based and cognitive performance meta-analysis.
 * Neurometabolites in schizophrenia and bipolar disorder - a systematic review and meta-analysis.
 * A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder.
 * Evidence of diagnostic specificity in the neural correlates of facial affect processing in bipolar disorder and schizophrenia: a meta-analysis of functional imaging studies.
 * Brain glutamate levels measured by magnetic resonance spectroscopy in patients with bipolar disorder: a meta-analysis.
 * Circadian abnormalities as markers of susceptibility in bipolar disorders.
 * Origin of cyclicity in bipolar disorders: a computational approach.
 * Neurophysiological findings in patients with bipolar disorder.
 * Translating neurotrophic and cellular plasticity: from pathophysiology to improved therapeutics for bipolar disorder.
 * Calcium signalling and psychiatric disease: bipolar disorder and schizophrenia.
 * Role of neuro-immunological factors in the pathophysiology of mood disorders.
 * Neurotrophins, inflammation and oxidative stress as illness activity biomarkers in bipolar disorder
 * Signaling: cellular insights into the pathophysiology of bipolar disorder.
 * The possible involvement of NMDA glutamate receptor in the etiopathogenesis of bipolar disorder.
 * Investigating the underlying mechanisms of aberrant behaviors in bipolar disorder from patients to models: Rodent and human studies.
 * Molecular neurobiological clues to the pathogenesis of bipolar disorder.
 * Metabotropic glutamate receptors as emerging research targets in bipolar disorder.
 * Brain structure, function, and neurochemistry in schizophrenia and bipolar disorder-a systematic review of the magnetic resonance neuroimaging literature.
 * Gray matter abnormalities as brain structural vulnerability factors for bipolar disorder: A review of neuroimaging studies of individuals at high genetic risk for bipolar disorder.
 * The structural neuroimaging of bipolar disorder.
 * Magnetic resonance findings in bipolar disorder.
 * Functional neuroimaging studies of bipolar disorder: examining the wide clinical spectrum in the search for disease endophenotypes.
 * Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications.
 * Neurobiology of Risk for Bipolar Disorder.
 * Dissecting bipolar disorder complexity through epigenomic approach.
 * Mania secondary to focal brain lesions: implications for understanding the functional neuroanatomy of bipolar disorder.
 * The Neurobiology of Bipolar Disorder: An Integrated Approach.
 * The Neurobiology of Bipolar Disorder: An Integrated Approach.
 * The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies.
 * The relationship between bipolar disorder and biological rhythms.
 * The neuropsychology and neuroanatomy of bipolar affective disorder: a critical review.
 * The relationship between genetic risk variants with brain structure and function in bipolar disorder: A systematic review of genetic-neuroimaging studies.
 * The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment.
 * Neurobiological underpinnings of bipolar disorder focusing on findings of diffusion tensor imaging: a systematic review.
 * Can neuroimaging disentangle bipolar disorder?

GSK-3

 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055312/
 * https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523227/
 * http://journal.frontiersin.org/article/10.3389/fnmol.2012.00001/full

IP

 * https://www.ncbi.nlm.nih.gov/pubmed/15558078
 * https://www.ncbi.nlm.nih.gov/pubmed/15654927

=Psychosis=

Models

 * Neurodevelopment model of schizophrenia: updated 2012
 * Risk factors: toxoplasmosis gondii, Obstetric complications, Low birth weight, Urban environment,Immigration Status,Childhood trauma
 * Neurexin SNPs associated with schizophrenia
 * Drawn out period of development, remodeling and instability lasts into late thirties


 * Schizophrenia and reelin: a model based on prenatal stress to study epigenetics, brain development and behavior.
 * Reduced mRNA of GAD67 in the PFC, reduced GABAergic cells, reduced inhibitory synapses
 * Prenatal stress increases risk of schizophrenia, and has been demonstrated to lead to delayed migration, and morphological changes in PFC cells.
 * Reelin has been demonstrated to be hypermethylated in schizophrenia, and therefore under expressed. Heterozygous knockout mouse demonstrate similar alterations in neurodevelopment, and a reduction in GABAergic neurons that are characteristic of schizophrenia.  Furthermore, stress had been observed in animal models to lead to underexpression


 * Toward a Neurobiology of Delusions
 * Functional neuroimaging studies have found that aberrant prediction error signalling occurs in schizophrenics, and correlates with delusion severity
 * Schizophrenics are more susceptible to illusions produced by altering sensory experience
 * Schizophrenics demonstrate abnormalities with predicting the effects of their actions
 * The role of NMDA in schizophrenia and the ability for NMDA anagonists to mimic schizophrenia fit in with the model suggesting that delusions are a result of dysfunctional prediction systems


 * Cellular models to study schizophrenia: A systematic review.
 * Morphological differences in dendrites


 * On the neurobiology of hallucinations
 * Schizophrenics demonstrate deficits in the ability to correctly attribute stimuli, or link actions to sensory outcomes. Disruption of the thalamocortical gamma bands may play a role.


 * The neural basis of hallucinations and delusions.
 * Abnormal connectivity between the frontal and parietal lobes are suggested to give rise to a decreased sense of control, but an increased sense of agency

Genetics

 * Genome-wide association studies (GWAS) of schizophrenia: does bigger lead to better results?
 * Genes associated with SCZ include TCF4, NRGN, VRK2, MIR137, PCGEM1, CSMD1, MMP16, CNNM2, NT5C2, and CACNA1C
 * The most commonly associated genes are generally involved in MHC regions, synaptic plasticity, and neurodevelopment


 * Epigenetic aspects in schizophrenia etiology and pathogenesis
 * DGCR8 has been observed to be prone to deletion in schizophrenics, and is deferentially expressed.
 * DGCR8 being differential expressed leads to altered transcription of synaptic proteins.
 * Increased methylation of H3 histone R17 in the PFC of schizophrenics


 * Brain vs behavior: an effect size comparison of neuroimaging and cognitive studies of genetic risk for schizophrenia.
 * Most neuroimaging studies demonstrate a more significant effect size compared to cognitive studies. The greatest gene associated with neuroimaging alterations was DAOA


 * Genomic and network patterns of schizophrenia genetic variation in human evolutionary accelerated regions.
 * Most of the genes associated with recent primate evolution that are associated with schizophrenia are involved in synaptic regulation, and are expressed in the PFC in higher concentrations.


 * Genetic influences on schizophrenia and subcortical brain volumes: large-scale proof of concept.
 * Evaluating historical candidate genes for schizophrenia
 * No historical candidate genes were found to be significant in the SZgene study, but four genes (DRD2, GRM3, NOTCH4, TNF) have been found to be significant in the PCG. Two have been found in the MHC.


 * The Role of Genetics in the Etiology of Schizophrenia
 * NRXN1 and MHC genes have been most frequently associated with schizophrenia(along with NOTCH4 and the aforementioned TNF)

Environment

 * The environment and susceptibility to schizophrenia
 * Infections during the prenatal period have been associated with schizophrenia. Some evidence points towards the effect of pro-inflammatory proteins on neurodevelopment(including IL-8 and TNF)
 * Famine and materna nutritional deficiencies have been associated with an increase risk of schizophrenia.
 * Advanced paternal age
 * Prenatal stress has been linked to schizophrenia, but not as strongly as low birth weight, which prenatal stress has been strongly linked with. CRH and inflammatory mechanisms may be involved
 * Cannabis use has been associated with schizophrenia when used in adolescence, and a dose response relationship has been suggested. This finding has been replicated a number of times, with a meta analysis reporting a pooled odds ratio of 2.3 in studies assessing cannabis use before schizophrenia onset, suggesting a causative role.


