Causes of schizophrenia: Difference between revisions

Content deleted Content added

Inline

Revision as of 06:08, 16 September 2018

File:Artistic view of how the world feels like with schizophrenia - journal.pmed.0020146.g001.jpg

Artistic view of what the world feels like with schizophrenia

The underlying mechanisms of schizophrenia, a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and schizophrenia,^[1] including the dopamine hypothesis and the glutamate hypothesis. These theories are separate from the causes of schizophrenia, which deal with the factors that lead to schizophrenia. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease.

Pathophysiology

The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.^[2]^[3]^[4] More recent theories center around specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.^[5]^[6]^[7]^[8]^[9]^[10]

Dopamine dysfunction

The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased striatal availability of D₂/D₃ receptors in the striatum, as well as studies finding elevated CSF levels of dopamine metabolites. Subsequently, most antipsychotics were found to have affinity for D2 receptors. More modern investigations of the hypothesis suggest a link between striatal dopamine synthesis and positive symptoms, as well as increased and decreased dopamine transmission in subcortical and cortical regions respectively.

A meta analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of dopamine transporters or dopamine D₂/D₃ receptors. Both studies using radio labeled L-DOPA, an indicator of dopamine synthesis, and studies using amphetamine release challenges observed significant differences between schizophrenics and control. These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively. These findings were localized to the striatum, and were noted to be limited by the quality of studies used.^[11] A large degree of inconsistency has been observed in D₂/D₃ receptor binding, although a small but nonsignificant reduction in thalamic availability has been found.^[12] The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia.^[13]

Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations,^[14] while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions.^[15] Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex.^[16]

One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D₁ and NMDA receptor stimulation. This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.^[17]

Glutamate abnormalities

Beside the dopamine hypothesis, interest has also focused on the neurotransmitter glutamate and the reduced function of the NMDA glutamate receptor in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of glutamate receptors found in postmortem brains of people previously diagnosed with schizophrenia^[18] and the discovery that glutamate blocking drugs such as phencyclidine and ketamine can mimic the symptoms and cognitive problems associated with the condition.^[19]

The fact that reduced glutamate function is linked to poor performance on tests requiring frontal lobe and hippocampal function and that glutamate can affect dopamine function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.^[20] Positive symptoms fail however to respond to glutamatergic medication.^[21]

Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from patients with schizophrenia.^[22] In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex of schizophrenic subjects post-mortem. Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2.^[23]

The large genome-wide association study mentioned above has supported glutamate abnormalities for schizophrenia, reporting several mutations in genes related to glutamatergic neurotransmission, such as GRIN2A, GRIA1, SRR, and GRM3.^[24]

Interneuron dysfunction

A novel hypothesis concerning the pathophysiology of schizophrenia, one that closely relates to the glutamate hypothesis, is one that evolves around dysfunction of interneurons in the brain.^[5]^[6]^[7] Interneurons in the brain are GABAergic and local, and function mainly through the inhibition of other cells. One type of interneuron, the fast-spiking, parvalbumin-positive interneuron, has been suggested to play a key role in schizophrenia pathophysiology.

Early studies have identified decreases in GAD67 mRNA and protein in post-mortem brains from schizophrenia patients compared to controls.^[25] These reductions were found in only a subset of cortical interneurons. Furthermore, GAD67 mRNA was completely undetectable in a subset of interneurons also expressing parvalbumin. Levels of parvalbumin protein and mRNA were also found to be lower in patient brains in various regions in the brain. Actual numbers of parvalbumin interneurons have been found to be unchanged in these studies, however, except for a single study showing a decrease in parvalbumin interneurons in the hippocampus.^[26] Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67.^[27] Together, this suggests that parvalbumin interneurons are somehow specifically affected in the disease.

Several studies have tried to assess levels in GABA in vivo in the patients with schizophrenia, but these findings have remained inconclusive.

EEG studies have indirectly also pointed to interneuron dysfunction in schizophrenia (see below).^[28] These studies have pointed to abnormalities in oscillatory activity in schizophrenia, particularly in the gamma band (30–80 Hz). Gamma band activity appears to originate from intact functioning parvalbumin-positive interneuron.^[29] Together with the post-mortem findings, these EEG abnormalities point to a role for dysfunctional parvalbumin interneurons in schizophrenia.

The largest meta-analysis on copy-number variations (CNVs), structural abnormalities in the form of genetic deletions or duplications, to date for schizophenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.^[30]

Myelination abnormalities

Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia.^[31]^[32]^[33] This theory originated from structural imaging studies, who found that white matter regions, in addition to grey matter regions, showed volumetric reductions in patients with schizophrenia (see below). In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in post-mortem brains of schizophrenia patients. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies.^[34]

It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells,^[35] as these have been found to be intact in schizophrenia brains.

Immune system abnormalities

Another hypothesis postulates that inflammation and immune system abnormalities could play a central role in the disease.^[10] Abnormal immune system development may help explain roles of environmental effect such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition to genetic effects.^[36] The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients.^[37] High levels of immune markers have also been associated with having more severe psychotic symptoms.^[38]^[39] Furthermore, a meta-analysis of genome-wide association studies discovered that 129 out of 136 single-nucleotide polymorphisms (SNP) significantly associated with schizophrenia were located in the major histocompatibility complex region of the genome.^[40]

A recent systematic review investigating neuroinflammatory markers in post-mortem schizophrenia brains has shown quite some variability, with some studies showing alterations in various markers but others failing to find any differences.^[41]

Oxidative stress

A theory that has gained more support in recent years is that a large role is played in the disease by oxidative stress.^[9]^[42]^[43] Redox dysregulation in early development can potentially influence development of different cell types that have been shown to be impaired in the disease.

Oxidative stress has also been indicated through genetic studies into schizophrenia.^[44]

Oxidative stress has been shown to affect maturation of oligodendrocytes,^[45] the myelinating cell types in the brain, potentially underlying the white matter abnormalities found in the brain (see below).

Furthermore, oxidative stress could also influence the development of GABAergic interneurons,^[46] which have also been found to be dysregulated in schizophrenia (see above).

Neuropathology

The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or gliosis. Abnormal neuronal organization and orientation (dysplasia) has been observed in the entorhinal cortex, hippocampus, and subcortical white matter, although results are not entirely consistent. A more consistent cytoarchitectural finding is reduced volume of purkinje cells and pyramidal cells in the hippocampus. This is consistent with the observation of decreased presynaptic terminals in the hippocampus, and a reduction in dendritic spines in the prefrontal cortex.^[47] The reductions in prefrontal and increase in striatal spine densities seem to be independent of antipsychotic drug use.^[48]

Structural abnormalities

Beside theories concerning the functional mechanism underlying the disease, structural findings have been identified as well using a wide range of imaging techniques. Studies have tended to show various subtle average differences in the volume of certain areas of brain structure between people with and without diagnoses of schizophrenia, although it has become increasingly clear that no single pathological neuropsychological or structural neuroanatomic profile exists.^[49]

Morphometry

Structural imaging studies have extensively reported differences in the size and structure of certain brain areas in schizophrenia.

The largest combined neuroimaging study with over 2000 patients and 2500 controls has replicated these previous findings.^[50] Here, the authors found volumetric increases in the lateral ventricles (+18%), caudate and pallidum, and extensive decreases in the hippocampus (-4%), thalamus, amygdala and nucleus accumbens. Together, this indicates that extensive changes occur in brains in patients suffering from schizophrenia.

A 2006 meta-analysis of MRI studies found that whole brain and hippocampal volume are reduced and that ventricular volume is increased in patients with a first psychotic episode relative to healthy controls. The average volumetric changes in these studies are however close to the limit of detection by MRI methods, so it remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.^[51] In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not.^[52] Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.^[53]

Abnormal findings in the prefrontal cortex, temporal cortex and anterior cingulate cortex are found before the first onset of schizophrenia symptoms. These regions are the regions of structural deficits found in schizophrenia and first-episode patients.^[54] Positive symptoms, such as thoughts of being persecuted, were found to be related to the medial prefrontal cortex, amygdala, and hippocampus region. Negative symptoms were found to be related to the ventrolateral prefrontal cortex and ventral striatum.^[54]

Ventricular and third ventricle enlargement, abnormal functioning of the amygdala, hippocampus, parahippocampal gyrus, neocortical temporal lobe regions, frontal lobe, prefontal gray matter, orbitofrontal areas, parietal lobs abnormalities and subcortical abnormalities including the cavum septi pellucidi, basal ganglia, corpus callosum, thalamus and cerebellar abnormalities. Such abnormalities usually present in the form of loss of volume.^[55]

Most schizophrenia studies have found average reduced volume of the left medial temporal lobe and left superior temporal gyrus, and half of studies have revealed deficits in certain areas of the frontal gyrus, parahippocampal gyrus and temporal gyrus.^[56] However, at variance with some findings in individuals with chronic schizophrenia significant group differences of temporal lobe and amygdala volumes are not shown in first-episode patients on average.^[57]

Finally, MRI studies utilizing modern cortical surface reconstruction techniques have shown widespread reduction in cerebral cortical thickness (i.e., "cortical thinning") in frontal and temporal regions^[58]^[59] and somewhat less widespread cortical thinning in occipital and parietal regions^[59] in patients with schizophrenia, relative to healthy control subjects. Moreover, one study decomposed cortical volume into its constituent parts, cortical surface area and cortical thickness, and reported widespread cortical volume reduction in schizophrenia, mainly driven by cortical thinning, but also reduced cortical surface area in smaller frontal, temporal, parietal and occipital cortical regions.^[60]

Computed Tomography scans of schizophrenic brains show several pathologies. The brain ventricles are enlarged as compared to normal brains. The ventricles hold cerebrospinal fluid (CSF) and enlarged ventricles indicate a loss of brain volume. Additionally, schizophrenic brains have widened sulci as compared to normal brains, also with increased CSF volumes and reduced brain volume.^[55]^[61]

White Matter

Diffusion tensor imaging (DTI) allows for the investigation of white matter more closely than traditional MRI.^[55] Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia.^[62]^[63] Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced fractional anisotropy in brains from patients with schizophrenia versus controls. Importantly, these differences between patients and controls could potentially be attributed to lifestyle effects, medication effects etc. Therefore, more recently several studies have been perform in first-onset schizophrenia patients that have never recent any medication, so-called medication-naive subjects. These studies, although still few in number, also found reduced fractional anisotropy in patient brains compared to control brains. As with earlier findings, abnormalities can be found throughout the brain, although the corpus callous seemed to be most commonly effected.

Functional abnormalities

During executive function tasks, Schizophrenics demonstrate decreased activity relative to controls in the bilateral dorsolateral prefrontal cortex(dlPFC), right anterior cingulate cortex(ACC), and left mediodorsal nucleus of the thalamus. Increased activation was observed in the left ACC and left inferior parietal lobe.^[64] During emotional processing tasks, reduced activations have been observed in the Medial prefrontal cortex, ACC, dlPFC and amygdala.^[65] A meta analysis of facial emotional processing observed decreased activation in the amygdala, parahippocampus, lentiform nuclei, fusiform gyrus and right superior frontal gyrus, as well as increased activation in the left insula.^[66]

One meta analysis of functional neuroiamging during acute auditory verbal hallucinations has reported increased activations in areas implicated in language, including the bilateral inferior frontal and post central gyri, as well as the left parietal operculum.^[67] Another meta analysis during both visual and auditory verbal hallucinations, replicated the findings in the inferior frontal and postcentral gyri during auditory verbal hallucinations, and also observed hippocampal, superior temporal, insular and medial prefrontal activations. Visual hallucinations were reported to be associated with increased activations in the secondary and associate visual cortices.^[68]

PET

PET scan findings in patients with schizophrenia indicate cerebral blood flow decreases in the left parahippocampal region. PET scans also show a reduced ability to metabolize glucose in the thalamus and frontal cortex. PET scans also show involvement of the medial part of the left temporal lobe and the limbic and frontal systems as suffering from developmental abnormality. PET scans show thought disorders stem from increased flow in the frontal and temporal regions while delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. PET scans done on patient who were actively having auditory hallucinations revealed increased blood flow in both thalami, left hippocampus, right striatum, parahippocampus, orbitofrontal, and cingulate areas.^[55]

In addition, a decrease in NAA uptake has been reported in the hippocampus and both the grey and white matter of the prefrontal cortex of those with schizophrenia. NAA may be an indicator of neural activity of number of viable neurons. however given methodological limitations and variance it is impossible to use this as a diagnostic method.^[70] Decreased PFC connectivity has also been observed.^[71] DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.^[72]^[73]

References

^ van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
^ Insel TR (November 2010). "Rethinking schizophrenia". Nature. 468 (7321): 187–93. Bibcode:2010Natur.468..187I. doi:10.1038/nature09552. PMID 21068826.
^ Elert E (April 2014). "Aetiology: Searching for schizophrenia's roots". Nature. 508 (7494): S2-3. doi:10.1038/508S2a. PMID 24695332.
^ van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.
^ ^a ^b Marín O (January 2012). "Interneuron dysfunction in psychiatric disorders". Nature Reviews. Neuroscience. 13 (2): 107–20. doi:10.1038/nrn3155. PMID 22251963.
^ ^a ^b Gonzalez-Burgos G, Cho RY, Lewis DA (June 2015). "Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia". Biological Psychiatry. 77 (12): 1031–40. doi:10.1016/j.biopsych.2015.03.010. PMC 4444373. PMID 25863358.
^ ^a ^b Pittman-Polletta BR, Kocsis B, Vijayan S, Whittington MA, Kopell NJ (June 2015). "Brain rhythms connect impaired inhibition to altered cognition in schizophrenia". Biological Psychiatry. 77 (12): 1020–30. doi:10.1016/j.biopsych.2015.02.005. PMC 4444389. PMID 25850619.
^ Feigenson KA, Kusnecov AW, Silverstein SM (January 2014). "Inflammation and the two-hit hypothesis of schizophrenia". Neuroscience and Biobehavioral Reviews. 38: 72–93. doi:10.1016/j.neubiorev.2013.11.006. PMC 3896922. PMID 24247023.
^ ^a ^b Steullet P, Cabungcal JH, Monin A, Dwir D, O'Donnell P, Cuenod M, Do KQ (September 2016). "Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?". Schizophrenia Research. 176 (1): 41–51. doi:10.1016/j.schres.2014.06.021. PMC 4282982. PMID 25000913.
^ ^a ^b Leza JC, García-Bueno B, Bioque M, Arango C, Parellada M, Do K, O'Donnell P, Bernardo M (August 2015). "Inflammation in schizophrenia: A question of balance". Neuroscience and Biobehavioral Reviews. 55: 612–26. doi:10.1016/j.neubiorev.2015.05.014. PMID 26092265.
^ Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (August 2012). "The nature of dopamine dysfunction in schizophrenia and what this means for treatment". Archives of General Psychiatry. 69 (8): 776–86. doi:10.1001/archgenpsychiatry.2012.169. PMC 3730746. PMID 22474070.
^ Kambeitz J, Abi-Dargham A, Kapur S, Howes OD (June 2014). "Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies". The British Journal of Psychiatry. 204 (6): 420–9. doi:10.1192/bjp.bp.113.132308. PMID 25029687.
^ Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (January 2017). "Pathway-Specific Dopamine Abnormalities in Schizophrenia". Biological Psychiatry. 81 (1): 31–42. doi:10.1016/j.biopsych.2016.03.2104. PMC 5177794. PMID 27206569.
^ Chun S, Westmoreland JJ, Bayazitov IT, Eddins D, Pani AK, Smeyne RJ, Yu J, Blundon JA, Zakharenko SS (June 2014). "Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models". Science. 344 (6188): 1178–82. doi:10.1126/science.1253895. PMC 4349506. PMID 24904170.
^ Kapur S (January 2003). "Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia". The American Journal of Psychiatry. 160 (1): 13–23. doi:10.1176/appi.ajp.160.1.13. PMID 12505794.
^ Takahashi H, Higuchi M, Suhara T (May 2006). "The role of extrastriatal dopamine D2 receptors in schizophrenia". Biological Psychiatry. 59 (10): 919–28. doi:10.1016/j.biopsych.2006.01.022. PMID 16682269.
^ Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH (November 2010). "Toward a neurobiology of delusions". Progress in Neurobiology. 92 (3): 345–69. doi:10.1016/j.pneurobio.2010.06.007. PMC 3676875. PMID 20558235.
^ Konradi C, Heckers S (February 2003). "Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment". Pharmacology & Therapeutics. 97 (2): 153–79. doi:10.1016/S0163-7258(02)00328-5. PMID 12559388.
^ Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (October 2001). "Effects of ketamine in normal and schizophrenic volunteers". Neuropsychopharmacology. 25 (4): 455–67. doi:10.1016/S0893-133X(01)00243-3. PMID 11557159.
^ Coyle JT, Tsai G, Goff D (November 2003). "Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia". Annals of the New York Academy of Sciences. 1003: 318–27. doi:10.1196/annals.1300.020. PMID 14684455.
^ Tuominen HJ, Tiihonen J, Wahlbeck K (January 2005). "Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis". Schizophrenia Research. 72 (2–3): 225–34. doi:10.1016/j.schres.2004.05.005. PMID 15560967.
^ Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW (November 2013). "Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia". Molecular Psychiatry. 18 (11): 1185–92. doi:10.1038/mp.2012.137. PMC 3807670. PMID 23070074.
^ Catts VS, Lai YL, Weickert CS, Weickert TW, Catts SV (April 2016). "A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?". Biological Psychology. 116: 57–67. doi:10.1016/j.biopsycho.2015.10.013. PMID 26549579.
^ "Biological insights from 108 schizophrenia-associated genetic loci". Nature. 511 (7510): 421–7. July 2014. doi:10.1038/nature13595. PMC 4112379. PMID 25056061.
^ Gonzalez-Burgos G, Hashimoto T, Lewis DA (August 2010). "Alterations of cortical GABA neurons and network oscillations in schizophrenia". Current Psychiatry Reports. 12 (4): 335–44. doi:10.1007/s11920-010-0124-8. PMC 2919752. PMID 20556669.
^ Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S (September 2011). "Hippocampal interneurons are abnormal in schizophrenia". Schizophrenia Research. 131 (1–3): 165–73. doi:10.1016/j.schres.2011.06.007. PMC 3159834. PMID 21745723.
^ Chung DW, Fish KN, Lewis DA (November 2016). "Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia". The American Journal of Psychiatry. 173 (11): 1131–1139. doi:10.1176/appi.ajp.2016.16010025. PMC 5089927. PMID 27444795.
^ Senkowski D, Gallinat J (June 2015). "Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia". Biological Psychiatry. 77 (12): 1010–9. doi:10.1016/j.biopsych.2015.02.034. PMID 25847179.
^ Sohal VS, Zhang F, Yizhar O, Deisseroth K (June 2009). "Parvalbumin neurons and gamma rhythms enhance cortical circuit performance". Nature. 459 (7247): 698–702. doi:10.1038/nature07991. PMC 3969859. PMID 19396159.
^ Pocklington AJ, Rees E, Walters JT, Han J, Kavanagh DH, Chambert KD, Holmans P, Moran JL, McCarroll SA, Kirov G, O'Donovan MC, Owen MJ (June 2015). "Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia". Neuron. 86 (5): 1203–14. doi:10.1016/j.neuron.2015.04.022. PMC 4460187. PMID 26050040.
^ Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D (2015-01-01). "Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules". NPJ Schizophrenia. 1: 15034. doi:10.1038/npjschz.2015.34. PMC 4849457. PMID 27336040.
^ Mighdoll MI, Tao R, Kleinman JE, Hyde TM (January 2015). "Myelin, myelin-related disorders, and psychosis". Schizophrenia Research. 161 (1): 85–93. doi:10.1016/j.schres.2014.09.040. PMID 25449713.
^ Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G (November 2014). "Myelination, oligodendrocytes, and serious mental illness". Glia. 62 (11): 1856–77. doi:10.1002/glia.22716. PMID 25056210.
^ Stedehouder J, Kushner SA (January 2017). "Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia". Molecular Psychiatry. 22 (1): 4–12. doi:10.1038/mp.2016.147. PMID 27646261.
^ Mauney SA, Pietersen CY, Sonntag KC, Woo TW (December 2015). "Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia". Schizophrenia Research. 169 (1–3): 374–380. doi:10.1016/j.schres.2015.10.042. PMC 4681621. PMID 26585218.
^ Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, Butler R (March 2010). "A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction". Medical Hypotheses. 74 (3): 555–63. doi:10.1016/j.mehy.2009.09.040. PMID 19836903.
^ Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA (November 2009). "Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor". Bipolar Disorders. 11 (7): 726–34. doi:10.1111/j.1399-5618.2009.00757.x. PMID 19839997.
^ Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (January 2010). "The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder". Expert Review of Neurotherapeutics. 10 (1): 59–76. doi:10.1586/ern.09.144. PMID 20021321.
^ Hope S, Ueland T, Steen NE, Dieset I, Lorentzen S, Berg AO, Agartz I, Aukrust P, Andreassen OA (April 2013). "Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder". Schizophrenia Research. 145 (1–3): 36–42. doi:10.1016/j.schres.2012.12.023. PMID 23403415.
^ "Genome-wide association study identifies five new schizophrenia loci". Nature Genetics. 43 (10): 969–76. September 2011. doi:10.1038/ng.940. PMC 3303194. PMID 21926974.
^ Trépanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP (August 2016). "Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review". Molecular Psychiatry. 21 (8): 1009–26. doi:10.1038/mp.2016.90. PMC 4960446. PMID 27271499.
^ Emiliani FE, Sedlak TW, Sawa A (May 2014). "Oxidative stress and schizophrenia: recent breakthroughs from an old story". Current Opinion in Psychiatry. 27 (3): 185–90. doi:10.1097/YCO.0000000000000054. PMC 4054867. PMID 24613987.
^ Hardingham GE, Do KQ (February 2016). "Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis". Nature Reviews. Neuroscience. 17 (2): 125–34. doi:10.1038/nrn.2015.19. PMID 26763624.
^ Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, et al. (March 2017). "High-resolution copy number variation analysis of schizophrenia in Japan". Molecular Psychiatry. 22 (3): 430–440. doi:10.1038/mp.2016.88. PMID 27240532.
^ Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, et al. (July 2015). "Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients". Molecular Psychiatry. 20 (7): 827–38. doi:10.1038/mp.2014.88. PMID 25155877.
^ Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ (March 2013). "Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine". Biological Psychiatry. 73 (6): 574–82. doi:10.1016/j.biopsych.2012.09.020. PMID 23140664.
^ Harrison PJ (December 2000). "Postmortem studies in schizophrenia". Dialogues in Clinical Neuroscience. 2 (4): 349–57. PMC 3181616. PMID 22033474.
^ Glausier JR, Lewis DA (October 2013). "Dendritic spine pathology in schizophrenia". Neuroscience. 251: 90–107. doi:10.1016/j.neuroscience.2012.04.044. PMC 3413758. PMID 22546337.
^ Flashman LA, Green MF (March 2004). "Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment". The Psychiatric Clinics of North America. 27 (1): 1–18, vii. doi:10.1016/S0193-953X(03)00105-9. PMID 15062627.
^ van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, et al. (April 2016). "Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium". Molecular Psychiatry. 21 (4): 547–53. doi:10.1038/mp.2015.63. PMC 4668237. PMID 26033243.
^ Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA (June 2006). "Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies". The British Journal of Psychiatry. 188: 510–8. doi:10.1192/bjp.188.6.510. PMID 16738340.
^ Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG (September 2008). "Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection". Pharmacological Reviews. 60 (3): 358–403. doi:10.1124/pr.107.00107. PMID 18922967.
^ DeLisi LE (March 2008). "The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia". Schizophrenia Bulletin. 34 (2): 312–21. doi:10.1093/schbul/sbm164. PMC 2632405. PMID 18263882.
^ ^a ^b Jung WH, Jang JH, Byun MS, An SK, Kwon JS (December 2010). "Structural brain alterations in individuals at ultra-high risk for psychosis: a review of magnetic resonance imaging studies and future directions". Journal of Korean Medical Science. 25 (12): 1700–9. doi:10.3346/jkms.2010.25.12.1700. PMC 2995221. PMID 21165282.
^ ^a ^b ^c ^d Shenton ME, Dickey CC, Frumin M, McCarley RW (April 2001). "A review of MRI findings in schizophrenia". Schizophrenia Research. 49 (1–2): 1–52. doi:10.1016/s0920-9964(01)00163-3. PMC 2812015. PMID 11343862.
^ Honea R, Crow TJ, Passingham D, Mackay CE (December 2005). "Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies". The American Journal of Psychiatry. 162 (12): 2233–45. doi:10.1176/appi.ajp.162.12.2233. PMID 16330585.
^ Vita A, De Peri L, Silenzi C, Dieci M (February 2006). "Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies". Schizophrenia Research. 82 (1): 75–88. doi:10.1016/j.schres.2005.11.004. PMID 16377156.
^ Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B (September 2003). "Regionally localized thinning of the cerebral cortex in schizophrenia". Archives of General Psychiatry. 60 (9): 878–88. doi:10.1001/archpsyc.60.9.878. PMID 12963669.
^ ^a ^b Rimol LM, Hartberg CB, Nesvåg R, Fennema-Notestine C, Hagler DJ, Pung CJ, Jennings RG, Haukvik UK, Lange E, Nakstad PH, Melle I, Andreassen OA, Dale AM, Agartz I (July 2010). "Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder". Biological Psychiatry. 68 (1): 41–50. doi:10.1016/j.biopsych.2010.03.036. PMID 20609836.
^ Rimol LM, Nesvåg R, Hagler DJ, Bergmann O, Fennema-Notestine C, Hartberg CB, Haukvik UK, Lange E, Pung CJ, Server A, Melle I, Andreassen OA, Agartz I, Dale AM (March 2012). "Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder". Biological Psychiatry. 71 (6): 552–60. doi:10.1016/j.biopsych.2011.11.026. PMID 22281121.
^ Ropper AH, Brown RH. Adams and Victor's Principles of Neurology. 8th ed. New York: McGraw-Hill; 2005. ISBN 0-07-141620-X. p. 1324.
^ Fitzsimmons J, Kubicki M, Shenton ME (March 2013). "Review of functional and anatomical brain connectivity findings in schizophrenia". Current Opinion in Psychiatry. 26 (2): 172–87. doi:10.1097/YCO.0b013e32835d9e6a. PMID 23324948.
^ Ellison-Wright I, Bullmore E (March 2009). "Meta-analysis of diffusion tensor imaging studies in schizophrenia". Schizophrenia Research. 108 (1–3): 3–10. doi:10.1016/j.schres.2008.11.021. PMID 19128945.
^ Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (August 2009). "Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia". Archives of General Psychiatry. 66 (8): 811–22. doi:10.1001/archgenpsychiatry.2009.91. PMC 2888482. PMID 19652121.
^ Taylor SF, Kang J, Brege IS, Tso IF, Hosanagar A, Johnson TD (January 2012). "Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia". Biological Psychiatry. 71 (2): 136–45. doi:10.1016/j.biopsych.2011.09.007. PMC 3237865. PMID 21993193.
^ Li H, Chan RC, McAlonan GM, Gong QY (September 2010). "Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data". Schizophrenia Bulletin. 36 (5): 1029–39. doi:10.1093/schbul/sbn190. PMC 2930350. PMID 19336391.
^ Kühn S, Gallinat J (June 2012). "Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia". Schizophrenia Bulletin. 38 (4): 779–86. doi:10.1093/schbul/sbq152. PMC 3406531. PMID 21177743.
^ Zmigrod L, Garrison JR, Carr J, Simons JS (October 2016). "The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies". Neuroscience and Biobehavioral Reviews. 69: 113–23. doi:10.1016/j.neubiorev.2016.05.037. PMID 27473935.
^ Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (March 2002). "Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia". Nature Neuroscience. 5 (3): 267–71. doi:10.1038/nn804. PMID 11865311.
^ Steen RG, Hamer RM, Lieberman JA (November 2005). "Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis". Neuropsychopharmacology. 30 (11): 1949–62. doi:10.1038/sj.npp.1300850. PMID 16123764.
^ Davis, Kenneth L.; American College of Neuropsychopharmacology (2002). "Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia". Neuropsychopharmacology: The Fifth Generation of Progress : an Official Publication of the American College of Neuropsychopharmacology,. Lippincott Williams & Wilkins. pp. 731–743. ISBN 9780781728379. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)
^ Fusar-Poli P, Meyer-Lindenberg A (January 2013). "Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies". Schizophrenia Bulletin. 39 (1): 33–42. doi:10.1093/schbul/sbr180. PMC 3523905. PMID 22282454.
^ Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (January 2017). "Pathway-Specific Dopamine Abnormalities in Schizophrenia". Biological Psychiatry. 81 (1): 31–42. doi:10.1016/j.biopsych.2016.03.2104. PMC 5177794. PMID 27206569.

External links

Media related to Mechanisms of schizophrenia at Wikimedia Commons

[Lancet09-1] van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.

[2] Insel TR (November 2010). "Rethinking schizophrenia". Nature. 468 (7321): 187–93. Bibcode:2010Natur.468..187I. doi:10.1038/nature09552. PMID 21068826.

[3] Elert E (April 2014). "Aetiology: Searching for schizophrenia's roots". Nature. 508 (7494): S2-3. doi:10.1038/508S2a. PMID 24695332.

[4] van Os J, Kapur S (August 2009). "Schizophrenia". Lancet. 374 (9690): 635–45. doi:10.1016/S0140-6736(09)60995-8. PMID 19700006.

[pmid22251963-5] Marín O (January 2012). "Interneuron dysfunction in psychiatric disorders". Nature Reviews. Neuroscience. 13 (2): 107–20. doi:10.1038/nrn3155. PMID 22251963.

[pmid25863358-6] Gonzalez-Burgos G, Cho RY, Lewis DA (June 2015). "Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia". Biological Psychiatry. 77 (12): 1031–40. doi:10.1016/j.biopsych.2015.03.010. PMC 4444373. PMID 25863358.

[pmid25850619-7] Pittman-Polletta BR, Kocsis B, Vijayan S, Whittington MA, Kopell NJ (June 2015). "Brain rhythms connect impaired inhibition to altered cognition in schizophrenia". Biological Psychiatry. 77 (12): 1020–30. doi:10.1016/j.biopsych.2015.02.005. PMC 4444389. PMID 25850619.

[8] Feigenson KA, Kusnecov AW, Silverstein SM (January 2014). "Inflammation and the two-hit hypothesis of schizophrenia". Neuroscience and Biobehavioral Reviews. 38: 72–93. doi:10.1016/j.neubiorev.2013.11.006. PMC 3896922. PMID 24247023.

[pmid25000913-9] Steullet P, Cabungcal JH, Monin A, Dwir D, O'Donnell P, Cuenod M, Do KQ (September 2016). "Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?". Schizophrenia Research. 176 (1): 41–51. doi:10.1016/j.schres.2014.06.021. PMC 4282982. PMID 25000913.

[pmid26092265-10] Leza JC, García-Bueno B, Bioque M, Arango C, Parellada M, Do K, O'Donnell P, Bernardo M (August 2015). "Inflammation in schizophrenia: A question of balance". Neuroscience and Biobehavioral Reviews. 55: 612–26. doi:10.1016/j.neubiorev.2015.05.014. PMID 26092265.

[11] Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S (August 2012). "The nature of dopamine dysfunction in schizophrenia and what this means for treatment". Archives of General Psychiatry. 69 (8): 776–86. doi:10.1001/archgenpsychiatry.2012.169. PMC 3730746. PMID 22474070.

[12] Kambeitz J, Abi-Dargham A, Kapur S, Howes OD (June 2014). "Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies". The British Journal of Psychiatry. 204 (6): 420–9. doi:10.1192/bjp.bp.113.132308. PMID 25029687.

[13] Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (January 2017). "Pathway-Specific Dopamine Abnormalities in Schizophrenia". Biological Psychiatry. 81 (1): 31–42. doi:10.1016/j.biopsych.2016.03.2104. PMC 5177794. PMID 27206569.

[14] Chun S, Westmoreland JJ, Bayazitov IT, Eddins D, Pani AK, Smeyne RJ, Yu J, Blundon JA, Zakharenko SS (June 2014). "Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models". Science. 344 (6188): 1178–82. doi:10.1126/science.1253895. PMC 4349506. PMID 24904170.

[15] Kapur S (January 2003). "Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia". The American Journal of Psychiatry. 160 (1): 13–23. doi:10.1176/appi.ajp.160.1.13. PMID 12505794.

[16] Takahashi H, Higuchi M, Suhara T (May 2006). "The role of extrastriatal dopamine D2 receptors in schizophrenia". Biological Psychiatry. 59 (10): 919–28. doi:10.1016/j.biopsych.2006.01.022. PMID 16682269.

[17] Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH (November 2010). "Toward a neurobiology of delusions". Progress in Neurobiology. 92 (3): 345–69. doi:10.1016/j.pneurobio.2010.06.007. PMC 3676875. PMID 20558235.

[Konradi2003-18] Konradi C, Heckers S (February 2003). "Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment". Pharmacology & Therapeutics. 97 (2): 153–79. doi:10.1016/S0163-7258(02)00328-5. PMID 12559388.

[Lahti2001-19] Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA (October 2001). "Effects of ketamine in normal and schizophrenic volunteers". Neuropsychopharmacology. 25 (4): 455–67. doi:10.1016/S0893-133X(01)00243-3. PMID 11557159.

[Coyle2003-20] Coyle JT, Tsai G, Goff D (November 2003). "Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia". Annals of the New York Academy of Sciences. 1003: 318–27. doi:10.1196/annals.1300.020. PMID 14684455.

[Touminen2005-21] Tuominen HJ, Tiihonen J, Wahlbeck K (January 2005). "Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis". Schizophrenia Research. 72 (2–3): 225–34. doi:10.1016/j.schres.2004.05.005. PMID 15560967.

[22] Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW (November 2013). "Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia". Molecular Psychiatry. 18 (11): 1185–92. doi:10.1038/mp.2012.137. PMC 3807670. PMID 23070074.

[23] Catts VS, Lai YL, Weickert CS, Weickert TW, Catts SV (April 2016). "A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?". Biological Psychology. 116: 57–67. doi:10.1016/j.biopsycho.2015.10.013. PMID 26549579.

[:0-24] "Biological insights from 108 schizophrenia-associated genetic loci". Nature. 511 (7510): 421–7. July 2014. doi:10.1038/nature13595. PMC 4112379. PMID 25056061.

[25] Gonzalez-Burgos G, Hashimoto T, Lewis DA (August 2010). "Alterations of cortical GABA neurons and network oscillations in schizophrenia". Current Psychiatry Reports. 12 (4): 335–44. doi:10.1007/s11920-010-0124-8. PMC 2919752. PMID 20556669.

[26] Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S (September 2011). "Hippocampal interneurons are abnormal in schizophrenia". Schizophrenia Research. 131 (1–3): 165–73. doi:10.1016/j.schres.2011.06.007. PMC 3159834. PMID 21745723.

[27] Chung DW, Fish KN, Lewis DA (November 2016). "Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia". The American Journal of Psychiatry. 173 (11): 1131–1139. doi:10.1176/appi.ajp.2016.16010025. PMC 5089927. PMID 27444795.