 * Gene-Environment Interactions in Schizophrenia: Review of Epidemiological Findings and Future Directions
 * While most genetic and environmental studies have reported small effects, assessing GxE associations has significantly increased effect.


 * Environmental risk factors for psychosis
 * Urbanization, childhood stress, migration, and adverse life events, and being born during the winter or spring have been associated with schizophrenia.


 * Schizophrenia: a consequence of gene-environment interactions?
 * Oxidative stress may cause NMDA receptor hypofunction due to genetic alterations in synaptic regulation combined with stress.


 * Fetal Environment and Schizophrenia
 * Along with the aforementioned associations with infections and maternal famine, maternal obesity has been associated with SCZ as well.

Neurochemical

 * Glutamate and dopamine in schizophrenia: an update for the 21st century.
 * Post mortem studies while few in number are associated with a reduction in post-synaptic dopamine receptors, and an increase in presynaptic D2 receptors, as well as an increase in TH, no change in DAT, elavation of D4 receptors, a reduction in D2 monomers, and a large increase in D2 dimers
 * In Vivo neurochemical imaging has demonstrated a large increase in presynaptic dopamine metabolism, but the post-synaptic dopaminergic protein results have been inconsistent
 * While genetic studies and the mimicry of SCZ symptoms by NMDA agonists implicates glutamate dysfunction in SCZ, a lack of consistency in post-mortem studies suggests that a deficit in NMDA receptor expression may be too simple a model, rather NMDA dysfunction may be characterized by dysfunctional regional expression and altered subunit composition.
 * While those with familial risk, first episode psychosis, or psychotic symptoms demonstrate increased glutamine levels using in vivo imaging, chronic schizophrenics demonstrate a reduction or normal levels. Furthermore, an increase in glutamine/gluamate ratio has been observed in some studies


 * Neurodevelopment, GABA, and Schizophrenia
 * Due to the lack of a definitive neurodegenerative course in the morphological changes associated with schizophrenia, the common finding of reduced cortical thickness and increase ventricle volume are thought to be a result of developmental processes.
 * Variable findings in interstitial white matter have been observed with regard to GABAergic neurons.
 * Both genetic and environmental risk factors for SCZ have been associated with altered GABAergic development


 * The nature of dopamine dysfunction in schizophrenia and what this means for treatment
 * Significant elavation in presynaptic dopamine metabolism, increase in D2/D3 receptor expression(post-synaptic) and no effect on DAT


 * Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.
 * Altered expression of D1 in the ACC, uncus, and D2 in the PFC have been osberved, as well as DAT alterations in the thalamus


 * The role of extrastriatal dopamine D2 receptors in schizophrenia.
 * D2 receptor expression in the thalamus and ACC is reduced in schizophrenia


 * Pathway-Specific Dopamine Abnormalities in Schizophrenia.
 * Stimulant evoked DA release is elevated in the striatum, but reduced elsewhere

Neurobiological

 * The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia
 * NMDARs are necessary for large network connectivity and heavily influence GABAergic development. Both genetic and post-mortem studies have demonstrated alterations in GABAergic and NMDAR proteins and regulating genes, and a widely replciated finding is a reduction in NMDA receptors globally, although this effect is particularly significant in GABAergic neurons, and is especially prominent in NR1 and NR2C subunits in the PFC.
 * Intact GABAergic signalling is necessary for gamma band activity


 * Glutamatergic postsynaptic density protein dysfunctions in synaptic plasticity and dendritic spines morphology: relevance to schizophrenia and other behavioral disorders pathophysiology, and implications for novel therapeutic approaches.
 * Younger SCZs demonstrate decreased expression of PSD-95 with concurrent increases in thalamic NR2B, while the elderly with SCZ demonstrate the inverse.


 * The impact of NMDA Receptor hypofunction on GABAergic interneurons in the pathophysiology of schizophrenia
 * Expression of NMDA subunits appears to be decreased in the prefrontal cortex, as well as in general. Combined with evidence from NMDA receptor antagonists, this data suggests that schizophrenia involves hypofunctioning of NMDA receptors. This may contribute to resting state abnormalities in connectivity, as well as dopaminergic abnormalities.


 * GABAergic interneuron origin of schizophrenia pathophysiology.


 * The involvement of N-methyl-D-aspartate receptor (NMDAR) subunit NR1 in the pathophysiology of schizophrenia.


 * Schizophrenia: Evidence implicating hippocampal GluN2B protein and REST epigenetics in psychosis pathophysiology.

Neurocircuitry

 * Synchrony in schizophrenia: a window into circuit-level pathophysiology.
 * Ehh not really a great review


 * Neuroimaging studies of social cognition in schizophrenia.
 * Paywalled


 * Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia.
 * Ctrl>SCZ: dlPFC, Amygdala, Hippocampus, ACC, Thalamus, Caudate and Midbrain.
 * SCZ>Ctrl: Parietal Lobule, Precentral Gyrus and STG.
 * Variable Amygdala findings, possibly reflecting general reduced responsively to social stimuli.


 * Detecting neuroimaging biomarkers for schizophrenia: a meta-analysis of multivariate pattern recognition studies.
 * Meta-analysis of 41 Functional Neuroimaging Studies of Executive Function in Schizophrenia
 * Ctrl>SCZ: dlPFC, right vPFC, rACC and anterior ACC extending into the mPFC, right ventral PMC, putamen and thalamus.
 * SCZ>Ctrl: left dorsal and ventral PMC, dorsal ACC and amygdala.
 * Possible due to frontal top down dysfunction, leading to brain wide dysfunction


 * Beyond hypofrontality: a quantitative meta-analysis of functional neuroimaging studies of working memory in schizophrenia.
 * Although reduced dlPFC was observed, hyperactivity in the frontal pole and ACC were also found


 * Meta-Analysis of Functional Neuroimaging and Cognitive Control Studies in Schizophrenia: Preliminary Elucidation of a Core Dysfunctional Timing Network.
 * Ctrl>SCZ bilaterally in the IFG and SMA, and unilaterally in the basal ganglia, superior OCC, SMA, IPG, and cuneus.
 * SCZ>Ctrl in post-central gyrus and fusiform gyrus


 * Progressive loss of cortical gray matter in schizophrenia: a meta-analysis and meta-regression of longitudinal MRI studies.
 * Reduction in STG over course of SCZ


 * Meta-analysis of gray matter anomalies in schizophrenia: application of anatomic likelihood estimation and network analysis.
 * Reductions in GMV were seen in the insula and ACC,the left parahippocampus, left MFG, left postcentral gyrus, and left thalamus.


 * Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium.
 * Reduced hippocampus, amygdala, thalamus, NAcc, and GP volumes.
 * Structural correlates of auditory hallucinations in schizophrenia: a meta-analysis.
 * AVH correlated with Ctrl>SCZ in left ins, right STG


 * Neuroanatomical abnormalities in schizophrenia: a multimodal voxelwise meta-analysis and meta-regression analysis.
 * Ctrl>SCZ: FA/WM in inter hemispheric fibers, anterior thalamic radiations, inferior longitudinal occipital fascicule, cingulum, and fornix
 * Ctrl>SCZ: GM in Insula, Interior frontal cortex, STG, ACC, thalamus, left amygdala

=BG=
 * Selection of actions in the basal ganglia-thalamocortical circuits: review and model.
 * Synaptic organisation of the basal ganglia
 * Chapter 6 Basal ganglia-thalamocortical circuits: Parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions
 * Functional anatomy of the basal ganglia. I. The cortico-basal ganglia-thalamo-cortical loop.
 * Functional architecture of basal ganglia circuits: neural substrates of parallel processing.
 * The primate basal ganglia: parallel and integrative networks.
 * Changing Views of Basal Ganglia Circuits and Circuit Disorders
 * Update on models of basal ganglia function and dysfunction
 * The cortico-basal ganglia integrative network: the role of the thalamus
 * Circuits and Circuit Disorders of the Basal Ganglia
 * Thalamic Relay Nuclei of the Basal Ganglia Form Both Reciprocal and Nonreciprocal Cortical Connections, Linking Multiple Frontal Cortical Areas
 * The cortico-basal ganglia-thalamocortical circuit with synaptic plasticity. II. Mechanism of synergistic modulation of thalamic activity via the direct and indirect pathways through the basal ganglia
 * Basal ganglia and cerebellar loops: motor and cognitive circuits
 * PARALLEL ORGANIZATION OF FUNCTIONALLY SEGREGATED CIRCUITS LINKING BASAL GANGLIA AND CORTEX
 * FROM REINFORCEMENT LEARNING MODELS OF THE BASAL GANGLIA TO THE PATHOPHYSIOLOGY OF PSYCHIATRIC AND NEUROLOGICAL DISORDERS
 * The basal ganglia: An overview of circuits and function
 * Parallel basal ganglia circuits for voluntary and automatic behaviour to reach rewards
 * Basal ganglia circuit loops, dopamine and motivation: A review and enquiry
 * The basal ganglia: a vertebrate solution to the selection problem?
 * Computational models of basal-ganglia pathway functions: focus on functional neuroanatomy
 * Direct and Indirect Pathways of Basal Ganglia: A Critical Reappraisal
 * Integration of Navigation and Action Selection Functionalities in a Computational Model of Cortico-Basal-Ganglia–Thalami-Cortical Loops
 * Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes
 * Functional Neuroanatomy of the Basal Ganglia
 * Physiology and pathophysiology of the basal ganglia-thalamo-cortical networks.
 * Physiology and pathophysiology of cortico-basal ganglia-thalamocortical loops: theoretical and practical aspects.
 * Basal ganglia-thalamocortical circuits: their role in control of movements.
 * Inhibitory Control in the Cortico-Basal Ganglia-Thalamocortical Loop: Complex Regulation and Interplay with Memory and Decision Processes
 * Neuronal circuits and physiological roles of the basal ganglia in terms of transmitters, receptors and related disorders.
 * Basal ganglia circuit loops, dopamine and motivation: A review and enquiry.
 * Striatal direct and indirect pathways control decision-making behavior.
 * Functional implications of dopamine D1 vs. D2 receptors: A 'prepare and select' model of the striatal direct vs. indirect pathways.
 * Reassessing models of basal ganglia function and dysfunction.
 * The place of dopamine in the cortico-basal ganglia circuit.
 * The basal ganglia, the ideal machinery for the cost-benefit analysis of action plans.
 * Goal-directed and habitual control in the basal ganglia: implications for Parkinson's disease.
 * Cholinergic interneurons in the dorsal and ventral striatum: anatomical and functional considerations in normal and diseased conditions.
 * Investigating striatal function through cell-type-specific manipulations.
 * Striatal plasticity and basal ganglia circuit function.
 * Contributions of the striatum to learning, motivation, and performance: an associative account.
 * Corticostriatal circuitry.
 * Cortico-basal ganglia networks subserving goal-directed behavior mediated by conditional visuo-goal association.

=Schizophrenia cont=
 * The symptoms of schizophrenia largely fall into three categories, reality distortion, negative symptoms and disorganization. The dichotomy, traced back to work by Kraepalin, whereby bipolar affective and psychotic disorders are treated as separate entities, is contradicted by continuity of affective and psychotic symptoms through genetic and neurobiological factors.
 * The heritability of Schizophrenia is estimated to be roughly 80%. The heritable component is evident in monozygotic and dizygotic concordance, 41-65% and 0-28% respectively, as well as the elevated risk of developing in schizophrenia in those with first degree relative with schizophrenia, or bipolar disorder. Schizophrenia has been associated in GWAS studies with.
 * MIR137
 * SDCCAG8-rs6703335
 * VRK2-rs2312147
 * ZNF804A-rs1344706
 * PCGEM1-rs17662626
 * ITIH3-rs2239547
 * Extended Major Histocompatibility Complex Regions
 * CSMD1-rs10503253
 * LSM1-rs16887244
 * MMP16-rs7004633
 * ANK3-rs10994359
 * CNNM2-rs7914558
 * NT5C2-rs11191580
 * AMBRA1-rs11819869
 * ODZ4-rs12576775
 * NRGN-rs12807809
 * CACNA1C-rs4765905
 * TCF4-rs9960767
 * CCDC68-rs12966547
 * NCAN-rs1064395

Significant overlap in GWAS studies of bipolar and schizophrenia have been observed at ANK3, CACNA1C, ZNF804A, and ITIH3-ITIH4. Studies of brain structure and function in Schizophrenia have included longitudinal, patient-control constrast, and at-risk study designs. Schizophrenia is associated with reduced volumes, usually of the magnitude 5-10%. Robust structural findings include 1)Ventricular enlargement, 2)Reduced whole brain volume, 3)Reduced GMV of the medial temporal lobe extending to the hippocampus and amygdala, 4)Reduced GMV in the STG. thirty-five out of forty-six studies report significant STG volume reduction, and eighteen out of thirty studies reported correlations between STG volume and severity of auditory hallucinations or though disorders. Thirteen studies have reported bilateral thalamic reductions, including studies on both first episodes and chronic patients. Grey matter reductions are particularly evident in the anterior ingulate, medial and inferior frontal lobes, and anterior insula. Bipolar parients and Schizophrenic pateints exhibit significant overlaps in the ACC, mPFC, lPFC, and bilateral insula, only differing in magnitude. The Cerebellum, Corpus Callosum, and Basal Ganglia are frequently observed to be structurally abnormal, although the findings as well as direction of changes is inconsistent. Longitudinal neuroimaging suggests that schizophrenia appears to be more of a neurodevelopment disorder, rather than a neurodegenerative disorder. Schizophrenics exhibit hypoactivity in the dlPFC during executive function tasks, frequently extending to the ACC, thalamus, and inferior and posterior parietal cortices. Hyperactivity during executive function tasks have been observed in midline cortical regions, premotor cortcices and the vlPFC. Reduced activation of the dlPFC during episodic memory tasks has been observed. Reality distortion has been assocaited with increased medial temporal blood flow, and decreased prefrontl boodflow in the other two symptom dimensions. Negtative symptoms in schizophrenia are characterized by more pronounced and widespread GMV losses. MTL generally differentiates affective disorders from less affective psychotic disorders. Longitutinally, Schizophrenia is associated with continual reductions in thalamic and prefrontal volumes and less consistend temporal lobe changes. Hippocampal reductions over time are more contested. In those at high risk for psychosis, inferior frontal and superior temporal reductions are associated with transition to psychosis. Magnetic resonance spectroscopy observe first episode increased in Gln and decreased in Glu, followed by accelerated age related decreased in Gln and Glu relative to controls--->Taken to mean first episode increased in Glu--->Increased in Gln+Decreaese in Glu>Thereafter reductions in Gln+Glu.