[28] Senkowski D, Gallinat J (June 2015). "Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia". Biological Psychiatry. 77 (12): 1010–9. doi:10.1016/j.biopsych.2015.02.034. PMID 25847179.

[29] Sohal VS, Zhang F, Yizhar O, Deisseroth K (June 2009). "Parvalbumin neurons and gamma rhythms enhance cortical circuit performance". Nature. 459 (7247): 698–702. doi:10.1038/nature07991. PMC 3969859. PMID 19396159.

[30] Pocklington AJ, Rees E, Walters JT, Han J, Kavanagh DH, Chambert KD, Holmans P, Moran JL, McCarroll SA, Kirov G, O'Donovan MC, Owen MJ (June 2015). "Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia". Neuron. 86 (5): 1203–14. doi:10.1016/j.neuron.2015.04.022. PMC 4460187. PMID 26050040.

[31] Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D (2015-01-01). "Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules". NPJ Schizophrenia. 1: 15034. doi:10.1038/npjschz.2015.34. PMC 4849457. PMID 27336040.

[32] Mighdoll MI, Tao R, Kleinman JE, Hyde TM (January 2015). "Myelin, myelin-related disorders, and psychosis". Schizophrenia Research. 161 (1): 85–93. doi:10.1016/j.schres.2014.09.040. PMID 25449713.

[33] Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G (November 2014). "Myelination, oligodendrocytes, and serious mental illness". Glia. 62 (11): 1856–77. doi:10.1002/glia.22716. PMID 25056210.

[34] Stedehouder J, Kushner SA (January 2017). "Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia". Molecular Psychiatry. 22 (1): 4–12. doi:10.1038/mp.2016.147. PMID 27646261.

[35] Mauney SA, Pietersen CY, Sonntag KC, Woo TW (December 2015). "Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia". Schizophrenia Research. 169 (1–3): 374–380. doi:10.1016/j.schres.2015.10.042. PMC 4681621. PMID 26585218.

[36] Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, Butler R (March 2010). "A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction". Medical Hypotheses. 74 (3): 555–63. doi:10.1016/j.mehy.2009.09.040. PMID 19836903.

[37] Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA (November 2009). "Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor". Bipolar Disorders. 11 (7): 726–34. doi:10.1111/j.1399-5618.2009.00757.x. PMID 19839997.

[38] Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA (January 2010). "The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder". Expert Review of Neurotherapeutics. 10 (1): 59–76. doi:10.1586/ern.09.144. PMID 20021321.

[39] Hope S, Ueland T, Steen NE, Dieset I, Lorentzen S, Berg AO, Agartz I, Aukrust P, Andreassen OA (April 2013). "Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder". Schizophrenia Research. 145 (1–3): 36–42. doi:10.1016/j.schres.2012.12.023. PMID 23403415.

[40] "Genome-wide association study identifies five new schizophrenia loci". Nature Genetics. 43 (10): 969–76. September 2011. doi:10.1038/ng.940. PMC 3303194. PMID 21926974.

[41] Trépanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP (August 2016). "Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review". Molecular Psychiatry. 21 (8): 1009–26. doi:10.1038/mp.2016.90. PMC 4960446. PMID 27271499.

[42] Emiliani FE, Sedlak TW, Sawa A (May 2014). "Oxidative stress and schizophrenia: recent breakthroughs from an old story". Current Opinion in Psychiatry. 27 (3): 185–90. doi:10.1097/YCO.0000000000000054. PMC 4054867. PMID 24613987.

[43] Hardingham GE, Do KQ (February 2016). "Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis". Nature Reviews. Neuroscience. 17 (2): 125–34. doi:10.1038/nrn.2015.19. PMID 26763624.

[44] Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, et al. (March 2017). "High-resolution copy number variation analysis of schizophrenia in Japan". Molecular Psychiatry. 22 (3): 430–440. doi:10.1038/mp.2016.88. PMID 27240532.

[45] Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, et al. (July 2015). "Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients". Molecular Psychiatry. 20 (7): 827–38. doi:10.1038/mp.2014.88. PMID 25155877.

[46] Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ (March 2013). "Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine". Biological Psychiatry. 73 (6): 574–82. doi:10.1016/j.biopsych.2012.09.020. PMID 23140664.

[47] Harrison PJ (December 2000). "Postmortem studies in schizophrenia". Dialogues in Clinical Neuroscience. 2 (4): 349–57. PMC 3181616. PMID 22033474.

[48] Glausier JR, Lewis DA (October 2013). "Dendritic spine pathology in schizophrenia". Neuroscience. 251: 90–107. doi:10.1016/j.neuroscience.2012.04.044. PMC 3413758. PMID 22546337.

[Flashman04-49] Flashman LA, Green MF (March 2004). "Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment". The Psychiatric Clinics of North America. 27 (1): 1–18, vii. doi:10.1016/S0193-953X(03)00105-9. PMID 15062627.

[50] van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, et al. (April 2016). "Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium". Molecular Psychiatry. 21 (4): 547–53. doi:10.1038/mp.2015.63. PMC 4668237. PMID 26033243.

[Steen2006-51] Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA (June 2006). "Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies". The British Journal of Psychiatry. 188: 510–8. doi:10.1192/bjp.188.6.510. PMID 16738340.

[Lieberman08-52] Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG (September 2008). "Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection". Pharmacological Reviews. 60 (3): 358–403. doi:10.1124/pr.107.00107. PMID 18922967.

[DeLisi08-53] DeLisi LE (March 2008). "The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia". Schizophrenia Bulletin. 34 (2): 312–21. doi:10.1093/schbul/sbm164. PMC 2632405. PMID 18263882.

[Jung2010-54] Jung WH, Jang JH, Byun MS, An SK, Kwon JS (December 2010). "Structural brain alterations in individuals at ultra-high risk for psychosis: a review of magnetic resonance imaging studies and future directions". Journal of Korean Medical Science. 25 (12): 1700–9. doi:10.3346/jkms.2010.25.12.1700. PMC 2995221. PMID 21165282.

[Shenton2001-55] Shenton ME, Dickey CC, Frumin M, McCarley RW (April 2001). "A review of MRI findings in schizophrenia". Schizophrenia Research. 49 (1–2): 1–52. doi:10.1016/s0920-9964(01)00163-3. PMC 2812015. PMID 11343862.

[Honea05-56] Honea R, Crow TJ, Passingham D, Mackay CE (December 2005). "Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies". The American Journal of Psychiatry. 162 (12): 2233–45. doi:10.1176/appi.ajp.162.12.2233. PMID 16330585.

[Vita06-57] Vita A, De Peri L, Silenzi C, Dieci M (February 2006). "Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies". Schizophrenia Research. 82 (1): 75–88. doi:10.1016/j.schres.2005.11.004. PMID 16377156.

[Kuperberg_et_al.,_2003-58] Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B (September 2003). "Regionally localized thinning of the cerebral cortex in schizophrenia". Archives of General Psychiatry. 60 (9): 878–88. doi:10.1001/archpsyc.60.9.878. PMID 12963669.

[Rimol_et_al.,_2010-59] Rimol LM, Hartberg CB, Nesvåg R, Fennema-Notestine C, Hagler DJ, Pung CJ, Jennings RG, Haukvik UK, Lange E, Nakstad PH, Melle I, Andreassen OA, Dale AM, Agartz I (July 2010). "Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder". Biological Psychiatry. 68 (1): 41–50. doi:10.1016/j.biopsych.2010.03.036. PMID 20609836.

[Rimol_et_al.,_2012-60] Rimol LM, Nesvåg R, Hagler DJ, Bergmann O, Fennema-Notestine C, Hartberg CB, Haukvik UK, Lange E, Pung CJ, Server A, Melle I, Andreassen OA, Agartz I, Dale AM (March 2012). "Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder". Biological Psychiatry. 71 (6): 552–60. doi:10.1016/j.biopsych.2011.11.026. PMID 22281121.

[Adams&Victor-61] Ropper AH, Brown RH. Adams and Victor's Principles of Neurology. 8th ed. New York: McGraw-Hill; 2005. ISBN 0-07-141620-X. p. 1324.

[62] Fitzsimmons J, Kubicki M, Shenton ME (March 2013). "Review of functional and anatomical brain connectivity findings in schizophrenia". Current Opinion in Psychiatry. 26 (2): 172–87. doi:10.1097/YCO.0b013e32835d9e6a. PMID 23324948.

[Ellison-Wright2009-63] Ellison-Wright I, Bullmore E (March 2009). "Meta-analysis of diffusion tensor imaging studies in schizophrenia". Schizophrenia Research. 108 (1–3): 3–10. doi:10.1016/j.schres.2008.11.021. PMID 19128945.

[64] Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC (August 2009). "Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia". Archives of General Psychiatry. 66 (8): 811–22. doi:10.1001/archgenpsychiatry.2009.91. PMC 2888482. PMID 19652121.

[65] Taylor SF, Kang J, Brege IS, Tso IF, Hosanagar A, Johnson TD (January 2012). "Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia". Biological Psychiatry. 71 (2): 136–45. doi:10.1016/j.biopsych.2011.09.007. PMC 3237865. PMID 21993193.

[66] Li H, Chan RC, McAlonan GM, Gong QY (September 2010). "Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data". Schizophrenia Bulletin. 36 (5): 1029–39. doi:10.1093/schbul/sbn190. PMC 2930350. PMID 19336391.

[67] Kühn S, Gallinat J (June 2012). "Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia". Schizophrenia Bulletin. 38 (4): 779–86. doi:10.1093/schbul/sbq152. PMC 3406531. PMID 21177743.

[68] Zmigrod L, Garrison JR, Carr J, Simons JS (October 2016). "The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies". Neuroscience and Biobehavioral Reviews. 69: 113–23. doi:10.1016/j.neubiorev.2016.05.037. PMID 27473935.

[Meyer-Lindenberg2002-69] Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF (March 2002). "Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia". Nature Neuroscience. 5 (3): 267–71. doi:10.1038/nn804. PMID 11865311.

[70] Steen RG, Hamer RM, Lieberman JA (November 2005). "Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis". Neuropsychopharmacology. 30 (11): 1949–62. doi:10.1038/sj.npp.1300850. PMID 16123764.

[71] Davis, Kenneth L.; American College of Neuropsychopharmacology (2002). "Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia". Neuropsychopharmacology: The Fifth Generation of Progress : an Official Publication of the American College of Neuropsychopharmacology,. Lippincott Williams & Wilkins. pp. 731–743. ISBN 9780781728379. {{cite book}}: Unknown parameter |name-list-format= ignored (|name-list-style= suggested) (help)

[72] Fusar-Poli P, Meyer-Lindenberg A (January 2013). "Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies". Schizophrenia Bulletin. 39 (1): 33–42. doi:10.1093/schbul/sbr180. PMC 3523905. PMID 22282454.

[73] Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A (January 2017). "Pathway-Specific Dopamine Abnormalities in Schizophrenia". Biological Psychiatry. 81 (1): 31–42. doi:10.1016/j.biopsych.2016.03.2104. PMC 5177794. PMID 27206569.

[1]

[2]

[3]

[4]

[5]

[6]

[7]

[8]

[9]

[10]

[11]

[12]

[13]

[14]

[15]

[16]

[17]

[18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30]

[31]

[32]

[33]

[34]

[35]

[36]

[37]

[38]

[39]

[40]

[41]

[42]

[43]

[44]

[45]

[46]

[47]

[48]

[49]

[50]

[51]

[52]

[53]

[54]

[55]

[56]

[57]

[58]

[59]

[60]

[61]

[62]

[63]

[64]

[65]

[66]

[67]

[68]

[69]

[70]

[71]

[72]

[73]