While there is no argument that schizophrenia is associated with cognitive deficits which are in turn associated with abnormalities in the prefrontal cortex and medial temporal lobe, the fundemental cognitive processes that malfunctioning are yet to be determined. Endophenotypic and medication status-independent deficits in WM are observed in schizophrenia, regardless of the modality tested(i.e. verbal versus visual). The temporal characteristics of WM deficits in schizophrenia have led some authors to postulate that deficits are encoding related; in line with this, deficits are constant regardless of delay. However, maintence appears to be dysfunctional as well. While "hypofrontality" is a major principal in schizophenia theories, the relationship between WM task deficit appears to follow a biphasic curve, with increased dlPFC signals occuring earlier in schizophrenic patients, indicating less efficient systems of internal representation. Episodic memory also impaired, and evidence suggests that this is most prominently expressed in relational reasoning caused by hippocampal and prefrontal dysfunction. Hedonic, valenced, processing in schizophrenia appears to largely be intact, as ventral-striatal responses and subjective "liking" is not diminished, although loss-avoidance responsivity is impaired. Despite the aforementioned findings, increased anhedonia(negative symptoms) have also been reportedly associated with reduced striatal responsiveness to rewards. While basal ganglia dysfuncton is present in schizophrenia, simple reinforcement learning is not impaired. However, when reinforcement learning paradigms increase in complexity, impairment becomes apparent. While these impairments are fairly consistent, whether or the deficit is a result of online processing mechanisms(e.g. dlPFC mediated WM), associative processes, or both, is unknown. Monetary incentive delay tasks, assesing desire or "wanting" is frequently associated with reduced ventral striatal signaling in schizophrenia. This has been correlated with various symptoms and symptom dimensions, including apathy and negative symptoms in both medication naive and medicated patients. Reduced prediction errors have also been observed.
 * Overall, a failure of on line maintence and reward associativty is thought to lead to impairment in the generation of cognition and behavior recquired to obtain rewads, despite normal hedonic responses.  From a longitudinal standpoint, deficits in verbal, nonverbal and mathematical, tests scores have been observed in people who go on to develop schizophrenia.  Attentional deficits has the ability to identify which children of parents with schizophrenia will and wont go on to develop the disease themselves.  One study examining the Iowa test found that deficits were only significant after the onset of puberty in those who went on to develop the disease in adulthood.

Neuropathological studies suggest that volumetric deficits in the temporal lobes, prefrontal lobes, and subiculum of those with Schizophrenia can be better attributed to deficits in neuropil(neuronal extensions such as dendrites) rather than fewer cells. Postmortem gene expression studies have observed reductions in protein associated with myelin formation and regulation, which is congruent with the association between NRGN and DISC1 genetic polymorphisms and schizophrenia. Reductions in GAD67 mRNA levels in the prefrontal cortex and general reduction in parvalbumin mRNA have been observed in schizophrenia, being most significant but not limited to prefrontal regions. The reductions in GABAergic neuronal proteins may be linked to the observed reductions of TrKB and BDNF as the latter proteins are involved in the regulation of the former. The reduction may also be linked to reduced excitation of GABAergic neurons, possible due to hypofunction of NMDA receptors.

=Biology of bipolar disorder= The biology of bipolar disorder is unknown. Various abnormalities in studies of brain structure and function have been demonstrated. Various theories have posited dysfunction in monoaminergic regulation, neural circuitry, and mitochondria function as underlying bipolar disorder.
 * Resting state hypofrontality.
 * Rediced activation in the right middle frontal gyrus, right inferior parietal lobule, and right insula during attentional tasks. Increased activation in the left insula duting memory task.
 * Insula, inferior frontal cortex, superior temporal gyrus, anterior cingulate cortex, medial frontal cortex, thalamus and left amygdala volume reductions. Reduced fractional anisotropy or white matter in interhemispheric fibers, anterior thalamic radiations,  inferior longitudinal fasiculus, inferior frontal occipital fasiculi, cingulum and fornix.

Etiology
The etiology of bipolar disorder is unknown. The overall heritability of bipolar is estimated at 79%-93%, and first degree relatives of bipolar probands have a relative risk of developing bipolar around 7-10. While the heritability is high, no specific genes have been conclusively associated with bipolar, and a number of hypothesis have been posited to explain this fact. The polygenic common rare variant hypothesis suggests that a large number of risk conferring genes are carried in a population, and that a disease manifests when a person has a sufficient number of these genes. The multiple rare variant model suggests that multiple genes that are rare in the population are capable of causing a disease, and that carrying one or a few can lead to disease.

A number of genome wide associations have been reported, including CACNA1C and ODZ4. Less consistently reported loci include ANK3 and NCAN, ITIH1, ITIH3 and NEK4. Significant overlaps with schizophrenia have been reported at CACNA1C, ITIH, ANK3, and ZNF804A. This overlap is congruent with the observation that relatives of probands with schizophrenia are at higher risk for bipolar disorder and vice versa. In light of associations between bipolar and circadian abnormalities(such as decreased need for sleep and increased sleep latency), polymorphisms in the CLOCK gene have been tested for association, although findings have been inconsistent. Other circadian genes associated with bipolar at relaxed significance thresholds include ARTNL, RORB, and DEC1. One meta analysis reported a significant association of the short allele of the serotonin transporter, although the study was specific to european populations. Two polymorphisms in the tryptophan hydroxylase 2 gene have been associated with bipolar disorder.

No significant association exists for the BDNF Val66Met allele and bipolar disorder, except in a subgroup of bipolar II cases.

Neuroimaging
Structural neuroimaging studies consistently report increased frequency of white matter hyperintensities in people with bipolar. However, whether or not the lesions play a causative role is unknown. It is possible that they are a result of secondary factors, such as in increased risk of cardiovascular disease in bipolar. On the other hand, the observation of reduced white matter integrity in frontal-subcortical regions makes it possible that these hyperintensities play a role dysfunction between limbic and cortical regions. Global brain volume and morphology are normal in bipolar. Regional deficits in volume have been reported in ventrolateral and dorsolateral prefrontal regions. Based on this, it has been suggested that reduced limbic regulation by prefrontal regions plays a role in bipolar. Findings related to the volume of the basal ganglia have been inconsistent.

Functional neuroimaging studies, contrary to structural studies, consistently find hyperactivation of the basal ganglia, amygdala, and thalamus. Prefrontal abnormalities are less consistently reported, although hyperactivation in the ventral prefrontal cortex is a fairly consistent finding. Mania is generally associated with frontal/ventral hypoactivation, while depression is generally associated with the opposite. A degree of lateralization with regard to abnormalities has been reported, with mania being associated with the right hemisphere, and depression the left. Trait abnormalities in euthymic patients have been observed, including hypoactivity in the ventral prefrontal cortex, and hyperactvity in the amygdala. Hyperactivity in the amygdala and hypoactivity in the medial and ventral prefrontal cortex during exposure to emotional stimuli has been interpreted as reflecting dysfunction in emotional regulation circuits. Increased effective connectivity between the amygdala and orbitofrontal cortex, and elevated striatal responsiveness during reward tasks have been interpreted as hyper-responsiveness in positive emotion and reward circuitry. The abnormal activity in these circuits has been observed in non-emotional tasks, and is congruent with changes in grey and white matter in these circuits. Neural response during reward tasks differentiates unipolar depression from bipolar depression, with the former being associated with reduced neural response and the latter being associated with elevated neural response.

Meta analyses of structural neuroimaging studies have reported reductions in fronto-insula cortices, the anterior cingulate cortex, ventricular enlargement, increased volumes of the globus pallidus and increased amygdala volume relative to those with schizophrenia, and reduced grey matter in the claustrum and temporal cortex. A significant overlap of bipolar disorder with schizophrenia in grey matter volume reduction occurs in the anterior cingulate cortex, medial prefrontal cortex, lateral prefrontal cortex and bilateral insula.

Regardless of mood state, during response inhibition tasks, people with bipolar disorder underactivate the right inferior frontal gyrus. Changes specific on euthymia include hyperactivations in the left superior temporal gyrus and hypoactivations in the basal ganglia, and changes specific to mania include hyperactivation in the basal ganglia. A meta analysis of fMRI studies reported underactivations in the inferior frontal gyrus and putamen and hyperactivation of the parahippocampus, hippocampus, and amygdala. State specific abnormalities were reported for mania and euthymia. During mania, hypoactivation was significant in the inferior frontal gyrus, while euthymia was associated wit hypoactivation of the lingual gyrus and hyperactivation of the amygdala.

Neurometabolites
Increased combined glutamine and glutamate(Glx) have been observed globally, regardless of medication status. Increased Glx has been associated with reduced frontal mismatch negativity, interpreted as dysfunction in NMDA signaling. N-acetyl aspartate levels in the basal ganglia are reduced in bipolar disorder, and trends towards increased in the dorsolateral prefrontal cortex. NAA to creatine ratios are reduced in the hippocampus.

Neurochemistry
Various hypotheses related to monoamines have been proposed. The biogenic amine hypothesis posits general dysregulation of monoamines underlies bipolar and affective disorders. The cholinergic aminergic balance hypothesis posits that an increased ratio of cholingeric activity relative to adrenergic signaling underlies depression, while increased adrenergic signaling relative to cholinergic signaling underlies mania. The permissive hypothesis suggests that serotonin is necessary but not sufficient for affective symptoms, and that reduced serotonergic tone is common to both depression and mania.

Studies of the binding potential of Dopamine receptor D2 and dopamine transporter have been inconsistent but Dopamine receptor D1's binding potential has been observed to be decreased, interpreted as reflecting increased synaptic dopamine in mania. Drugs that release dopamine produce effects similar to mania, further supporting the hypothesis of increase catecholaminergic activity in mania. The binding potential of muscarinic receptors are reduced in vivo during depression, as well as in post mortem studies, supporting the cholinergic aminergic balance hypothesis.

Further evidence for monoamine dysfunction in bipolar comes on studies of neurotransmitter metabolites. Reduced concentration of homovallinic acid, the primary metabolite of dopamine, in the cerebrospinal fluid(CSF) of people with depression is consistently reported. This finding is related to psychomotor retardation and anhedonia. Furthermore, parkinson's disease is associated with high rates of depression, and one case study has reported the abolishment of parkinson's symptoms during manic episodes. The binding potential of VMAT2 is also elevated in bipolar I patients with a history of psychosis, although this finding is inconsistent with finding that valproate increases VMAT2 expression in rodents.

Studies of serotonin's primary metabolite 5-HIAA have been inconsistent, although limited evidence points towards reduced central serotonin signaling in a subgroup of aggressive or suicidal patients. Studies assessing the binding potential of the serotonin transporter or serotonin receptors have also been inconsistent, but generally point towards abnormal serotonin signalling.

Bipolar disorder is associated with elevated basal and dexamethasone elicited cortisol and Adrenocorticotropic hormone(ACTH). These abnormalities are particularly prominent in mania, and are inversely associated with antipsychotic use.

Intracellular Signaling
The levels of Gαs but not other g proteins is increased in the frontal, temporal and occipital cortices. The binding of serotonin receptors to g proteins is also elevated globally. Leukocyte and platelet levels of Gαs and Gαi is also elavated in those with bipolar disorder. Downstream targets of g protein signaling is also altered in bipolar disorder. Increased levels of adenylyl cyclase, protein kinase A(PKA), and cyclic adenosine monophosphate induced PKA activity is also elevated. Phosphoinositide signaling is also altered, with elevated levels of phospholipase C, protein kinase C, and Gαq being reported in bipolar.

Glycogen synthase kinase 3 has been implicated in bipolar disorder, as bipolar medications lithium and valproate have been shown to increase ints phosphorylation, thereby inhibiting it. However, postmortem studies hvae not shown any differences in GSK-3 levels or the levels of a downstream target β-catenin.

Mitochondrial Dysfunction
Some researchers have suggested bipolar disorder is a mitochondrial disease. Some cases of familial chronic progressive external ophthalmoplegia demonstrate increased rates of bipolar disorder before the onset of CPEO, and the higher rate of maternal inheritance patterns support this hypothesis. Further support this hypothesis is the abnormal findings in magnetic resonance spectroscopy studies of brain metabolites in people with bipolar.

Neuropathology
A number of abnormalities in GABAergic neurons have been reported in people with bipolar disorder. People with bipolar demonstrate reduced expression of GAD67 in CA3/CA2 subregion of the hippocampus. More extensive reductions of other indicators of GABA function have been reported in in the CA4 and CA1. Abnormal expression of kainate receptors on GABAergic cells have been reported, with reductions in GRIK1 and GRIK2 mRNA in the CA2/CA3 being found in people with bipolar. Decreased levels of HCN channels have also been reported, which, along with abnormal glutamate signaling, could contribute to reduced GABAergic tone in the hippocampus.

The observation of increased Glx in the prefrontal cortex is congruent with the observation of reduced glial cell counts and prefrontal cortex volume, as glia play an important role in glutamate homeostasis.

Immune Dysfunction
Elevated levels of IL-6, C-reactive protein(CRP) and TNFα have been reported in bipolar. Levels of some(IL-6 and CRP) but not all (TNFα) may be reduced by treatment. Increases in IL-6 have been reported in mood episodes, regardless of polarity.

=Sources to Integrate=

Bipolar

 * Meta-analysis of regional white matter volume in bipolar disorder with replication in an independent sample using coordinates, T-maps, and individual MRI data.
 * The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatmen
 * Neurobiological underpinnings of bipolar disorder focusing on findings of diffusion tensor imaging: a systematic review
 * DTI and Myelin Plasticity in Bipolar Disorder: Integrating Neuroimaging and Neuropathological Findings
 * Biomarkers and staging of bipolar disorder: a systematic review
 * The Kraepelinian dichotomy viewed by neuroimaging
 * A review of MR spectroscopy studies of pediatric bipolar disorder.
 * Assessing working memory via N-back task in euthymic bipolar I disorder patients: a review of functional magnetic resonance imaging studies.
 * Overlapping prefrontal systems involved in cognitive and emotional processing in euthymic bipolar disorder and following sleep deprivation: a review of functional neuroimaging studies.
 * Mechanistic comparisons of functional domains across pediatric and adult bipolar disorder highlight similarities, as well as differences, influenced by the developing brain.
 * Neurocognitive and neuroimaging predictors of clinical outcome in bipolar disorder.
 * Bipolar disorder: from genes to behavior pathways.
 * A neural model of voluntary and automatic emotion regulation: implications for understanding the pathophysiology and neurodevelopment of bipolar disorder.
 * Neuroimaging in bipolar disorder: a critical review of current findings.
 * In vivo imaging of synaptic function in the central nervous system: II. Mental and affective disorders.