@@ Line 1: / Line 1: @@
 [[File:Artistic view of how the world feels like with schizophrenia - journal.pmed.0020146.g001.jpg|thumb|Artistic view of what the world feels like with schizophrenia]]
-The underlying '''mechanisms of schizophrenia''', a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and [[schizophrenia]],<ref name=Lancet09>{{vcite journal |author=[[Jim van Os|van Os J]], Kapur S |title=Schizophrenia |journal=Lancet |volume=374 |issue=9690 |pages=635–45 |year=2009 |month=August |pmid=19700006 |doi=10.1016/S0140-6736(09)60995-8 }}</ref> including the [[Dopamine hypothesis of schizophrenia|dopamine hypothesis]] and the [[glutamate hypothesis of schizophrenia|glutamate hypothesis]]. These theories are separate from the [[causes of schizophrenia]], which deal with the factors that lead to schizophrenia. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease.
+The underlying '''mechanisms of schizophrenia''', a mental disorder characterized by a disintegration of the processes of thinking and of emotional responsiveness, are complex. A number of theories attempt to explain the link between altered brain function and [[schizophrenia]],<ref name=Lancet09>{{cite journal | vauthors = van Os J, Kapur S | title = Schizophrenia | journal = Lancet | volume = 374 | issue = 9690 | pages = 635–45 | date = August 2009 | pmid = 19700006 | doi = 10.1016/S0140-6736(09)60995-8 }}</ref> including the [[Dopamine hypothesis of schizophrenia|dopamine hypothesis]] and the [[glutamate hypothesis of schizophrenia|glutamate hypothesis]]. These theories are separate from the [[causes of schizophrenia]], which deal with the factors that lead to schizophrenia. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease.
 == Pathophysiology ==
-The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.<ref>{{Cite journal | last1 = Insel | first1 = T. R. | title = Rethinking schizophrenia | journal = Nature | volume = 468 | pages = 187–193 | year = 2010 | doi = 10.1038/nature09552| pmid = 21068826|bibcode = 2010Natur.468..187I | issue=7321}}</ref><ref>{{Cite journal | pmid = 24695332| year = 2014| author1 = Elert| first1 = E| title = Aetiology: Searching for schizophrenia's roots| journal = Nature| volume = 508| issue = 7494| pages = S2–3| doi = 10.1038/508S2a}}</ref><ref>{{Cite journal| last1 = Van Os | first1 = J.| last2 = Kapur | first2 = S.| title = Schizophrenia| journal = The Lancet| volume = 374| pages = 635–645| issue= 9690| pmid = 19700006| year = 2009| doi = 10.1016/S0140-6736(09)60995-8}}</ref> More recent theories center around specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.<ref name="pmid22251963">{{Cite journal | pmid = 22251963| year = 2012| author1 = Marín| first1 = O| title = Interneuron dysfunction in psychiatric disorders| journal = Nature Reviews Neuroscience| volume = 13| issue = 2| pages = 107–20| doi = 10.1038/nrn3155}}</ref><ref name="pmid25863358">{{Cite journal | pmid = 25863358| year = 2015| author1 = Gonzalez-Burgos| first1 = G| title = Alterations in Cortical Network Oscillations and Parvalbumin Neurons in Schizophrenia| journal = Biological Psychiatry| volume = 77| issue = 12| pages = 1031–40| last2 = Cho| first2 = R. Y.| last3 = Lewis| first3 = D. A.| doi = 10.1016/j.biopsych.2015.03.010| pmc=4444373}}</ref><ref name="pmid25850619">{{Cite journal | pmid = 25850619| year = 2015| author1 = Pittman-Polletta| first1 = B. R.| title = Brain Rhythms Connect Impaired Inhibition to Altered Cognition in Schizophrenia| journal = Biological Psychiatry| volume = 77| issue = 12| pages = 1020–30| last2 = Kocsis| first2 = B| last3 = Vijayan| first3 = S| last4 = Whittington| first4 = M. A.| last5 = Kopell| first5 = N. J.| doi = 10.1016/j.biopsych.2015.02.005| pmc=4444389}}</ref><ref>{{Cite journal | pmid = 24247023| pmc = 3896922| year = 2014| author1 = Feigenson| first1 = K. A.| title = Inflammation and the two-hit hypothesis of schizophrenia| journal = Neuroscience & Biobehavioral Reviews| volume = 38| pages = 72–93| last2 = Kusnecov| first2 = A. W.| last3 = Silverstein| first3 = S. M.| doi = 10.1016/j.neubiorev.2013.11.006}}</ref><ref name="pmid25000913">{{Cite journal | pmid = 25000913| pmc = 4282982| year = 2014| author1 = Steullet| first1 = P| title = Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology?| journal = Schizophrenia Research| volume = 176| issue = 1| pages = 41–51| last2 = Cabungcal| first2 = J. H.| last3 = Monin| first3 = A| last4 = Dwir| first4 = D| last5 = O'Donnell| first5 = P| last6 = Cuenod| first6 = M| last7 = Do| first7 = K. Q.| doi = 10.1016/j.schres.2014.06.021}}</ref><ref name="pmid26092265">{{cite journal|pmid= 26092265|year= 2015|author1= Leza|first1= J. C.|title= Inflammation in schizophrenia: A question of balance|journal= Neuroscience & Biobehavioral Reviews|volume= 55|pages= 612–26|last2= García-Bueno|first2= B|last3= Bioque|first3= M|last4= Arango|first4= C|last5= Parellada|first5= M|last6= Do|first6= K|last7= O'Donnell|first7= P|last8= Bernardo|first8= M|doi= 10.1016/j.neubiorev.2015.05.014}}</ref>
+The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis.<ref>{{cite journal | vauthors = Insel TR | title = Rethinking schizophrenia | journal = Nature | volume = 468 | issue = 7321 | pages = 187–93 | date = November 2010 | pmid = 21068826 | doi = 10.1038/nature09552 | bibcode = 2010Natur.468..187I }}</ref><ref>{{cite journal | vauthors = Elert E | title = Aetiology: Searching for schizophrenia's roots | journal = Nature | volume = 508 | issue = 7494 | pages = S2-3 | date = April 2014 | pmid = 24695332 | doi = 10.1038/508S2a }}</ref><ref>{{cite journal | vauthors = van Os J, Kapur S | title = Schizophrenia | journal = Lancet | volume = 374 | issue = 9690 | pages = 635–45 | date = August 2009 | pmid = 19700006 | doi = 10.1016/S0140-6736(09)60995-8 }}</ref> More recent theories center around specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.<ref name="pmid22251963">{{cite journal | vauthors = Marín O | title = Interneuron dysfunction in psychiatric disorders | journal = Nature Reviews. Neuroscience | volume = 13 | issue = 2 | pages = 107–20 | date = January 2012 | pmid = 22251963 | doi = 10.1038/nrn3155 }}</ref><ref name="pmid25863358">{{cite journal | vauthors = Gonzalez-Burgos G, Cho RY, Lewis DA | title = Alterations in cortical network oscillations and parvalbumin neurons in schizophrenia | journal = Biological Psychiatry | volume = 77 | issue = 12 | pages = 1031–40 | date = June 2015 | pmid = 25863358 | pmc = 4444373 | doi = 10.1016/j.biopsych.2015.03.010 }}</ref><ref name="pmid25850619">{{cite journal | vauthors = Pittman-Polletta BR, Kocsis B, Vijayan S, Whittington MA, Kopell NJ | title = Brain rhythms connect impaired inhibition to altered cognition in schizophrenia | journal = Biological Psychiatry | volume = 77 | issue = 12 | pages = 1020–30 | date = June 2015 | pmid = 25850619 | pmc = 4444389 | doi = 10.1016/j.biopsych.2015.02.005 }}</ref><ref>{{cite journal | vauthors = Feigenson KA, Kusnecov AW, Silverstein SM | title = Inflammation and the two-hit hypothesis of schizophrenia | journal = Neuroscience and Biobehavioral Reviews | volume = 38 | pages = 72–93 | date = January 2014 | pmid = 24247023 | pmc = 3896922 | doi = 10.1016/j.neubiorev.2013.11.006 }}</ref><ref name="pmid25000913">{{cite journal | vauthors = Steullet P, Cabungcal JH, Monin A, Dwir D, O'Donnell P, Cuenod M, Do KQ | title = Redox dysregulation, neuroinflammation, and NMDA receptor hypofunction: A "central hub" in schizophrenia pathophysiology? | journal = Schizophrenia Research | volume = 176 | issue = 1 | pages = 41–51 | date = September 2016 | pmid = 25000913 | pmc = 4282982 | doi = 10.1016/j.schres.2014.06.021 }}</ref><ref name="pmid26092265">{{cite journal | vauthors = Leza JC, García-Bueno B, Bioque M, Arango C, Parellada M, Do K, O'Donnell P, Bernardo M | title = Inflammation in schizophrenia: A question of balance | journal = Neuroscience and Biobehavioral Reviews | volume = 55 | pages = 612–26 | date = August 2015 | pmid = 26092265 | doi = 10.1016/j.neubiorev.2015.05.014 }}</ref>
 === Dopamine dysfunction ===
@@ Line 10: / Line 10: @@
 The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased striatal availability of [[Dopamine D2 receptor|D<sub>2</sub>]]/[[Dopamine D3 receptor|D<sub>3</sub>]] receptors in the striatum, as well as studies finding elevated CSF levels of dopamine metabolites.  Subsequently, most antipsychotics were found to have affinity for D2 receptors.  More modern investigations of the hypothesis suggest a link between striatal dopamine synthesis and positive symptoms, as well as increased and decreased dopamine transmission in subcortical and cortical regions respectively.
-A meta analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of [[dopamine transporter]]s or dopamine D<sub>2</sub>/D<sub>3</sub> receptors.  Both studies using radio labeled [[L-DOPA]], an indicator of dopamine synthesis, and studies using [[amphetamine]] release challenges observed significant differences between schizophrenics and control.  These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively.  These findings were localized to the striatum, and were noted to be limited by the quality of studies used.<ref>{{cite journal|last1=Howes|first1=OD|last2=Kambeitz|first2=J|last3=Kim|first3=E|last4=Stahl|first4=D|last5=Slifstein|first5=M|last6=Abi-Dargham|first6=A|last7=Kapur|first7=S|title=The nature of dopamine dysfunction in schizophrenia and what this means for treatment.|journal=Archives of General Psychiatry|date=August 2012|volume=69|issue=8|pages=776–86|doi=10.1001/archgenpsychiatry.2012.169|pmid=22474070|pmc=3730746}}</ref>  A large degree of inconsistency has been observed in D<sub>2</sub>/D<sub>3</sub> receptor binding, although a small but nonsignificant reduction in thalamic availability has been found.<ref>{{cite journal|last1=Kambeitz|first1=J|last2=Abi-Dargham|first2=A|last3=Kapur|first3=S|last4=Howes|first4=OD|title=Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies.|journal=The British Journal of Psychiatry|date=June 2014|volume=204|issue=6|pages=420–9|doi=10.1192/bjp.bp.113.132308|pmid=25029687}}</ref>  The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia.<ref>{{cite journal|last1=Weinstein|first1=JJ|last2=Chohan|first2=MO|last3=Slifstein|first3=M|last4=Kegeles|first4=LS|last5=Moore|first5=H|last6=Abi-Dargham|first6=A|title=Pathway-Specific Dopamine Abnormalities in Schizophrenia.|journal=Biological Psychiatry|date=1 January 2017|volume=81|issue=1|pages=31–42|doi=10.1016/j.biopsych.2016.03.2104|pmid=27206569|pmc=5177794}}</ref>
+A meta analysis of molecular imaging studies observed increased presynaptic indicators of dopamine function, but no difference in the availability of [[dopamine transporter]]s or dopamine D<sub>2</sub>/D<sub>3</sub> receptors.  Both studies using radio labeled [[L-DOPA]], an indicator of dopamine synthesis, and studies using [[amphetamine]] release challenges observed significant differences between schizophrenics and control.  These findings were interpreted as increased synthesis of dopamine, and increased release of dopamine respectively.  These findings were localized to the striatum, and were noted to be limited by the quality of studies used.<ref>{{cite journal | vauthors = Howes OD, Kambeitz J, Kim E, Stahl D, Slifstein M, Abi-Dargham A, Kapur S | title = The nature of dopamine dysfunction in schizophrenia and what this means for treatment | journal = Archives of General Psychiatry | volume = 69 | issue = 8 | pages = 776–86 | date = August 2012 | pmid = 22474070 | pmc = 3730746 | doi = 10.1001/archgenpsychiatry.2012.169 }}</ref>  A large degree of inconsistency has been observed in D<sub>2</sub>/D<sub>3</sub> receptor binding, although a small but nonsignificant reduction in thalamic availability has been found.<ref>{{cite journal | vauthors = Kambeitz J, Abi-Dargham A, Kapur S, Howes OD | title = Alterations in cortical and extrastriatal subcortical dopamine function in schizophrenia: systematic review and meta-analysis of imaging studies | journal = The British Journal of Psychiatry | volume = 204 | issue = 6 | pages = 420–9 | date = June 2014 | pmid = 25029687 | doi = 10.1192/bjp.bp.113.132308 }}</ref>  The inconsistent findings with respect to receptor expression has been emphasized as not precluding dysfunction in dopamine receptors, as many factors such as regional heterogeneity and medication status may lead to variable findings. When combined with findings in presynaptic dopamine function, most evidence suggests dysregulation of dopamine in schizophrenia.<ref>{{cite journal | vauthors = Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A | title = Pathway-Specific Dopamine Abnormalities in Schizophrenia | journal = Biological Psychiatry | volume = 81 | issue = 1 | pages = 31–42 | date = January 2017 | pmid = 27206569 | pmc = 5177794 | doi = 10.1016/j.biopsych.2016.03.2104 }}</ref>
-Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations,<ref>{{cite journal|pmid= 24904170|pmc= 4349506|year= 2014|author1= Chun|first1= S|title= Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models|journal= Science|volume= 344|issue= 6188|pages= 1178–82|last2= Westmoreland|first2= J. J.|last3= Bayazitov|first3= I. T.|last4= Eddins|first4= D|last5= Pani|first5= A. K.|last6= Smeyne|first6= R. J.|last7= Yu|first7= J|last8= Blundon|first8= J. A.|last9= Zakharenko|first9= S. S.|doi= 10.1126/science.1253895}}</ref> while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions.<ref>{{cite journal|pmid= 12505794|year= 2003|author1= Kapur|first1= S|title= Psychosis as a state of aberrant salience: A framework linking biology, phenomenology, and pharmacology in schizophrenia|journal= The American Journal of Psychiatry|volume= 160|issue= 1|pages= 13–23|doi= 10.1176/appi.ajp.160.1.13}}</ref> Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex.<ref>{{cite journal|last1=Takahashi|first1=H|last2=Higuchi|first2=M|last3=Suhara|first3=T|title=The role of extrastriatal dopamine D2 receptors in schizophrenia.|journal=Biological Psychiatry|date=15 May 2006|volume=59|issue=10|pages=919–28|doi=10.1016/j.biopsych.2006.01.022|pmid=16682269}}</ref>
+Exactly how dopamine dysregulation can contribute to schizophrenia symptoms remains unclear. Some studies have suggested that disruption of the auditory thalamocortical projections give rise to hallucinations,<ref>{{cite journal | vauthors = Chun S, Westmoreland JJ, Bayazitov IT, Eddins D, Pani AK, Smeyne RJ, Yu J, Blundon JA, Zakharenko SS | title = Specific disruption of thalamic inputs to the auditory cortex in schizophrenia models | journal = Science | volume = 344 | issue = 6188 | pages = 1178–82 | date = June 2014 | pmid = 24904170 | pmc = 4349506 | doi = 10.1126/science.1253895 }}</ref> while dysregulated corticostriatal circuitry and reward circuitry in the form of aberrant salience can give rise to delusions.<ref>{{cite journal | vauthors = Kapur S | title = Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia | journal = The American Journal of Psychiatry | volume = 160 | issue = 1 | pages = 13–23 | date = January 2003 | pmid = 12505794 | doi = 10.1176/appi.ajp.160.1.13 }}</ref> Decreased inhibitory dopamine signals in the thalamus have been hypothesized to result in reduced sensory gating, and excessive activity in excitatory inputs into the cortex.<ref>{{cite journal | vauthors = Takahashi H, Higuchi M, Suhara T | title = The role of extrastriatal dopamine D2 receptors in schizophrenia | journal = Biological Psychiatry | volume = 59 | issue = 10 | pages = 919–28 | date = May 2006 | pmid = 16682269 | doi = 10.1016/j.biopsych.2006.01.022 }}</ref>
-One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D<sub>1</sub> and [[NMDA]] receptor stimulation.  This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.<ref>{{cite journal|last1=Corlett|first1=PR|last2=Taylor|first2=JR|last3=Wang|first3=XJ|last4=Fletcher|first4=PC|last5=Krystal|first5=JH|title=Toward a neurobiology of delusions.|journal=Progress in neurobiology|date=November 2010|volume=92|issue=3|pages=345–69|doi=10.1016/j.pneurobio.2010.06.007|pmid=20558235|pmc=3676875}}</ref>
+One hypothesis linking delusions in schizophrenia to dopamine suggests that unstable representation of expectations in prefrontal neurons occurs in psychotic states due to insufficient D<sub>1</sub> and [[NMDA]] receptor stimulation.  This, when combined with hyperactivity of expectations to modification by salient stimuli is thought to lead to improper formation of beliefs.<ref>{{cite journal | vauthors = Corlett PR, Taylor JR, Wang XJ, Fletcher PC, Krystal JH | title = Toward a neurobiology of delusions | journal = Progress in Neurobiology | volume = 92 | issue = 3 | pages = 345–69 | date = November 2010 | pmid = 20558235 | pmc = 3676875 | doi = 10.1016/j.pneurobio.2010.06.007 }}</ref>
 === Glutamate abnormalities ===
 {{Main|Glutamate hypothesis of schizophrenia}}
-Beside the dopamine hypothesis, interest has also focused on the neurotransmitter [[glutamate]] and the reduced function of the [[NMDA receptor|NMDA glutamate receptor]] in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of [[glutamate receptor]]s found in postmortem brains of people previously diagnosed with schizophrenia<ref name="Konradi2003">{{vcite journal |author=Konradi C, Heckers S |title=Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment |journal=Pharmacol. Ther. |volume=97 |issue=2 |pages=153–79 |year=2003 |month=February |pmid=12559388 |doi=10.1016/S0163-7258(02)00328-5}}</ref> and the discovery that glutamate blocking drugs such as [[phencyclidine]] and [[ketamine]] can mimic the symptoms and cognitive problems associated with the condition.<ref name="Lahti2001">{{vcite journal |author=Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA |title=Effects of ketamine in normal and schizophrenic volunteers |journal=Neuropsychopharmacology |volume=25 |issue=4 |pages=455–67 |year=2001 |month=October |pmid=11557159 |doi=10.1016/S0893-133X(01)00243-3}}</ref>