Obsessive-compulsive disorder

 * Bipolar I and II Disorders; A Systematic Review and Meta-Analysis on Differences in Comorbid Obsessive-Compulsive Disorder.

Bipolar

 * Voxel-Based Meta-Analytical Evidence of Structural Disconnectivity in Major Depression and Bipolar Disorder
 * Evidence of diagnostic specificity in the neural correlates of facial affect processing in bipolar disorder and schizophrenia: a meta-analysis of functional imaging studies
 * Structural neuroimaging studies in major depressive disorder. Meta-analysis and comparison with bipolar disorder
 * Toward a functional neuroanatomical signature of bipolar disorder: quantitative evidence from the neuroimaging literature
 * A meta-analysis of whole-brain diffusion tensor imaging studies in bipolar disorder.
 * Neuroimaging-based markers of bipolar disorder: evidence from two meta-analyses.
 * Gray matter, white matter, brain, and intracranial volumes in first-episode bipolar disorder: a meta-analysis of magnetic resonance imaging studies
 * Meta-analysis of amygdala volumes in children and adolescents with bipolar disorder
 * Fronto-limbic brain abnormalities in juvenile onset bipolar disorder
 * Meta-analysis of magnetic resonance imaging brain morphometry studies in bipolar disorder
 * Systematic review and voxel-based meta-analysis of diffusion tensor imaging studies in bipolar disorder.

Obsessive-compulsive disorder

 * Biological markers for anxiety disorders, OCD and PTSD: A consensus statement. Part II: Neurochemistry, neurophysiology and neurocognition

MDD
=Various Shenanigans=

=Pathophysiology of PTSD= =Anhedonia= =VTA=
 * The heterogeneity of ventral tegmental area neurons: Projection functions in a mood-related context
 * Reward and aversion in a heterogeneous midbrain dopamine system
 * Medial VTA DA neurons project to the medial shell of the NAc as well as the NAc core, the mPFC and the BLA. Lateral VTA DA neurons project to the lateral NAc shell, and likely represent the population of neurons that were historically assessed in studies that identified DA neurons by waveform and electrophysiological characteristics.
 * The LDTg projects to the lVTA, driving the lVTA to release DA in the lateral NAc shell, producing CPP. The LHb, on the other hand, excites RMTg neurons that inhibit lVTA-Lateral NAc shell projections, but also excites NAc-->mPFC projections, inducing CPA.


 * The antero-posterior heterogeneity of the ventral tegmental area
 * Dopamine and reward seeking: the role of ventral tegmental area
 * Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond
 * Opioid and hypocretin neuromodulation of ventral tegmental area neuronal subpopulations
 * Lateral Hypothalamic Control of the Ventral Tegmental Area: Reward Evaluation and the Driving of Motivated Behavior.
 * Organization of dopamine and serotonin system: Anatomical and functional mapping of monosynaptic inputs using rabies virus
 * The VTA receives input from the lOFC, ventral striatum, BNST, ventral pallidum, lateral hypothalamus, PPTg, and central nucleus of the amygdala. These areas encode a distributed representation of reward expectation and outcome with a high degree of redundancy.


 * Viral vector strategies for investigating midbrain dopamine circuits underlying motivated behaviors
 * The DR sends glutaminergic projections to the VTA which drive incentive salience; the LHb sends glutaminergic projections to the RMTg and mVTA to mPFC projections, the former of which provides general inhibition to DAergic neurons, and the latter of which excited mVTA to mPFC projections producing aversion; the BNST sends glutaminergic projections to GABAergic neurons, driving aversion, and GABAergic projections to GABAergic neurons, driving reward; the LH sends a pattern of projections similar to the BNST; the LDTg sends reward driving glutaminergic and GABAergic/glutaminergic coreleasing inputs to the VTA.


 * Ventral tegmental area: cellular heterogeneity, connectivity and behaviour
 * Supports similar results as with (Cardozo Pinto and Lammel), but also includes VTA--->NAc PV---|NAc producing aversion


 * Input-specific contributions to valence processing in the amygdala.
 * Ventral tegmental area subcircuits process rewarding and aversive experiences.
 * Dopamine reward prediction error coding
 * Ventral Tegmental Area Afferents and Drug-Dependent Behaviors.
 * Neurophysiology of Reward-Guided Behavior: Correlates Related to Predictions, Value, Motivation, Errors, Attention, and Action
 * OFC inputs to the VTA are necessary for error signals.


 * Neuronal Reward and Decision Signals: From Theories to Data

=Recent= =Schizophrenia= The cause and mechanism of schizophrenia is unknown. Evidence from phenomenology, pharmacology, neuroimaging, post mortem studies, genetics, and animal models implicate a number of possible and likely interrelated mechanisms, such as abnormalities in dopaminergic signalling, glutaminergic neurotransmission, and neurodevelopment. Many frameworks have been hypothesized to link these biological abnormalities to symptoms, including psychological and computational theories.
 * Role of Protein Kinase C in Bipolar Disorder: A Review of the Current Literature
 * The search for neuroimaging and cognitive endophenotypes: A critical systematic review of studies involving unaffected first-degree relatives of individuals with bipolar disorder
 * Assessing the role of cingulate cortex in bipolar disorder: neuropathological, structural and functional imaging data.
 * Neurobiological evidence for thalamic, hippocampal and related glutamatergic abnormalities in bipolar disorder: a review and synthesis.
 * Neuropsychological underpinnings of the dynamics of bipolar disorder.
 * Variants in Ion Channel Genes Link Phenotypic Features of Bipolar Illness to Specific Neurobiological Process Domains
 * New insights help define the pathophysiology of bipolar affective disorder: neuroimaging and neuropathology findings

Abnormal dopamine signalling has been implicated in schizophrenia by the efficacy of D2 receptor antagonists, as well as the consistent observation in positron emission tomography of elevated dopamine synthesis and release during acute psychosis. Abnormalities in dopaminergic symptoms have been hypothesized to underlie delusions via dysfunctional signalling of salience. Dopaminergic predictions errors, which mediate learning when expectancies are violated, are abnormal in schizophrenia, and these abnormalities correlate with the severity of delusions. Furthermore, impaired learning, putatively reflecting the functionality of the dopaminergic system, is present in schizophrenia and correlates with delusion severity. Dysfunctional prediction errors may be related to hyperactive input from the hippocampus, which is observed to be metabolically overactive in schizophrenia, and in turn may be related to abnormalities in NMDA receptor functioning on hippocampal interneurons. Hypoactivation of D1 receptors in the prefrontal cortex may also be responsible for deficits in working memory and cognition,   although direct evidence from neuroreceptor imaging studies is inconsistent.