+Beside the dopamine hypothesis, interest has also focused on the neurotransmitter [[glutamate]] and the reduced function of the [[NMDA receptor|NMDA glutamate receptor]] in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of [[glutamate receptor]]s found in postmortem brains of people previously diagnosed with schizophrenia<ref name="Konradi2003">{{cite journal | vauthors = Konradi C, Heckers S | title = Molecular aspects of glutamate dysregulation: implications for schizophrenia and its treatment | journal = Pharmacology & Therapeutics | volume = 97 | issue = 2 | pages = 153–79 | date = February 2003 | pmid = 12559388 | doi = 10.1016/S0163-7258(02)00328-5 }}</ref> and the discovery that glutamate blocking drugs such as [[phencyclidine]] and [[ketamine]] can mimic the symptoms and cognitive problems associated with the condition.<ref name="Lahti2001">{{cite journal | vauthors = Lahti AC, Weiler MA, Tamara Michaelidis BA, Parwani A, Tamminga CA | title = Effects of ketamine in normal and schizophrenic volunteers | journal = Neuropsychopharmacology | volume = 25 | issue = 4 | pages = 455–67 | date = October 2001 | pmid = 11557159 | doi = 10.1016/S0893-133X(01)00243-3 }}</ref>
-The fact that reduced glutamate function is linked to poor performance on tests requiring [[frontal lobe]] and [[hippocampus|hippocampal]] function and that glutamate can affect [[dopamine]] function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.<ref name="Coyle2003">{{vcite journal |author=Coyle JT, Tsai G, Goff D |title=Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia |journal=Annals of the New York Academy of Sciences |volume=1003 |issue= |pages=318–27 |year=2003 |month=November |pmid=14684455 |doi=10.1196/annals.1300.020}}</ref> Positive symptoms fail however to respond to glutamatergic medication.<ref name="Touminen2005">{{vcite journal |author=Tuominen HJ, Tiihonen J, Wahlbeck K |title=Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis |journal=Schizophr. Res. |volume=72 |issue=2-3 |pages=225–34 |year=2005 |month=January |pmid=15560967 |doi=10.1016/j.schres.2004.05.005 }}</ref>
+The fact that reduced glutamate function is linked to poor performance on tests requiring [[frontal lobe]] and [[hippocampus|hippocampal]] function and that glutamate can affect [[dopamine]] function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia.<ref name="Coyle2003">{{cite journal | vauthors = Coyle JT, Tsai G, Goff D | title = Converging evidence of NMDA receptor hypofunction in the pathophysiology of schizophrenia | journal = Annals of the New York Academy of Sciences | volume = 1003 | issue =  | pages = 318–27 | date = November 2003 | pmid = 14684455 | doi = 10.1196/annals.1300.020 }}</ref> Positive symptoms fail however to respond to glutamatergic medication.<ref name="Touminen2005">{{cite journal | vauthors = Tuominen HJ, Tiihonen J, Wahlbeck K | title = Glutamatergic drugs for schizophrenia: a systematic review and meta-analysis | journal = Schizophrenia Research | volume = 72 | issue = 2-3 | pages = 225–34 | date = January 2005 | pmid = 15560967 | doi = 10.1016/j.schres.2004.05.005 }}</ref>
-Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from patients with schizophrenia.<ref>{{cite journal|pmid= 23070074|pmc= 3807670|year= 2013|author1= Weickert|first1= C. S.|title= Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia|journal= Molecular Psychiatry|volume= 18|issue= 11|pages= 1185–92|last2= Fung|first2= S. J.|last3= Catts|first3= V. S.|last4= Schofield|first4= P. R.|last5= Allen|first5= K. M.|last6= Moore|first6= L. T.|last7= Newell|first7= K. A.|last8= Pellen|first8= D|last9= Huang|first9= X. F.|last10= Catts|first10= S. V.|last11= Weickert|first11= T. W.|doi= 10.1038/mp.2012.137}}</ref>  In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex of schizophrenic subjects post-mortem.  Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2.<ref>{{cite journal|last1=Catts|first1=Vibeke S.|last2=Lai|first2=Yan Ling|last3=Weickert|first3=Cyndi Shannon|last4=Weickert|first4=Thomas W.|last5=Catts|first5=Stanley V.|title=A quantitative review of the postmortem evidence for decreased cortical N-methyl-d-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits?|journal=Biological Psychology|date=1 April 2016|volume=116|pages=57–67|doi=10.1016/j.biopsycho.2015.10.013|url=http://www.sciencedirect.com/science/article/pii/S0301051115300740}}</ref>
+Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from patients with schizophrenia.<ref>{{cite journal | vauthors = Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW | title = Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia | journal = Molecular Psychiatry | volume = 18 | issue = 11 | pages = 1185–92 | date = November 2013 | pmid = 23070074 | pmc = 3807670 | doi = 10.1038/mp.2012.137 }}</ref>  In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex of schizophrenic subjects post-mortem.  Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2.<ref>{{cite journal | vauthors = Catts VS, Lai YL, Weickert CS, Weickert TW, Catts SV | title = A quantitative review of the postmortem evidence for decreased cortical N-methyl-D-aspartate receptor expression levels in schizophrenia: How can we link molecular abnormalities to mismatch negativity deficits? | journal = Biological Psychology | volume = 116 | pages = 57–67 | date = April 2016 | pmid = 26549579 | doi = 10.1016/j.biopsycho.2015.10.013 }}</ref>
-The large genome-wide association study mentioned above has supported glutamate abnormalities for schizophrenia, reporting several mutations in genes related to glutamatergic neurotransmission, such as [[GRIN2A]], [[GRIA1]], [[SRR (gene)|SRR]], and [[Metabotropic glutamate receptor 3|GRM3]].<ref name=":0">{{cite journal|pmid= 25056061|pmc= 4112379|year= 2014|author1= Schizophrenia Working Group of the Psychiatric Genomics Consortium|title= Biological insights from 108 schizophrenia-associated genetic loci|journal= Nature|volume= 511|issue= 7510|pages= 421–7|doi= 10.1038/nature13595|last2= Neale|first2= Benjamin M.|last3= Corvin|first3= Aiden|last4= Walters|first4= James T. R.|last5= Farh|first5= Kai-How|last6= Holmans|first6= Peter A.|last7= Lee|first7= Phil|last8= Bulik-Sullivan|first8= Brendan|last9= Collier|first9= David A.|last10= Huang|first10= Hailiang|last11= Pers|first11= Tune H.|last12= Agartz|first12= Ingrid|last13= Agerbo|first13= Esben|last14= Albus|first14= Margot|last15= Alexander|first15= Madeline|last16= Amin|first16= Farooq|last17= Bacanu|first17= Silviu A.|last18= Begemann|first18= Martin|last19= Belliveau Jr|first19= Richard A.|last20= Bene|first20= Judit|last21= Bergen|first21= Sarah E.|last22= Bevilacqua|first22= Elizabeth|last23= Bigdeli|first23= Tim B.|last24= Black|first24= Donald W.|last25= Bruggeman|first25= Richard|last26= Buccola|first26= Nancy G.|last27= Buckner|first27= Randy L.|last28= Byerley|first28= William|last29= Cahn|first29= Wiepke|last30= Cai|first30= Guiqing|display-authors= 29}}</ref>
+The large genome-wide association study mentioned above has supported glutamate abnormalities for schizophrenia, reporting several mutations in genes related to glutamatergic neurotransmission, such as [[GRIN2A]], [[GRIA1]], [[SRR (gene)|SRR]], and [[Metabotropic glutamate receptor 3|GRM3]].<ref name=":0">{{cite journal | vauthors =  | title = Biological insights from 108 schizophrenia-associated genetic loci | journal = Nature | volume = 511 | issue = 7510 | pages = 421–7 | date = July 2014 | pmid = 25056061 | pmc = 4112379 | doi = 10.1038/nature13595 }}</ref>
 === Interneuron dysfunction ===
 A novel hypothesis concerning the pathophysiology of schizophrenia, one that closely relates to the glutamate hypothesis, is one that evolves around dysfunction of [[interneurons]] in the brain.<ref name="pmid22251963"/><ref name="pmid25863358"/><ref name="pmid25850619"/> Interneurons in the brain are [[GABA]]ergic and local, and function mainly through the inhibition of other cells. One type of interneuron, the fast-spiking, [[parvalbumin]]-positive interneuron, has been suggested to play a key role in schizophrenia pathophysiology.
-Early studies have identified decreases in [[Glutamate decarboxylase|GAD67]] mRNA and protein in post-mortem brains from schizophrenia patients compared to controls.<ref>{{Cite journal | pmid = 20556669| pmc = 2919752| year = 2010| author1 = Gonzalez-Burgos| first1 = G| title = Alterations of cortical GABA neurons and network oscillations in schizophrenia| journal = Current Psychiatry Reports| volume = 12| issue = 4| pages = 335–44| last2 = Hashimoto| first2 = T| last3 = Lewis| first3 = D. A.| doi = 10.1007/s11920-010-0124-8}}</ref> These reductions were found in only a subset of cortical interneurons. Furthermore, GAD67 mRNA was completely undetectable in a subset of interneurons also expressing [[parvalbumin]]. Levels of parvalbumin protein and mRNA were also found to be lower in patient brains in various regions in the brain. Actual numbers of parvalbumin interneurons have been found to be unchanged in these studies, however, except for a single study showing a decrease in parvalbumin interneurons in the hippocampus.<ref>{{cite journal|pmid= 21745723|pmc= 3159834|year= 2011|author1= Konradi|first1= C|title= Hippocampal interneurons are abnormal in schizophrenia|journal= Schizophrenia Research|volume= 131|issue= 1–3|pages= 165–73|last2= Yang|first2= C. K.|last3= Zimmerman|first3= E. I.|last4= Lohmann|first4= K. M.|last5= Gresch|first5= P|last6= Pantazopoulos|first6= H|last7= Berretta|first7= S|last8= Heckers|first8= S|doi= 10.1016/j.schres.2011.06.007}}</ref> Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67.<ref>{{cite journal|last1=Chung|first1=DW|last2=Fish|first2=KN|last3=Lewis|first3=DA|title=Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia.|journal=The American Journal of Psychiatry|date=1 November 2016|volume=173|issue=11|pages=1131–1139|pmid=27444795|doi=10.1176/appi.ajp.2016.16010025|pmc=5089927}}</ref>  Together, this suggests that parvalbumin interneurons are somehow specifically affected in the disease.
+Early studies have identified decreases in [[Glutamate decarboxylase|GAD67]] mRNA and protein in post-mortem brains from schizophrenia patients compared to controls.<ref>{{cite journal | vauthors = Gonzalez-Burgos G, Hashimoto T, Lewis DA | title = Alterations of cortical GABA neurons and network oscillations in schizophrenia | journal = Current Psychiatry Reports | volume = 12 | issue = 4 | pages = 335–44 | date = August 2010 | pmid = 20556669 | pmc = 2919752 | doi = 10.1007/s11920-010-0124-8 }}</ref> These reductions were found in only a subset of cortical interneurons. Furthermore, GAD67 mRNA was completely undetectable in a subset of interneurons also expressing [[parvalbumin]]. Levels of parvalbumin protein and mRNA were also found to be lower in patient brains in various regions in the brain. Actual numbers of parvalbumin interneurons have been found to be unchanged in these studies, however, except for a single study showing a decrease in parvalbumin interneurons in the hippocampus.<ref>{{cite journal | vauthors = Konradi C, Yang CK, Zimmerman EI, Lohmann KM, Gresch P, Pantazopoulos H, Berretta S, Heckers S | title = Hippocampal interneurons are abnormal in schizophrenia | journal = Schizophrenia Research | volume = 131 | issue = 1-3 | pages = 165–73 | date = September 2011 | pmid = 21745723 | pmc = 3159834 | doi = 10.1016/j.schres.2011.06.007 }}</ref> Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67.<ref>{{cite journal | vauthors = Chung DW, Fish KN, Lewis DA | title = Pathological Basis for Deficient Excitatory Drive to Cortical Parvalbumin Interneurons in Schizophrenia | journal = The American Journal of Psychiatry | volume = 173 | issue = 11 | pages = 1131–1139 | date = November 2016 | pmid = 27444795 | pmc = 5089927 | doi = 10.1176/appi.ajp.2016.16010025 }}</ref>  Together, this suggests that parvalbumin interneurons are somehow specifically affected in the disease.
 Several studies have tried to assess levels in GABA ''in vivo'' in the patients with schizophrenia, but these findings have remained inconclusive.
-[[Electroencephalography|EEG]] studies have indirectly also pointed to interneuron dysfunction in schizophrenia (see below).<ref>{{Cite journal|last=Senkowski|first=Daniel|last2=Gallinat|first2=Jürgen|date=2015-06-15|title=Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia|journal=Biological Psychiatry|volume=77|issue=12|pages=1010–1019|doi=10.1016/j.biopsych.2015.02.034|issn=1873-2402|pmid=25847179}}</ref> These studies have pointed to abnormalities in oscillatory activity in schizophrenia, particularly in the gamma band (30–80&nbsp;Hz). Gamma band activity appears to originate from intact functioning [[parvalbumin]]-positive interneuron.<ref>{{Cite journal|last=Sohal|first=Vikaas S.|last2=Zhang|first2=Feng|last3=Yizhar|first3=Ofer|last4=Deisseroth|first4=Karl|date=2009-06-04|title=Parvalbumin neurons and gamma rhythms enhance cortical circuit performance|journal=Nature|volume=459|issue=7247|pages=698–702|doi=10.1038/nature07991|issn=1476-4687|pmc=3969859|pmid=19396159}}</ref> Together with the post-mortem findings, these EEG abnormalities point to a role for dysfunctional parvalbumin interneurons in schizophrenia.
+[[Electroencephalography|EEG]] studies have indirectly also pointed to interneuron dysfunction in schizophrenia (see below).<ref>{{cite journal | vauthors = Senkowski D, Gallinat J | title = Dysfunctional prefrontal gamma-band oscillations reflect working memory and other cognitive deficits in schizophrenia | journal = Biological Psychiatry | volume = 77 | issue = 12 | pages = 1010–9 | date = June 2015 | pmid = 25847179 | doi = 10.1016/j.biopsych.2015.02.034 }}</ref> These studies have pointed to abnormalities in oscillatory activity in schizophrenia, particularly in the gamma band (30–80&nbsp;Hz). Gamma band activity appears to originate from intact functioning [[parvalbumin]]-positive interneuron.<ref>{{cite journal | vauthors = Sohal VS, Zhang F, Yizhar O, Deisseroth K | title = Parvalbumin neurons and gamma rhythms enhance cortical circuit performance | journal = Nature | volume = 459 | issue = 7247 | pages = 698–702 | date = June 2009 | pmid = 19396159 | pmc = 3969859 | doi = 10.1038/nature07991 }}</ref> Together with the post-mortem findings, these EEG abnormalities point to a role for dysfunctional parvalbumin interneurons in schizophrenia.
-The largest meta-analysis on [[copy-number variation]]s (CNVs), structural abnormalities in the form of genetic deletions or duplications, to date for schizophenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.<ref>{{cite journal|pmid= 26050040|pmc= 4460187|year= 2015|author1= Pocklington|first1= A. J.|title= Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia|journal= Neuron|volume= 86|issue= 5|pages= 1203–14|last2= Rees|first2= E|last3= Walters|first3= J. T.|last4= Han|first4= J|last5= Kavanagh|first5= D. H.|last6= Chambert|first6= K. D.|last7= Holmans|first7= P|last8= Moran|first8= J. L.|last9= McCarroll|first9= S. A.|last10= Kirov|first10= G|last11= O'Donovan|first11= M. C.|last12= Owen|first12= M. J.|doi= 10.1016/j.neuron.2015.04.022}}</ref>
+The largest meta-analysis on [[copy-number variation]]s (CNVs), structural abnormalities in the form of genetic deletions or duplications, to date for schizophenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.<ref>{{cite journal | vauthors = Pocklington AJ, Rees E, Walters JT, Han J, Kavanagh DH, Chambert KD, Holmans P, Moran JL, McCarroll SA, Kirov G, O'Donovan MC, Owen MJ | title = Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia | journal = Neuron | volume = 86 | issue = 5 | pages = 1203–14 | date = June 2015 | pmid = 26050040 | pmc = 4460187 | doi = 10.1016/j.neuron.2015.04.022 }}</ref>
 === Myelination abnormalities ===
-Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia.<ref>{{Cite journal|last=Cassoli|first=Juliana Silva|last2=Guest|first2=Paul C.|last3=Malchow|first3=Berend|last4=Schmitt|first4=Andrea|last5=Falkai|first5=Peter|last6=Martins-de-Souza|first6=Daniel|date=2015-01-01|title=Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules|journal=NPJ schizophrenia|volume=1|pages=15034|doi=10.1038/npjschz.2015.34|pmc=4849457|pmid=27336040}}</ref><ref>{{Cite journal|last=Mighdoll|first=Michelle I.|last2=Tao|first2=Ran|last3=Kleinman|first3=Joel E.|last4=Hyde|first4=Thomas M.|date=2015-01-01|title=Myelin, myelin-related disorders, and psychosis|journal=Schizophrenia Research|volume=161|issue=1|pages=85–93|doi=10.1016/j.schres.2014.09.040|issn=1573-2509|pmid=25449713}}</ref><ref>{{Cite journal|last=Haroutunian|first=V.|last2=Katsel|first2=P.|last3=Roussos|first3=P.|last4=Davis|first4=K. L.|last5=Altshuler|first5=L. L.|last6=Bartzokis|first6=G.|date=2014-11-01|title=Myelination, oligodendrocytes, and serious mental illness|journal=Glia|volume=62|issue=11|pages=1856–1877|doi=10.1002/glia.22716|issn=1098-1136|pmid=25056210}}</ref> This theory originated from structural imaging studies, who found that white matter regions, in addition to grey matter regions, showed volumetric reductions in patients with schizophrenia (see below). In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in post-mortem brains of schizophrenia patients. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies.<ref>{{Cite journal|last=Stedehouder|first=J.|last2=Kushner|first2=S. A.|date=2017-01-01|title=Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia|journal=Molecular Psychiatry|volume=22|issue=1|pages=4–12|doi=10.1038/mp.2016.147|issn=1476-5578|pmid=27646261}}</ref>
+Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia.<ref>{{cite journal | vauthors = Cassoli JS, Guest PC, Malchow B, Schmitt A, Falkai P, Martins-de-Souza D | title = Disturbed macro-connectivity in schizophrenia linked to oligodendrocyte dysfunction: from structural findings to molecules | journal = NPJ Schizophrenia | volume = 1 | pages = 15034 | date = 2015-01-01 | pmid = 27336040 | pmc = 4849457 | doi = 10.1038/npjschz.2015.34 }}</ref><ref>{{cite journal | vauthors = Mighdoll MI, Tao R, Kleinman JE, Hyde TM | title = Myelin, myelin-related disorders, and psychosis | journal = Schizophrenia Research | volume = 161 | issue = 1 | pages = 85–93 | date = January 2015 | pmid = 25449713 | doi = 10.1016/j.schres.2014.09.040 }}</ref><ref>{{cite journal | vauthors = Haroutunian V, Katsel P, Roussos P, Davis KL, Altshuler LL, Bartzokis G | title = Myelination, oligodendrocytes, and serious mental illness | journal = Glia | volume = 62 | issue = 11 | pages = 1856–77 | date = November 2014 | pmid = 25056210 | doi = 10.1002/glia.22716 }}</ref> This theory originated from structural imaging studies, who found that white matter regions, in addition to grey matter regions, showed volumetric reductions in patients with schizophrenia (see below). In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in post-mortem brains of schizophrenia patients. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies.<ref>{{cite journal | vauthors = Stedehouder J, Kushner SA | title = Myelination of parvalbumin interneurons: a parsimonious locus of pathophysiological convergence in schizophrenia | journal = Molecular Psychiatry | volume = 22 | issue = 1 | pages = 4–12 | date = January 2017 | pmid = 27646261 | doi = 10.1038/mp.2016.147 }}</ref>
-It has been suggested that myelination abnormalities could originate from impaired maturation of [[Oligodendrocyte progenitor cell|oligodendrocyte precursor cells]],<ref>{{Cite journal|last=Mauney|first=Sarah A.|last2=Pietersen|first2=Charmaine Y.|last3=Sonntag|first3=Kai-C.|last4=Woo|first4=Tsung-Ung W.|date=2015-12-01|title=Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia|journal=Schizophrenia Research|volume=169|issue=1–3|pages=374–380|doi=10.1016/j.schres.2015.10.042|issn=1573-2509|pmc=4681621|pmid=26585218}}</ref> as these have been found to be intact in schizophrenia brains.
+It has been suggested that myelination abnormalities could originate from impaired maturation of [[Oligodendrocyte progenitor cell|oligodendrocyte precursor cells]],<ref>{{cite journal | vauthors = Mauney SA, Pietersen CY, Sonntag KC, Woo TW | title = Differentiation of oligodendrocyte precursors is impaired in the prefrontal cortex in schizophrenia | journal = Schizophrenia Research | volume = 169 | issue = 1-3 | pages = 374–380 | date = December 2015 | pmid = 26585218 | pmc = 4681621 | doi = 10.1016/j.schres.2015.10.042 }}</ref> as these have been found to be intact in schizophrenia brains.
 === Immune system abnormalities ===
-Another hypothesis postulates that inflammation and immune system abnormalities could play a central role in the disease.<ref name="pmid26092265" /> Abnormal immune system development may help explain roles of environmental effect such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition to genetic effects.<ref>{{vcite journal |author=Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, Butler R |title=A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction |journal=Med. Hypotheses |volume=74 |issue=3 |pages=555–63 |year=2010 |month=March |pmid=19836903 |doi=10.1016/j.mehy.2009.09.040 |url=}}</ref> The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients.<ref>{{vcite journal | author = Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA | date = Nov 2009 | title = Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor | url = | journal = Bipolar Disord | volume = 11 | issue = 7| pages = 726–34 | doi = 10.1111/j.1399-5618.2009.00757.x | pmid = 19839997 }}</ref> High levels of immune markers have also been associated with having more severe psychotic symptoms.<ref>{{vcite journal |author=Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen Lv, Beumer W, Versnel MA, Drexhage HA |title=The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder |journal=Expert Rev Neurother |volume=10 |issue=1 |pages=59–76 |year=2010 |month=January |pmid=20021321 |doi=10.1586/ern.09.144 |url=}}</ref><ref>{{Cite journal | pmid = 23403415| year = 2013| author1 = Hope| first1 = S| title = Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder| journal = Schizophrenia Research| volume = 145| issue = 1–3| pages = 36–42| last2 = Ueland| first2 = T| last3 = Steen| first3 = N. E.| last4 = Dieset| first4 = I| last5 = Lorentzen| first5 = S| last6 = Berg| first6 = A. O.| last7 = Agartz| first7 = I| last8 = Aukrust| first8 = P| last9 = Andreassen| first9 = O. A.| doi = 10.1016/j.schres.2012.12.023}}</ref> Furthermore, a meta-analysis of genome-wide association studies discovered that 129 out of 136 [[single-nucleotide polymorphism]]s (SNP) significantly associated with schizophrenia were located in the [[major histocompatibility complex]] region of the genome.<ref>{{Cite journal | pmid = 21926974| year = 2011| author1 = Schizophrenia Psychiatric Genome-Wide Association Study (GWAS) Consortium| title = Genome-wide association study identifies five new schizophrenia loci| journal = Nature Genetics| volume = 43| issue = 10| pages = 969–76| doi = 10.1038/ng.940| last2 = Sanders| first2 = Alan R| last3 = Kendler| first3 = Kenneth S| last4 = Levinson| first4 = Douglas F| last5 = Sklar| first5 = Pamela| last6 = Holmans| first6 = Peter A| last7 = Lin| first7 = Dan-Yu| last8 = Duan| first8 = Jubao| last9 = Ophoff| first9 = Roel A| last10 = Andreassen| first10 = Ole A| last11 = Scolnick| first11 = Edward| last12 = Cichon| first12 = Sven| last13 = St. Clair| first13 = David| last14 = Corvin| first14 = Aiden| last15 = Gurling| first15 = Hugh| last16 = Werge| first16 = Thomas| last17 = Rujescu| first17 = Dan| last18 = Blackwood| first18 = Douglas H R| last19 = Pato| first19 = Carlos N| last20 = Malhotra| first20 = Anil K| last21 = Purcell| first21 = Shaun| last22 = Dudbridge| first22 = Frank| last23 = Neale| first23 = Benjamin M| last24 = Rossin| first24 = Lizzy| last25 = Visscher| first25 = Peter M| last26 = Posthuma| first26 = Danielle| last27 = Ruderfer| first27 = Douglas M| last28 = Fanous| first28 = Ayman| last29 = Stefansson| first29 = Hreinn| last30 = Steinberg| first30 = Stacy| display-authors = 29| pmc = 3303194}}</ref>
+Another hypothesis postulates that inflammation and immune system abnormalities could play a central role in the disease.<ref name="pmid26092265" /> Abnormal immune system development may help explain roles of environmental effect such as prenatal hazards, post-pubertal onset, stress, climate, and infections, in addition to genetic effects.<ref>{{cite journal | vauthors = Kinney DK, Hintz K, Shearer EM, Barch DH, Riffin C, Whitley K, Butler R | title = A unifying hypothesis of schizophrenia: abnormal immune system development may help explain roles of prenatal hazards, post-pubertal onset, stress, genes, climate, infections, and brain dysfunction | journal = Medical Hypotheses | volume = 74 | issue = 3 | pages = 555–63 | date = March 2010 | pmid = 19836903 | doi = 10.1016/j.mehy.2009.09.040 }}</ref> The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients.<ref>{{cite journal | vauthors = Hope S, Melle I, Aukrust P, Steen NE, Birkenaes AB, Lorentzen S, Agartz I, Ueland T, Andreassen OA | title = Similar immune profile in bipolar disorder and schizophrenia: selective increase in soluble tumor necrosis factor receptor I and von Willebrand factor | journal = Bipolar Disorders | volume = 11 | issue = 7 | pages = 726–34 | date = November 2009 | pmid = 19839997 | doi = 10.1111/j.1399-5618.2009.00757.x }}</ref> High levels of immune markers have also been associated with having more severe psychotic symptoms.<ref>{{cite journal | vauthors = Drexhage RC, Knijff EM, Padmos RC, Heul-Nieuwenhuijzen L, Beumer W, Versnel MA, Drexhage HA | title = The mononuclear phagocyte system and its cytokine inflammatory networks in schizophrenia and bipolar disorder | journal = Expert Review of Neurotherapeutics | volume = 10 | issue = 1 | pages = 59–76 | date = January 2010 | pmid = 20021321 | doi = 10.1586/ern.09.144 }}</ref><ref>{{cite journal | vauthors = Hope S, Ueland T, Steen NE, Dieset I, Lorentzen S, Berg AO, Agartz I, Aukrust P, Andreassen OA | title = Interleukin 1 receptor antagonist and soluble tumor necrosis factor receptor 1 are associated with general severity and psychotic symptoms in schizophrenia and bipolar disorder | journal = Schizophrenia Research | volume = 145 | issue = 1-3 | pages = 36–42 | date = April 2013 | pmid = 23403415 | doi = 10.1016/j.schres.2012.12.023 }}</ref> Furthermore, a meta-analysis of genome-wide association studies discovered that 129 out of 136 [[single-nucleotide polymorphism]]s (SNP) significantly associated with schizophrenia were located in the [[major histocompatibility complex]] region of the genome.<ref>{{cite journal | vauthors =  | title = Genome-wide association study identifies five new schizophrenia loci | journal = Nature Genetics | volume = 43 | issue = 10 | pages = 969–76 | date = September 2011 | pmid = 21926974 | pmc = 3303194 | doi = 10.1038/ng.940 }}</ref>
-A recent systematic review investigating neuroinflammatory markers in post-mortem schizophrenia brains has shown quite some variability, with some studies showing alterations in various markers but others failing to find any differences.<ref>{{Cite journal|last=Trépanier|first=M. O.|last2=Hopperton|first2=K. E.|last3=Mizrahi|first3=R.|last4=Mechawar|first4=N.|last5=Bazinet|first5=R. P.|date=2016-08-01|title=Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review|journal=Molecular Psychiatry|volume=21|issue=8|pages=1009–1026|doi=10.1038/mp.2016.90|issn=1476-5578|pmc=4960446|pmid=27271499}}</ref>
+A recent systematic review investigating neuroinflammatory markers in post-mortem schizophrenia brains has shown quite some variability, with some studies showing alterations in various markers but others failing to find any differences.<ref>{{cite journal | vauthors = Trépanier MO, Hopperton KE, Mizrahi R, Mechawar N, Bazinet RP | title = Postmortem evidence of cerebral inflammation in schizophrenia: a systematic review | journal = Molecular Psychiatry | volume = 21 | issue = 8 | pages = 1009–26 | date = August 2016 | pmid = 27271499 | pmc = 4960446 | doi = 10.1038/mp.2016.90 }}</ref>
 === Oxidative stress===
-A theory that has gained more support in recent years is that a large role is played in the disease by [[oxidative stress]].<ref name="pmid25000913"/><ref>{{Cite journal | pmid = 24613987| pmc = 4054867| year = 2014| author1 = Emiliani| first1 = F. E.| title = Oxidative stress and schizophrenia: Recent breakthroughs from an old story| journal = Current Opinion in Psychiatry| volume = 27| issue = 3| pages = 185–90| last2 = Sedlak| first2 = T. W.| last3 = Sawa| first3 = A| doi = 10.1097/YCO.0000000000000054}}</ref><ref>{{Cite journal|last=Hardingham|first=Giles E.|last2=Do|first2=Kim Q.|date=2016-02-01|title=Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis|journal=Nature Reviews. Neuroscience|volume=17|issue=2|pages=125–134|doi=10.1038/nrn.2015.19|issn=1471-0048|pmid=26763624}}</ref> Redox dysregulation in early development can potentially influence development of different cell types that have been shown to be impaired in the disease.
+A theory that has gained more support in recent years is that a large role is played in the disease by [[oxidative stress]].<ref name="pmid25000913"/><ref>{{cite journal | vauthors = Emiliani FE, Sedlak TW, Sawa A | title = Oxidative stress and schizophrenia: recent breakthroughs from an old story | journal = Current Opinion in Psychiatry | volume = 27 | issue = 3 | pages = 185–90 | date = May 2014 | pmid = 24613987 | pmc = 4054867 | doi = 10.1097/YCO.0000000000000054 }}</ref><ref>{{cite journal | vauthors = Hardingham GE, Do KQ | title = Linking early-life NMDAR hypofunction and oxidative stress in schizophrenia pathogenesis | journal = Nature Reviews. Neuroscience | volume = 17 | issue = 2 | pages = 125–34 | date = February 2016 | pmid = 26763624 | doi = 10.1038/nrn.2015.19 }}</ref> Redox dysregulation in early development can potentially influence development of different cell types that have been shown to be impaired in the disease.
-Oxidative stress has also been indicated through genetic studies into schizophrenia.<ref>{{Cite journal|last=Kushima|first=I.|last2=Aleksic|first2=B.|last3=Nakatochi|first3=M.|last4=Shimamura|first4=T.|last5=Shiino|first5=T.|last6=Yoshimi|first6=A.|last7=Kimura|first7=H.|last8=Takasaki|first8=Y.|last9=Wang|first9=C.|date=2017-03-01|title=High-resolution copy number variation analysis of schizophrenia in Japan|journal=Molecular Psychiatry|volume=22|issue=3|pages=430–440|doi=10.1038/mp.2016.88|issn=1476-5578|pmid=27240532}}</ref>
+Oxidative stress has also been indicated through genetic studies into schizophrenia.<ref>{{cite journal | vauthors = Kushima I, Aleksic B, Nakatochi M, Shimamura T, Shiino T, Yoshimi A, Kimura H, Takasaki Y, Wang C, Xing J, Ishizuka K, Oya-Ito T, Nakamura Y, Arioka Y, Maeda T, Yamamoto M, Yoshida M, Noma H, Hamada S, Morikawa M, Uno Y, Okada T, Iidaka T, Iritani S, Yamamoto T, Miyashita M, Kobori A, Arai M, Itokawa M, Cheng MC, Chuang YA, Chen CH, Suzuki M, Takahashi T, Hashimoto R, Yamamori H, Yasuda Y, Watanabe Y, Nunokawa A, Someya T, Ikeda M, Toyota T, Yoshikawa T, Numata S, Ohmori T, Kunimoto S, Mori D, Iwata N, Ozaki N | display-authors = 6 | title = High-resolution copy number variation analysis of schizophrenia in Japan | journal = Molecular Psychiatry | volume = 22 | issue = 3 | pages = 430–440 | date = March 2017 | pmid = 27240532 | doi = 10.1038/mp.2016.88 }}</ref>
-Oxidative stress has been shown to affect maturation of [[oligodendrocyte]]s,<ref>{{cite journal|pmid= 25155877|year= 2015|author1= Monin|first1= A|title= Glutathione deficit impairs myelin maturation: Relevance for white matter integrity in schizophrenia patients|journal= Molecular Psychiatry|volume= 20|issue= 7|pages= 827–38|last2= Baumann|first2= P. S.|last3= Griffa|first3= A|last4= Xin|first4= L|last5= Mekle|first5= R|last6= Fournier|first6= M|last7= Butticaz|first7= C|last8= Klaey|first8= M|last9= Cabungcal|first9= J. H.|last10= Steullet|first10= P|last11= Ferrari|first11= C|last12= Cuenod|first12= M|last13= Gruetter|first13= R|last14= Thiran|first14= J. P.|last15= Hagmann|first15= P|last16= Conus|first16= P|last17= Do|first17= K. Q.|doi= 10.1038/mp.2014.88}}</ref> the myelinating cell types in the brain, potentially underlying the white matter abnormalities found in the brain (see below).
+Oxidative stress has been shown to affect maturation of [[oligodendrocyte]]s,<ref>{{cite journal | vauthors = Monin A, Baumann PS, Griffa A, Xin L, Mekle R, Fournier M, Butticaz C, Klaey M, Cabungcal JH, Steullet P, Ferrari C, Cuenod M, Gruetter R, Thiran JP, Hagmann P, Conus P, Do KQ | display-authors = 6 | title = Glutathione deficit impairs myelin maturation: relevance for white matter integrity in schizophrenia patients | journal = Molecular Psychiatry | volume = 20 | issue = 7 | pages = 827–38 | date = July 2015 | pmid = 25155877 | doi = 10.1038/mp.2014.88 }}</ref> the myelinating cell types in the brain, potentially underlying the white matter abnormalities found in the brain (see below).
-Furthermore, oxidative stress could also influence the development of GABAergic interneurons,<ref>{{cite journal|pmid= 23140664|year= 2013|author1= Cabungcal|first1= J. H.|title= Early-life insults impair parvalbumin interneurons via oxidative stress: Reversal by N-acetylcysteine|journal= Biological Psychiatry|volume= 73|issue= 6|pages= 574–82|last2= Steullet|first2= P|last3= Kraftsik|first3= R|last4= Cuenod|first4= M|last5= Do|first5= K. Q.|doi= 10.1016/j.biopsych.2012.09.020}}</ref> which have also been found to be dysregulated in schizophrenia (see above).
+Furthermore, oxidative stress could also influence the development of GABAergic interneurons,<ref>{{cite journal | vauthors = Cabungcal JH, Steullet P, Kraftsik R, Cuenod M, Do KQ | title = Early-life insults impair parvalbumin interneurons via oxidative stress: reversal by N-acetylcysteine | journal = Biological Psychiatry | volume = 73 | issue = 6 | pages = 574–82 | date = March 2013 | pmid = 23140664 | doi = 10.1016/j.biopsych.2012.09.020 }}</ref> which have also been found to be dysregulated in schizophrenia (see above).
 ===Neuropathology===
-The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or [[gliosis]].  Abnormal neuronal organization and orientation ([[dysplasia]]) has been observed in the [[entorhinal cortex]], hippocampus, and subcortical white matter, although results are not entirely consistent.  A more consistent cytoarchitectural finding is reduced volume of purkinje cells and pyramidal cells in the hippocampus.  This is consistent with the observation of decreased presynaptic terminals in the hippocampus, and a reduction in dendritic spines in the prefrontal cortex.<ref>{{cite journal|last1=Harrison|first1=PJ|title=Postmortem studies in schizophrenia.|journal=Dialogues in clinical neuroscience|date=December 2000|volume=2|issue=4|pages=349–57|pmid=22033474|pmc=3181616}}</ref>  The reductions in prefrontal and increase in striatal spine densities seem to be independent of antipsychotic drug use.<ref>{{cite journal|last1=Glausier|first1=JR|last2=Lewis|first2=DA|title=Dendritic spine pathology in schizophrenia.|journal=Neuroscience|date=22 October 2013|volume=251|pages=90–107|doi=10.1016/j.neuroscience.2012.04.044|pmid=22546337|pmc=3413758}}</ref>
+The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or [[gliosis]].  Abnormal neuronal organization and orientation ([[dysplasia]]) has been observed in the [[entorhinal cortex]], hippocampus, and subcortical white matter, although results are not entirely consistent.  A more consistent cytoarchitectural finding is reduced volume of purkinje cells and pyramidal cells in the hippocampus.  This is consistent with the observation of decreased presynaptic terminals in the hippocampus, and a reduction in dendritic spines in the prefrontal cortex.<ref>{{cite journal | vauthors = Harrison PJ | title = Postmortem studies in schizophrenia | journal = Dialogues in Clinical Neuroscience | volume = 2 | issue = 4 | pages = 349–57 | date = December 2000 | pmid = 22033474 | pmc = 3181616 }}</ref>  The reductions in prefrontal and increase in striatal spine densities seem to be independent of antipsychotic drug use.<ref>{{cite journal | vauthors = Glausier JR, Lewis DA | title = Dendritic spine pathology in schizophrenia | journal = Neuroscience | volume = 251 | pages = 90–107 | date = October 2013 | pmid = 22546337 | pmc = 3413758 | doi = 10.1016/j.neuroscience.2012.04.044 }}</ref>