Reduced NMDA receptor signalling is suggested by multiple lines of evidence. Post-mortem studies demonstrate reduced NMDA receptor expression and NMDA receptor antagonists mimic both schizophrenia symptoms and the electrophysiological abnormalities associated with schizophrenia (notable reduced mismatch negativity and P300). Two meta analyses of magnetic resonance spectroscopy studies have found evidence interpreted to be consistent with abnormal glutaminergic signalling, possible involving NMDA receptor abnormalities, despite contradictory findings (i.e. reduced versus elevated glutamate/glutamine ratios). This deficit in NMDA signalling may be related to the abnormalities observed in parvalbumin interneurons that express NMDA receptors. Post mortem studies consistently find that a subset of these neurons fail to express GAD67 in addition to abnormalities in morphology, although neuroimaging studies examining indicators of GABAergic signalling do not consistently report abnormalities. The subsets of interneurons that are abnormal in schizophrenia are responsible for the synchronizing of neural ensembles that is necessary during working memory tasks, a process that is electrophysiologically reflected in gamma frequency (30-80 Hz) oscillations. Both working memory tasks and gamma oscillations are impaired in schizophrenia, which may reflect abnormal interneuron functionality.

Multiple lines of evidence suggest that schizophrenia has a neurodevelopmental component. Schizophrenia is associated with premorbid impairments in cognition, social functioning, and motor skills, and prenatal insults such as maternal infection, maternal malnutrition and obsteric complications all increase risk for schizophrenia. Animal models of these insults demonstrate patterns of cellular and molecular abnormalities similar to those in schizophrenia, such as increased RELN methylation and abnormal GABAergic cell development. Schizophrenia usually emerges symptomatically during late adolescence, 18-25, an age period that overlaps with certain stages of neurodevelopment that are implicated in schizophrenia, such as abnormal synaptic pruning and myelination.

Deficits in executive functions, such as planning, inhibition, and working memory, are pervasive in schizophrenia. Although these functions are dissociable, their dysfunction in schizophrenia may reflect an underlying deficit in the ability to represent goal related information in working memory, and to utilize this to direct cognition and behavior. These impairments have been linked to a number of neuroimaging and neuropathological abnormalities. For example, functional neuroimaging studies report evidence of reduced neural processing efficiency, whereby the dorsolateral prefrontal cortex is activated to a greater degree to achieve a certain level of performance relative to controls on working memory tasks. These abnormalities may be linked to the consistent post-mortem finding of reduced neuropil, evidenced by increased pyramidal cell density, reduced dentritic spine density, and reduced expression mRNA associated with synapses. These cellular and functional abnormalities may also be reflected in structural neuroimaging studies that find reduced grey matter volume in association with deficits in working memory tasks.

Different symptoms have been linked to specific neuroanatomical abnormalities or neurobiological models. For example, positive and negative symptoms have been linked to reduced cortical thickness in the superior temporal lobe, and orbitofrontal cortex, respectively. Auditory hallucinations, a prominent component of positive symptoms, are also reflected in functional hyperactivity of auditory cortices, and in the predictive coding framework are hypothesized to reflect impaired feedforward cancellation of internally generated speech. Anhedonia, traditionally defined as a reduced capacity to experience pleasure, is frequently reported in schizophrenia. However, a large body of evidence suggests that hedonic responses are intact in schizophrenia, and that what is reported to be anhedonia is a reflection of dysfunction in other processes related to reward. Overall, a failure of online maintenance and reward associativity is thought to lead to impairment in the generation of cognition and behavior required to obtain rewards, despite normal hedonic responses. A meta analysis of neuroimaging studies examining reward related paradigms reported results consistent with impairments in the neural substrates that mediate learning, but not in the experience of reward.

Bayesian models of brain function have been utilized to link abnormalities in cellular functioning to symptoms. These models propose that the brain generates predictive models in order to explain sensory information, and that predictive units are organized in a hierarchical fashion that reflect a more abstract model of causes for sensory information higher in the hierarchy. The essential computation performed by these models involves the minimization of error generated by discrepancies in top down predictions by modifying synaptic weights with the least precision. Improper specification of precision in bayesian models is largely consistent with the behavioral, neuroimaging, and electrophysiological abnormalities associated with schizophrenia. Both a failure to attenuate sensory precision and excessive weighting or priors have been proposed as potential and not necessarily conflicting explanations. In canonical models of circuits that mediate predictive coding, hypoactive NMDA receptor activation and abnormalities in dopaminergic signalling, similar to that seen in schizophrenia, could theoretically result in classic symptoms of schizophrenia such as delusions and hallucinations.

=Images= OLS Regression Results ============================================================================== Dep. Variable:              g factor   R-squared:                       0.202 Model:                           OLS   Adj. R-squared:                  0.201 Method:                Least Squares   F-statistic:                     293.2 Date:               Thu, 02 Aug 2018   Prob (F-statistic):          1.11e-169 Time:                       12:11:03   Log-Likelihood:                -4542.1 No. Observations:               3478   AIC:                             9090. Df Residuals:                   3475   BIC:                             9109. Df Model:                          3 Covariance Type:           nonrobust ==============================================================================                 coef    std err          t      P>|t|      [0.025      0.975] -- RELIMP       -0.0836      0.016     -5.372      0.000      -0.114      -0.053 AGE          -0.4253      0.015    -27.717      0.000      -0.455      -0.395 GENDER       -0.0582      0.015     -3.782      0.000      -0.088      -0.028 ============================================================================== Omnibus:                      12.035   Durbin-Watson:                   1.977 Prob(Omnibus):                 0.002   Jarque-Bera (JB):                9.991 Skew:                          0.057   Prob(JB):                      0.00677 Kurtosis:                      2.763   Cond. No.                        1.26 ==============================================================================

OLS Regression Results ============================================================================== Dep. Variable:              g factor   R-squared:                       0.199 Model:                           OLS   Adj. R-squared:                  0.198 Method:                Least Squares   F-statistic:                     288.0 Date:               Thu, 02 Aug 2018   Prob (F-statistic):          5.32e-167 Time:                       12:11:03   Log-Likelihood:                -4566.8 No. Observations:               3491   AIC:                             9140. Df Residuals:                   3488   BIC:                             9158. Df Model:                          3 Covariance Type:           nonrobust ==============================================================================                 coef    std err          t      P>|t|      [0.025      0.975] -- PRAY         -0.0586      0.016     -3.718      0.000      -0.090      -0.028 AGE          -0.4313      0.015    -28.260      0.000      -0.461      -0.401 GENDER       -0.0600      0.016     -3.820      0.000      -0.091      -0.029 ============================================================================== Omnibus:                      11.895   Durbin-Watson:                   1.976 Prob(Omnibus):                 0.003   Jarque-Bera (JB):                9.650 Skew:                          0.043   Prob(JB):                      0.00803 Kurtosis:                      2.757   Cond. No.                        1.33 ==============================================================================

OLS Regression Results ============================================================================== Dep. Variable:              g factor   R-squared:                       0.201 Model:                           OLS   Adj. R-squared:                  0.201 Method:                Least Squares   F-statistic:                     293.0 Date:               Thu, 02 Aug 2018   Prob (F-statistic):          1.27e-169 Time:                       12:11:03   Log-Likelihood:                -4555.1 No. Observations:               3487   AIC:                             9116. Df Residuals:                   3484   BIC:                             9135. Df Model:                          3 Covariance Type:           nonrobust ==============================================================================                 coef    std err          t      P>|t|      [0.025      0.975] -- REL          -0.0780      0.015     -5.050      0.000      -0.108      -0.048 AGE          -0.4275      0.015    -27.954      0.000      -0.457      -0.398 GENDER       -0.0622      0.015     -4.062      0.000      -0.092      -0.032 ============================================================================== Omnibus:                      11.538   Durbin-Watson:                   1.967 Prob(Omnibus):                 0.003   Jarque-Bera (JB):                9.534 Skew:                          0.050   Prob(JB):                      0.00851 Kurtosis:                      2.764   Cond. No.                        1.22 ============================================================================== REL: Response to "How religious are you?", on a scale of 1-4, with 1 being the least religious and 4 being the most religious RELIMP: Response to "How important is religion to you?", on a scale of 1-4, with 1 being the least important and 4 being the most important PRAY: Response to "How often do you pray?", on a scale of 1-6, with 1 being never and 6 being once or more a day

=References= <!-- Proposed changes to Human brain article.