 == Structural abnormalities ==
-Beside theories concerning the functional mechanism underlying the disease, structural findings have been identified as well using a wide range of imaging techniques. Studies have tended to show various subtle average differences in the volume of certain areas of brain structure between people with and without diagnoses of schizophrenia, although it has become increasingly clear that no single pathological neuropsychological or structural neuroanatomic profile exists.<ref name=Flashman04>{{vcite journal |author=Flashman LA, Green MF |title=Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment |journal=Psychiatr. Clin. North Am |volume=27 |issue=1 |pages=1–18, vii |year=2004 |month=March |pmid=15062627 |doi=10.1016/S0193-953X(03)00105-9 }}</ref>
+Beside theories concerning the functional mechanism underlying the disease, structural findings have been identified as well using a wide range of imaging techniques. Studies have tended to show various subtle average differences in the volume of certain areas of brain structure between people with and without diagnoses of schizophrenia, although it has become increasingly clear that no single pathological neuropsychological or structural neuroanatomic profile exists.<ref name=Flashman04>{{cite journal | vauthors = Flashman LA, Green MF | title = Review of cognition and brain structure in schizophrenia: profiles, longitudinal course, and effects of treatment | journal = The Psychiatric Clinics of North America | volume = 27 | issue = 1 | pages = 1–18, vii | date = March 2004 | pmid = 15062627 | doi = 10.1016/S0193-953X(03)00105-9 }}</ref>
 === Morphometry ===
 Structural imaging studies have extensively reported differences in the size and structure of certain brain areas in schizophrenia.
-The largest combined neuroimaging study with over 2000 patients and 2500 controls has replicated these previous findings.<ref>{{cite journal|last2=Hibar|first2=D. P.|last3=Rasmussen|first3=J. M.|last4=Glahn|first4=D. C.|last5=Pearlson|first5=G. D.|last6=Andreassen|first6=O. A.|last7=Agartz|first7=I|last8=Westlye|first8=L. T.|last9=Haukvik|first9=U. K.|year=2015|title=Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium|journal=Molecular Psychiatry|volume=21|issue=4|pages=547–53|doi=10.1038/mp.2015.63|pmc=4668237|pmid=26033243|author1=Van Erp|first1=T. G.|last10=Dale|first10=A. M.|last11=Melle|first11=I|last12=Hartberg|first12=C. B.|last13=Gruber|first13=O|last14=Kraemer|first14=B|last15=Zilles|first15=D|last16=Donohoe|first16=G|last17=Kelly|first17=S|last18=McDonald|first18=C|last19=Morris|first19=D. W.|last20=Cannon|first20=D. M.|last21=Corvin|first21=A|last22=Machielsen|first22=M. W.|last23=Koenders|first23=L|last24=De Haan|first24=L|last25=Veltman|first25=D. J.|last26=Satterthwaite|first26=T. D.|last27=Wolf|first27=D. H.|last28=Gur|first28=R. C.|last29=Gur|first29=R. E.|last30=Potkin|first30=S. G.|display-authors=29}}</ref> Here, the authors found volumetric increases in the lateral ventricles (+18%), caudate and pallidum, and extensive decreases in the hippocampus (-4%), thalamus, amygdala and nucleus accumbens. Together, this indicates that extensive changes occur in brains in patients suffering from schizophrenia.
+The largest combined neuroimaging study with over 2000 patients and 2500 controls has replicated these previous findings.<ref>{{cite journal | vauthors = van Erp TG, Hibar DP, Rasmussen JM, Glahn DC, Pearlson GD, Andreassen OA, Agartz I, Westlye LT, Haukvik UK, Dale AM, Melle I, Hartberg CB, Gruber O, Kraemer B, Zilles D, Donohoe G, Kelly S, McDonald C, Morris DW, Cannon DM, Corvin A, Machielsen MW, Koenders L, de Haan L, Veltman DJ, Satterthwaite TD, Wolf DH, Gur RC, Gur RE, Potkin SG, Mathalon DH, Mueller BA, Preda A, Macciardi F, Ehrlich S, Walton E, Hass J, Calhoun VD, Bockholt HJ, Sponheim SR, Shoemaker JM, van Haren NE, Hulshoff Pol HE, Pol HE, Ophoff RA, Kahn RS, Roiz-Santiañez R, Crespo-Facorro B, Wang L, Alpert KI, Jönsson EG, Dimitrova R, Bois C, Whalley HC, McIntosh AM, Lawrie SM, Hashimoto R, Thompson PM, Turner JA | display-authors = 6 | title = Subcortical brain volume abnormalities in 2028 individuals with schizophrenia and 2540 healthy controls via the ENIGMA consortium | journal = Molecular Psychiatry | volume = 21 | issue = 4 | pages = 547–53 | date = April 2016 | pmid = 26033243 | pmc = 4668237 | doi = 10.1038/mp.2015.63 }}</ref> Here, the authors found volumetric increases in the lateral ventricles (+18%), caudate and pallidum, and extensive decreases in the hippocampus (-4%), thalamus, amygdala and nucleus accumbens. Together, this indicates that extensive changes occur in brains in patients suffering from schizophrenia.
-A 2006 meta-analysis of MRI studies found that whole brain and [[hippocampal]] volume are reduced and that [[Ventricular system|ventricular]] volume is increased in patients with a first psychotic episode relative to healthy controls. The average volumetric changes in these studies are however close to the limit of detection by MRI methods, so it remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.<ref name="Steen2006">{{vcite journal|author=Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA|title=Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies|journal=Br J Psychiatry|volume=188|pages=510–8|year=2006|month=June|pmid=16738340|doi=10.1192/bjp.188.6.510|url=http://bjp.rcpsych.org/cgi/content/full/188/6/510}}</ref> In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not.<ref name="Lieberman08">{{vcite journal |author=Lieberman JA, Bymaster FP, Meltzer HY, ''et al'' |title=Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection |journal=Pharmacol. Rev. |volume=60 |issue=3 |pages=358–403 |year=2008 |month=September |pmid=18922967 |doi=10.1124/pr.107.00107}}</ref> Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.<ref name="DeLisi08">{{vcite journal |author=DeLisi LE |title=The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia |journal=Schizophr Bull |volume=34 |issue=2 |pages=312–21 |year=2008 |month=March |pmid=18263882 |pmc=2632405 |doi=10.1093/schbul/sbm164 }}</ref>
+A 2006 meta-analysis of MRI studies found that whole brain and [[hippocampal]] volume are reduced and that [[Ventricular system|ventricular]] volume is increased in patients with a first psychotic episode relative to healthy controls. The average volumetric changes in these studies are however close to the limit of detection by MRI methods, so it remains to be determined whether schizophrenia is a neurodegenerative process that begins at about the time of symptom onset, or whether it is better characterised as a neurodevelopmental process that produces abnormal brain volumes at an early age.<ref name="Steen2006">{{cite journal | vauthors = Steen RG, Mull C, McClure R, Hamer RM, Lieberman JA | title = Brain volume in first-episode schizophrenia: systematic review and meta-analysis of magnetic resonance imaging studies | journal = The British Journal of Psychiatry | volume = 188 | pages = 510–8 | date = June 2006 | pmid = 16738340 | doi = 10.1192/bjp.188.6.510 }}</ref> In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not.<ref name="Lieberman08">{{cite journal | vauthors = Lieberman JA, Bymaster FP, Meltzer HY, Deutch AY, Duncan GE, Marx CE, Aprille JR, Dwyer DS, Li XM, Mahadik SP, Duman RS, Porter JH, Modica-Napolitano JS, Newton SS, Csernansky JG | title = Antipsychotic drugs: comparison in animal models of efficacy, neurotransmitter regulation, and neuroprotection | journal = Pharmacological Reviews | volume = 60 | issue = 3 | pages = 358–403 | date = September 2008 | pmid = 18922967 | doi = 10.1124/pr.107.00107 }}</ref> Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.<ref name="DeLisi08">{{cite journal | vauthors = DeLisi LE | title = The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia | journal = Schizophrenia Bulletin | volume = 34 | issue = 2 | pages = 312–21 | date = March 2008 | pmid = 18263882 | pmc = 2632405 | doi = 10.1093/schbul/sbm164 }}</ref>
-Abnormal findings in the [[prefrontal cortex]], [[temporal cortex]] and [[anterior cingulate cortex]] are found before the first onset of schizophrenia symptoms. These regions are the regions of structural deficits found in schizophrenia and first-episode patients.<ref name=Jung2010>{{vcite journal |author=Jung WH, Jang JH, Byun MS, An SK, Kwon JS |title=Structural Brain Alterations in Individuals at Ultra-high Risk for Psychosis: A Review of Magnetic Resonance Imaging Studies and Future Directions |journal=J. Korean Med. Sci |volume=25 |issue=12 |pages=1700–9 |year=2010 |month=December |pmid=21165282 |pmc=2995221 |doi=10.3346/jkms.2010.25.12.1700 }}</ref> Positive symptoms, such as thoughts of being persecuted, were found to be related to the [[medial prefrontal cortex]], [[amygdala]], and [[hippocampus]] region. Negative symptoms were found to be related to the [[ventrolateral prefrontal cortex]] and [[ventral striatum]].<ref name=Jung2010 />
+Abnormal findings in the [[prefrontal cortex]], [[temporal cortex]] and [[anterior cingulate cortex]] are found before the first onset of schizophrenia symptoms. These regions are the regions of structural deficits found in schizophrenia and first-episode patients.<ref name=Jung2010>{{cite journal | vauthors = Jung WH, Jang JH, Byun MS, An SK, Kwon JS | title = Structural brain alterations in individuals at ultra-high risk for psychosis: a review of magnetic resonance imaging studies and future directions | journal = Journal of Korean Medical Science | volume = 25 | issue = 12 | pages = 1700–9 | date = December 2010 | pmid = 21165282 | pmc = 2995221 | doi = 10.3346/jkms.2010.25.12.1700 }}</ref> Positive symptoms, such as thoughts of being persecuted, were found to be related to the [[medial prefrontal cortex]], [[amygdala]], and [[hippocampus]] region. Negative symptoms were found to be related to the [[ventrolateral prefrontal cortex]] and [[ventral striatum]].<ref name=Jung2010 />
-Ventricular and third ventricle enlargement, abnormal functioning of the amygdala, hippocampus, parahippocampal gyrus,  neocortical temporal lobe regions, frontal lobe, prefontal gray matter, orbitofrontal areas, parietal lobs abnormalities and subcortical abnormalities including the [[cavum septi pellucidi]], basal ganglia, corpus callosum, thalamus and cerebellar abnormalities. Such abnormalities usually present in the form of loss of volume.<ref name="Shenton2001">{{vcite journal |author=Shenton ME, Dickey CC, Frumin M, McCarley RW |title=A review of MRI findings in schizophrenia |journal=Schizophr. Res. |volume=49 |issue=1-2 |pages=1–52 |year=2001 |month=April |pmid=11343862 |pmc=2812015 |doi=10.1016/s0920-9964(01)00163-3}}</ref>
+Ventricular and third ventricle enlargement, abnormal functioning of the amygdala, hippocampus, parahippocampal gyrus,  neocortical temporal lobe regions, frontal lobe, prefontal gray matter, orbitofrontal areas, parietal lobs abnormalities and subcortical abnormalities including the [[cavum septi pellucidi]], basal ganglia, corpus callosum, thalamus and cerebellar abnormalities. Such abnormalities usually present in the form of loss of volume.<ref name="Shenton2001">{{cite journal | vauthors = Shenton ME, Dickey CC, Frumin M, McCarley RW | title = A review of MRI findings in schizophrenia | journal = Schizophrenia Research | volume = 49 | issue = 1-2 | pages = 1–52 | date = April 2001 | pmid = 11343862 | pmc = 2812015 | doi = 10.1016/s0920-9964(01)00163-3 }}</ref>
-Most schizophrenia studies have found average reduced volume of the left medial [[temporal lobe]] and left [[superior temporal gyrus]], and half of studies have revealed deficits in certain areas of the [[frontal gyrus]], [[parahippocampal gyrus]] and temporal gyrus.<ref name="Honea05">{{vcite journal |author=Honea R, Crow TJ, Passingham D, Mackay CE |title=Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies |journal=Am J Psychiatry |volume=162 |issue=12 |pages=2233–45 |year=2005 |month=December |pmid=16330585 |doi=10.1176/appi.ajp.162.12.2233 }}</ref> However, at variance with some findings in individuals with chronic schizophrenia significant group differences of [[temporal lobe]] and [[amygdala]] volumes are not shown in first-episode patients on average.<ref name="Vita06">{{vcite journal |author=Vita A, De Peri L, Silenzi C, Dieci M |title=Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies |journal=Schizophr. Res. |volume=82 |issue=1 |pages=75–88 |year=2006 |month=February |pmid=16377156 |doi=10.1016/j.schres.2005.11.004}}</ref>
+Most schizophrenia studies have found average reduced volume of the left medial [[temporal lobe]] and left [[superior temporal gyrus]], and half of studies have revealed deficits in certain areas of the [[frontal gyrus]], [[parahippocampal gyrus]] and temporal gyrus.<ref name="Honea05">{{cite journal | vauthors = Honea R, Crow TJ, Passingham D, Mackay CE | title = Regional deficits in brain volume in schizophrenia: a meta-analysis of voxel-based morphometry studies | journal = The American Journal of Psychiatry | volume = 162 | issue = 12 | pages = 2233–45 | date = December 2005 | pmid = 16330585 | doi = 10.1176/appi.ajp.162.12.2233 }}</ref> However, at variance with some findings in individuals with chronic schizophrenia significant group differences of [[temporal lobe]] and [[amygdala]] volumes are not shown in first-episode patients on average.<ref name="Vita06">{{cite journal | vauthors = Vita A, De Peri L, Silenzi C, Dieci M | title = Brain morphology in first-episode schizophrenia: a meta-analysis of quantitative magnetic resonance imaging studies | journal = Schizophrenia Research | volume = 82 | issue = 1 | pages = 75–88 | date = February 2006 | pmid = 16377156 | doi = 10.1016/j.schres.2005.11.004 }}</ref>
-Finally, MRI studies utilizing modern cortical surface reconstruction techniques have shown widespread reduction in cerebral cortical thickness (i.e., "cortical thinning") in frontal and temporal regions<ref name="Kuperberg et al., 2003">{{vcite journal |author=Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B |title=Regionally localized thinning of the cerebral cortex in schizophrenia |journal=Arch Gen Psychiatry|volume=60 |issue=9 |pages=878–88 |year=2003 |pmid=12963669 |doi=10.1001/archpsyc.60.9.878}}</ref><ref name="Rimol et al., 2010">{{vcite journal |author=Rimol, L.M., Hartberg, C.B., Nesvag, R., Fennema-Notestine, C., Hagler, D.J., Jr., Pung, C.J., Jennings, R.G., Haukvik, U.K., Lange, E., Nakstad, P.H., Melle, I., Andreassen, O.A., Dale, A.M., Agartz, I |title=Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder |journal=Biol. Psychiatry |volume=68 |issue=1 |pages=41–50 |year=2010 |pmid=20609836 |doi=10.1016/j.biopsych.2010.03.036}}</ref> and somewhat less widespread cortical thinning in occipital and parietal regions<ref name="Rimol et al., 2010" /> in patients with schizophrenia, relative to healthy control subjects. Moreover, one study decomposed cortical volume into its constituent parts, cortical surface area and cortical thickness, and reported widespread cortical volume reduction in schizophrenia, mainly driven by cortical thinning, but also reduced cortical surface area in smaller frontal, temporal, parietal and occipital cortical regions.<ref name="Rimol et al., 2012">{{vcite journal |author=Rimol L.M., Nesvåg R., Hagler D. Jr, Bergmann Ø., Fennema-Notestine C., Hartberg C.B., Haukvik U.K., Lange E., Pung C.J., Server A., Melle I., Andreassen O.A., Agartz I., Dale A.M |title=Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder |journal=Biol. Psychiatry |volume=71 |issue=6 |pages=552–60 |year=2012 |pmid=22281121 |doi=10.1016/j.biopsych.2011.11.026}}</ref>
+Finally, MRI studies utilizing modern cortical surface reconstruction techniques have shown widespread reduction in cerebral cortical thickness (i.e., "cortical thinning") in frontal and temporal regions<ref name="Kuperberg et al., 2003">{{cite journal | vauthors = Kuperberg GR, Broome MR, McGuire PK, David AS, Eddy M, Ozawa F, Goff D, West WC, Williams SC, van der Kouwe AJ, Salat DH, Dale AM, Fischl B | title = Regionally localized thinning of the cerebral cortex in schizophrenia | journal = Archives of General Psychiatry | volume = 60 | issue = 9 | pages = 878–88 | date = September 2003 | pmid = 12963669 | doi = 10.1001/archpsyc.60.9.878 }}</ref><ref name="Rimol et al., 2010">{{cite journal | vauthors = Rimol LM, Hartberg CB, Nesvåg R, Fennema-Notestine C, Hagler DJ, Pung CJ, Jennings RG, Haukvik UK, Lange E, Nakstad PH, Melle I, Andreassen OA, Dale AM, Agartz I | title = Cortical thickness and subcortical volumes in schizophrenia and bipolar disorder | journal = Biological Psychiatry | volume = 68 | issue = 1 | pages = 41–50 | date = July 2010 | pmid = 20609836 | doi = 10.1016/j.biopsych.2010.03.036 }}</ref> and somewhat less widespread cortical thinning in occipital and parietal regions<ref name="Rimol et al., 2010" /> in patients with schizophrenia, relative to healthy control subjects. Moreover, one study decomposed cortical volume into its constituent parts, cortical surface area and cortical thickness, and reported widespread cortical volume reduction in schizophrenia, mainly driven by cortical thinning, but also reduced cortical surface area in smaller frontal, temporal, parietal and occipital cortical regions.<ref name="Rimol et al., 2012">{{cite journal | vauthors = Rimol LM, Nesvåg R, Hagler DJ, Bergmann O, Fennema-Notestine C, Hartberg CB, Haukvik UK, Lange E, Pung CJ, Server A, Melle I, Andreassen OA, Agartz I, Dale AM | title = Cortical volume, surface area, and thickness in schizophrenia and bipolar disorder | journal = Biological Psychiatry | volume = 71 | issue = 6 | pages = 552–60 | date = March 2012 | pmid = 22281121 | doi = 10.1016/j.biopsych.2011.11.026 }}</ref>