Functions
The human brain serves multiple functions, including sensorimotor functions, regulatory functions, and the production of higher level cognition.

Sensory Functions
The human brain receives external stimuli through the sensory systems, composed of the chemical sensory systems, auditory system, visual system, and somatosensory system. The chemical sensory system in includes senses such as taste, and olfactory system. Taste systems allow for the perception of flavor and consist of vagal, facial, and glossopharyngeal neurons that innervate the mouth and project into the nucleus of the solitary tract before projecting into the thalamus, hypothalamus, Stria terminalis, insula, frontal operculum, amygdala, and hippocampus. The specific taste is determined by activation of receptors on the tongue such as the TAS1R1 receptors. The brain determines the hedonic value of a taste, primarily involving the gustatory cortex, composed of regions of the frontal operculum and insula. The olfactory system is composed of olfactory neurons, which project into the olfactory bulb and olfactory cortex. The visual system allows organisms to perceive the surrounding environment using light sensitive neurons in the eye. These neurons carry information into the brain through the optic nerve, which innervates the lateral geniculate nucleus, superior colliculus, the nuclei of the oculomotor nerve, trochlear nerve, and Abducent nerve, and the visual cortex. The visual cortex consists of two streams, the dorsal and ventral, which are hypothesized to guide behavior and the identify objects respectively. The somatosensory system allows for the sensation of touch, divided into mechanoreceptor, thermoception, nociception, and proprioception. The somatosensory system consists of primary neurons that terminate in the spinal cord or medulla, followed by second order neurons originating in the spinal cord or medulla that terminate in the thalamus. The thalamic third order neurons then project into the sensory cortex. The nociceptive and thermoceptive systems are distinct from proprioceptive and mechanoceptive systems as they terminate in the spinal cord rather than the medulla, forming two distinct pathways.

Motor Functions
The motor system generates moment in humans. The motor system involved in generating basic movements such as locomotion and chewing are controlled by motor programs located in the brain stem and spinal cord. More goal directed behaviors involve the basal ganglia and hypothalamus, while more complex motor functions such as fine motor skills and speech are controlled cortical structures. The cortical structures are also involved in regulating more stereotypical movement generated by brain stem and spinal cord systems. The cerebellum plays an important role in coordination and motor correction. The motor system may also be divided into pyramidal system and extrapyramidal system. The pyramidal system consists of the cortical descending motor tracts, while the extrapyramidal system consists of the lower level motor tracts. The basal ganglia is generally considered extrapyramidal, however it's role in action selection makes it more of a prepyramidal system.

Regulatory Functions
The brain regulates many functions, including regulation of autonomic processes, cardiorespiratory function, food and water intake, the circadian rhythm and endocrine functions. The brainstem, spinal cord and hypothalamus are particularly relevant in regulation.

Cognitive Functions
The brain is capable of producing higher cognitive functions, such as learning, emotions, consciousness, executive functions, abstract reasoning, language, social behavior, causal reasoning, and memory. The circuits involved in generating these functions include both cortical and subcortical structures. Executive functions and learning involve subcortical structures such as the basal ganglia and cortical structures such as the prefrontal cortex and cingulate cortex. Language functions are generally localized to wernicke's area and broca's area. Emotional and mood functions have had many areas implicated in their function, such as the limbic system, cerebellum, basal ganglia, temporal cortex, prefrontal cortex, cingulate cortex, hypothalamus and brain stem monoamine nuclei.

Neurobiology


The the brain endocrine interactions are extremely relevant in the translation of stress into physiological and psychological changes. The autonomic nervous system, as mentioned above, plays an important role in translating stress into a response. The ANS responds reflexively to both physical stressors(for example baroreception), and to higher level inputs from the brain. The ANS is composed of the parasympathetic nervous system and sympathetic nervous system, two branches that are both tonically active with opposing activities. The ANS directly innervates tissue through the postganglionic tissue, which is controlled by preganglionic neurons originating in the intermediolateral cell column. The ANS receives inputs from the medulla, hypothalamus, limbic system, prefrontal cortex, midbrain and monoamine nuclei. The activity of the sympathetic nervous system drives what sometimes called the "fight or flight" response. The fight or flight response to emergency or stress involves mydriasis, increased heart rate and force contraction, vasoconstriction, bronchodialation, glycogenolysis, gluconeogenesis, lypolysis, sweating, decreased motility of the digestive system, secretion of the epinephrine and cortisol from the adrenal medulla, and relaxation of the bladder wall. The parasympathetic nervous response, "rest and digest", involves return to maintaining homeostasis, and involves miosis, bronchoconstriction, increased activity of the digestive system, and contraction of the bladder walls. Complex relationships between protective and vulnerability factors on the effect of childhood home stress on psychological illness, cardiovascular illness and adaption have been observed. ANS related mechanisms are though to contribute to increased risk of cardiovascular disease after major stressful events

The HPA axis is a neuroendocrine system that mediates a stress response. Neurons in the hypothalamus, particularly the paraventricular nucleus, release vassopressin and corticotropin releasing hormone, which travels through the hyphophysial portal vessel where it travels to and binds to Corticotropin-releasing hormone receptor on the anterior pituitary gland. Multiple CRH peptides have been identified, and receptors have been identified on multiple areas of the brain, including the amygdala. However, CRH is the main regulatory molecule of the release of ACTH. The secretion of ACTH into systemic circulation allows it to bind to and activate melanocortin type 2 receptor, where it stimulates the release of steroid hormones. Steroid hormones bind to glucocorticoid receptors in the brain, providing negative feedback by reducing ACTH release. Some evidence supports a second long term feedback that is non-sensitive to cortisol secretion. The PVN of the hypothalamus receives inputs from the nucleus of the solitary tract, and lamina terminalis. Through these inputs, it receives and can respond to changes in blood. The PVN innervation from the brain stem nuclei, particularly the noradrenergic nuclei stimulate CRH release. Other regions of the hypothalamus both directly and indirectly inhibit HPA axis activity. Hypothalamic neurons involved in regulating energy balance also influence HPA axis activity through the release of the neurotransmitters such as Neuropeptide Y, which stimulates HPA axis activity. Generally, the amygdala stimulates, and the prefrontal cortex and hippocampus attenuate HPA axis activity, however complex relationships do exist between the regions.