-[[Computed Tomography]] scans of schizophrenic brains show several pathologies. The [[brain ventricles]] are enlarged as compared to normal brains. The ventricles hold [[cerebrospinal fluid]] (CSF) and enlarged ventricles indicate a loss of brain volume. Additionally, schizophrenic brains have widened [[sulci (neuroanatomy)|sulci]] as compared to normal brains, also with increased CSF volumes and reduced brain volume.<ref name="Shenton2001" /><ref name="Adams&Victor">{{vcite book |title=Adams and Victor's Principles of Neurology |edition= 8th |author= Ropper AH, Brown RH |year=2005 |publisher= McGraw-Hill |location= New York|isbn=0-07-141620-X |page=1324 |accessdate=2010-12-28}}</ref>
+[[Computed Tomography]] scans of schizophrenic brains show several pathologies. The [[brain ventricles]] are enlarged as compared to normal brains. The ventricles hold [[cerebrospinal fluid]] (CSF) and enlarged ventricles indicate a loss of brain volume. Additionally, schizophrenic brains have widened [[sulci (neuroanatomy)|sulci]] as compared to normal brains, also with increased CSF volumes and reduced brain volume.<ref name="Shenton2001" /><ref name="Adams&Victor">{{vcite book |title=Adams and Victor's Principles of Neurology |edition= 8th |author= Ropper AH, Brown RH |year=2005 |publisher= McGraw-Hill |location= New York|isbn=0-07-141620-X |page=1324 |access-date=2010-12-28}}</ref>
 === White Matter ===
-[[Diffusion tensor imaging]] (DTI) allows for the investigation of white matter more closely than traditional MRI.<ref name="Shenton2001" /> Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia.<ref>{{Cite journal | pmid = 23324948| year = 2013| author1 = Fitzsimmons| first1 = J| title = Review of functional and anatomical brain connectivity findings in schizophrenia| journal = Current Opinion in Psychiatry| volume = 26| issue = 2| pages = 172–87| last2 = Kubicki| first2 = M| last3 = Shenton| first3 = M. E.| doi = 10.1097/YCO.0b013e32835d9e6a}}</ref><ref name="Ellison-Wright2009">{{vcite journal |author=Ellison-Wright I, Bullmore E |title=Meta-analysis of diffusion tensor imaging studies in schizophrenia |journal=Schizophr. Res. |volume=108 |issue=1-3 |pages=3–10 |year=2009 |month=March |pmid=19128945 |doi=10.1016/j.schres.2008.11.021 }}</ref> Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced [[fractional anisotropy]] in brains from patients with schizophrenia versus controls. Importantly, these differences between patients and controls could potentially be attributed to lifestyle effects, medication effects etc. Therefore, more recently several studies have been perform in first-onset schizophrenia patients that have never recent any medication, so-called medication-naive subjects. These studies, although still few in number, also found reduced [[fractional anisotropy]] in patient brains compared to control brains. As with earlier findings, abnormalities can be found throughout the brain, although the [[corpus callous]] seemed to be most commonly effected.
+[[Diffusion tensor imaging]] (DTI) allows for the investigation of white matter more closely than traditional MRI.<ref name="Shenton2001" /> Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia.<ref>{{cite journal | vauthors = Fitzsimmons J, Kubicki M, Shenton ME | title = Review of functional and anatomical brain connectivity findings in schizophrenia | journal = Current Opinion in Psychiatry | volume = 26 | issue = 2 | pages = 172–87 | date = March 2013 | pmid = 23324948 | doi = 10.1097/YCO.0b013e32835d9e6a }}</ref><ref name="Ellison-Wright2009">{{cite journal | vauthors = Ellison-Wright I, Bullmore E | title = Meta-analysis of diffusion tensor imaging studies in schizophrenia | journal = Schizophrenia Research | volume = 108 | issue = 1-3 | pages = 3–10 | date = March 2009 | pmid = 19128945 | doi = 10.1016/j.schres.2008.11.021 }}</ref> Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced [[fractional anisotropy]] in brains from patients with schizophrenia versus controls. Importantly, these differences between patients and controls could potentially be attributed to lifestyle effects, medication effects etc. Therefore, more recently several studies have been perform in first-onset schizophrenia patients that have never recent any medication, so-called medication-naive subjects. These studies, although still few in number, also found reduced [[fractional anisotropy]] in patient brains compared to control brains. As with earlier findings, abnormalities can be found throughout the brain, although the [[corpus callous]] seemed to be most commonly effected.
 == Functional abnormalities ==
-During [[executive function]] tasks, Schizophrenics demonstrate decreased activity relative to controls in the bilateral [[dorsolateral prefrontal cortex|dorsolateral prefrontal cortex(dlPFC)]], right [[anterior cingulate cortex|anterior cingulate cortex(ACC)]], and left mediodorsal nucleus of the [[thalamus]].  Increased activation was observed in the left ACC and left inferior parietal lobe.<ref>{{cite journal|last1=Minzenberg|first1=MJ|last2=Laird|first2=AR|last3=Thelen|first3=S|last4=Carter|first4=CS|last5=Glahn|first5=DC|title=Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia.|journal=Archives of General Psychiatry|date=August 2009|volume=66|issue=8|pages=811–22|doi=10.1001/archgenpsychiatry.2009.91|pmid=19652121|pmc=2888482}}</ref>  During emotional processing tasks, reduced activations have been observed in the [[Medial prefrontal cortex]], ACC, dlPFC and amygdala.<ref>{{cite journal|last1=Taylor|first1=SF|last2=Kang|first2=J|last3=Brege|first3=IS|last4=Tso|first4=IF|last5=Hosanagar|first5=A|last6=Johnson|first6=TD|title=Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia.|journal=Biological Psychiatry|date=15 January 2012|volume=71|issue=2|pages=136–45|doi=10.1016/j.biopsych.2011.09.007|pmid=21993193|pmc=3237865}}</ref>  A meta analysis of facial emotional processing observed decreased activation in the [[amygdala]], [[parahippocampus]], [[lentiform nuclei]], fusiform gyrus and right superior frontal gyrus, as well as increased activation in the left [[insular cortex|insula]].<ref>{{cite journal|last1=Li|first1=H|last2=Chan|first2=RC|last3=McAlonan|first3=GM|last4=Gong|first4=QY|title=Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data.|journal=Schizophrenia Bulletin|date=September 2010|volume=36|issue=5|pages=1029–39|doi=10.1093/schbul/sbn190|pmid=19336391|pmc=2930350}}</ref>
+During [[executive function]] tasks, Schizophrenics demonstrate decreased activity relative to controls in the bilateral [[dorsolateral prefrontal cortex|dorsolateral prefrontal cortex(dlPFC)]], right [[anterior cingulate cortex|anterior cingulate cortex(ACC)]], and left mediodorsal nucleus of the [[thalamus]].  Increased activation was observed in the left ACC and left inferior parietal lobe.<ref>{{cite journal | vauthors = Minzenberg MJ, Laird AR, Thelen S, Carter CS, Glahn DC | title = Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia | journal = Archives of General Psychiatry | volume = 66 | issue = 8 | pages = 811–22 | date = August 2009 | pmid = 19652121 | pmc = 2888482 | doi = 10.1001/archgenpsychiatry.2009.91 }}</ref>  During emotional processing tasks, reduced activations have been observed in the [[Medial prefrontal cortex]], ACC, dlPFC and amygdala.<ref>{{cite journal | vauthors = Taylor SF, Kang J, Brege IS, Tso IF, Hosanagar A, Johnson TD | title = Meta-analysis of functional neuroimaging studies of emotion perception and experience in schizophrenia | journal = Biological Psychiatry | volume = 71 | issue = 2 | pages = 136–45 | date = January 2012 | pmid = 21993193 | pmc = 3237865 | doi = 10.1016/j.biopsych.2011.09.007 }}</ref>  A meta analysis of facial emotional processing observed decreased activation in the [[amygdala]], [[parahippocampus]], [[lentiform nuclei]], fusiform gyrus and right superior frontal gyrus, as well as increased activation in the left [[insular cortex|insula]].<ref>{{cite journal | vauthors = Li H, Chan RC, McAlonan GM, Gong QY | title = Facial emotion processing in schizophrenia: a meta-analysis of functional neuroimaging data | journal = Schizophrenia Bulletin | volume = 36 | issue = 5 | pages = 1029–39 | date = September 2010 | pmid = 19336391 | pmc = 2930350 | doi = 10.1093/schbul/sbn190 }}</ref>
-One meta analysis of functional neuroiamging during acute auditory verbal hallucinations has reported increased activations in areas implicated in language, including the bilateral [[inferior frontal gyrus|inferior frontal]] and post central gyri, as well as the left parietal operculum.<ref>{{cite journal|last1=Kühn|first1=S|last2=Gallinat|first2=J|title=Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia.|journal=Schizophrenia Bulletin|date=June 2012|volume=38|issue=4|pages=779–86|doi=10.1093/schbul/sbq152|pmid=21177743|pmc=3406531}}</ref>  Another meta analysis during both visual and auditory verbal hallucinations, replicated the findings in the inferior frontal and postcentral gyri during auditory verbal hallucinations, and also observed hippocampal, superior temporal, insular and medial prefrontal activations.  Visual hallucinations were reported to be associated with increased activations in the secondary and associate visual cortices.<ref>{{cite journal|last1=Zmigrod|first1=L|last2=Garrison|first2=JR|last3=Carr|first3=J|last4=Simons|first4=JS|title=The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies.|journal=Neuroscience and Biobehavioral Reviews|date=October 2016|volume=69|pages=113–23|doi=10.1016/j.neubiorev.2016.05.037|pmid=27473935}}</ref>
+One meta analysis of functional neuroiamging during acute auditory verbal hallucinations has reported increased activations in areas implicated in language, including the bilateral [[inferior frontal gyrus|inferior frontal]] and post central gyri, as well as the left parietal operculum.<ref>{{cite journal | vauthors = Kühn S, Gallinat J | title = Quantitative meta-analysis on state and trait aspects of auditory verbal hallucinations in schizophrenia | journal = Schizophrenia Bulletin | volume = 38 | issue = 4 | pages = 779–86 | date = June 2012 | pmid = 21177743 | pmc = 3406531 | doi = 10.1093/schbul/sbq152 }}</ref>  Another meta analysis during both visual and auditory verbal hallucinations, replicated the findings in the inferior frontal and postcentral gyri during auditory verbal hallucinations, and also observed hippocampal, superior temporal, insular and medial prefrontal activations.  Visual hallucinations were reported to be associated with increased activations in the secondary and associate visual cortices.<ref>{{cite journal | vauthors = Zmigrod L, Garrison JR, Carr J, Simons JS | title = The neural mechanisms of hallucinations: A quantitative meta-analysis of neuroimaging studies | journal = Neuroscience and Biobehavioral Reviews | volume = 69 | pages = 113–23 | date = October 2016 | pmid = 27473935 | doi = 10.1016/j.neubiorev.2016.05.037 }}</ref>
 === PET ===
-[[File:Schizophrenia PET scan.jpg|thumb|Data from a [[Positron emission tomography|PET]] study<ref name="Meyer-Lindenberg2002">{{vcite journal |author=Meyer-Lindenberg A, Miletich RS, Kohn PD, ''et al'' |title=Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia |journal=Nat. Neurosci. |volume=5 |issue=3 |pages=267–71 |year=2002 |month=March |pmid=11865311 |doi=10.1038/nn804}}</ref> suggests that the less the [[frontal lobe]]s are activated (<span style="color:red;">red</span>) during a [[working memory]] task, the greater the increase in abnormal [[dopamine]] activity in the [[striatum]] (<span style="color:green;">green</span>), thought to be related to the [[neurocognitive deficit]]s in schizophrenia.]]
+[[File:Schizophrenia PET scan.jpg|thumb|Data from a [[Positron emission tomography|PET]] study<ref name="Meyer-Lindenberg2002">{{cite journal | vauthors = Meyer-Lindenberg A, Miletich RS, Kohn PD, Esposito G, Carson RE, Quarantelli M, Weinberger DR, Berman KF | title = Reduced prefrontal activity predicts exaggerated striatal dopaminergic function in schizophrenia | journal = Nature Neuroscience | volume = 5 | issue = 3 | pages = 267–71 | date = March 2002 | pmid = 11865311 | doi = 10.1038/nn804 }}</ref> suggests that the less the [[frontal lobe]]s are activated (<span style="color:red;">red</span>) during a [[working memory]] task, the greater the increase in abnormal [[dopamine]] activity in the [[striatum]] (<span style="color:green;">green</span>), thought to be related to the [[neurocognitive deficit]]s in schizophrenia.]]
 [[Positron emission tomography|PET]] scan findings in patients with schizophrenia indicate cerebral blood flow decreases in the left [[parahippocampus|parahippocampal]] region. PET scans also show a reduced ability to metabolize glucose in the [[thalamus]] and [[frontal cortex]]. PET scans also show involvement of the [[Medial (anatomy)|medial]] part of the left [[temporal lobe]] and the [[limbic]] and frontal systems as suffering from developmental abnormality. PET scans show thought disorders stem from increased flow in the frontal and temporal regions while delusions and hallucinations were associated with reduced flow in the cingulate, left frontal, and temporal areas. PET scans done on patient who were actively having auditory hallucinations revealed increased blood flow in both thalami, left hippocampus,  right striatum, parahippocampus, orbitofrontal, and cingulate areas.<ref name="Shenton2001" />
-In addition, a decrease in NAA uptake has been reported in the hippocampus and both the grey and white matter of the [[prefrontal cortex]] of those with schizophrenia. NAA may be an indicator of neural activity of number of viable neurons. however given methodological limitations and variance it is impossible to use this as a diagnostic method.<ref>{{cite journal|last1=Steen|first1=R. Grant|last2=Hamer|first2=Robert M.|last3=Lieberman|first3=Jeffrey A.|title=Measurement of Brain Metabolites by 1H Magnetic Resonance Spectroscopy in Patients with Schizophrenia: A Systematic Review and Meta-Analysis|journal=Neuropsychopharmacology|date=10 August 2005|volume=30|issue=11|pages=1949–1962|doi=10.1038/sj.npp.1300850|url=http://www.nature.com/npp/journal/v30/n11/full/1300850a.html|language=en|issn=0893-133X}}</ref>  Decreased PFC connectivity has also been observed.<ref>{{cite book|last1=Davis|first1=Kenneth L.|last2=Neuropsychopharmacology|first2=American College of|title=Neuropsychopharmacology: The Fifth Generation of Progress : an Official Publication of the American College of Neuropsychopharmacology, Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia|publisher=Lippincott Williams & Wilkins|isbn=9780781728379|pages=731–743|url=https://books.google.com/?id=BKwkonZwZD0C&pg=PA739&lpg=PA739&dq=Chapter+53:+Neural+Circuitry+and+the+Pathophysiology+of+Schizophrenia#v=onepage&q=Chapter%2053%3A%20Neural%20Circuitry%20and%20the%20Pathophysiology%20of%20Schizophrenia&f=false|language=en|year=2002}}</ref> DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the [[Nigrostriatal pathway|nigrostriatal system]] demonstrating a dopaminergic dysregulation.<ref>{{Cite journal|last=Fusar-Poli|first=Paolo|last2=Meyer-Lindenberg|first2=Andreas|date=2013-01-01|title=Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies|journal=Schizophrenia Bulletin|volume=39|issue=1|pages=33–42|doi=10.1093/schbul/sbr180|issn=1745-1701|pmc=3523905|pmid=22282454}}</ref><ref>{{Cite journal|last=Weinstein|first=Jodi J.|last2=Chohan|first2=Muhammad O.|last3=Slifstein|first3=Mark|last4=Kegeles|first4=Lawrence S.|last5=Moore|first5=Holly|last6=Abi-Dargham|first6=Anissa|date=2017-01-01|title=Pathway-Specific Dopamine Abnormalities in Schizophrenia|journal=Biological Psychiatry|volume=81|issue=1|pages=31–42|doi=10.1016/j.biopsych.2016.03.2104|issn=1873-2402|pmid=27206569|pmc=5177794}}</ref>
+In addition, a decrease in NAA uptake has been reported in the hippocampus and both the grey and white matter of the [[prefrontal cortex]] of those with schizophrenia. NAA may be an indicator of neural activity of number of viable neurons. however given methodological limitations and variance it is impossible to use this as a diagnostic method.<ref>{{cite journal | vauthors = Steen RG, Hamer RM, Lieberman JA | title = Measurement of brain metabolites by 1H magnetic resonance spectroscopy in patients with schizophrenia: a systematic review and meta-analysis | journal = Neuropsychopharmacology | volume = 30 | issue = 11 | pages = 1949–62 | date = November 2005 | pmid = 16123764 | doi = 10.1038/sj.npp.1300850 }}</ref>  Decreased PFC connectivity has also been observed.<ref>{{cite book|last1=Davis|first1=Kenneth L. | name-list-format = vanc | author2 = American College of Neuropsychopharmacology |title=Neuropsychopharmacology: The Fifth Generation of Progress : an Official Publication of the American College of Neuropsychopharmacology, | chapter = Chapter 53: Neural Circuitry and the Pathophysiology of Schizophrenia|publisher=Lippincott Williams & Wilkins|isbn=9780781728379|pages=731–743| chapter-url = https://books.google.com/?id=BKwkonZwZD0C&pg=PA739&lpg=PA739 |year=2002}}</ref> DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the [[Nigrostriatal pathway|nigrostriatal system]] demonstrating a dopaminergic dysregulation.<ref>{{cite journal | vauthors = Fusar-Poli P, Meyer-Lindenberg A | title = Striatal presynaptic dopamine in schizophrenia, part II: meta-analysis of [(18)F/(11)C]-DOPA PET studies | journal = Schizophrenia Bulletin | volume = 39 | issue = 1 | pages = 33–42 | date = January 2013 | pmid = 22282454 | pmc = 3523905 | doi = 10.1093/schbul/sbr180 }}</ref><ref>{{cite journal | vauthors = Weinstein JJ, Chohan MO, Slifstein M, Kegeles LS, Moore H, Abi-Dargham A | title = Pathway-Specific Dopamine Abnormalities in Schizophrenia | journal = Biological Psychiatry | volume = 81 | issue = 1 | pages = 31–42 | date = January 2017 | pmid = 27206569 | pmc = 5177794 | doi = 10.1016/j.biopsych.2016.03.2104 }}</ref>
+{{clear}}
+== References ==
+{{reflist|32em}}
+== External links ==
-==References==
-{{reflist|30em}}
-==External links==
 *{{Commonscat-inline}}