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=== Dopamine dysfunction ===
=== Dopamine dysfunction ===
{{Main|Dopamine hypothesis of schizophrenia}}
{{Main|Dopamine hypothesis of schizophrenia}}
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>]]s 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.
An influential theory, known as the "dopamine hypothesis of schizophrenia", proposes that a malfunction involving dopamine pathways is therefore the cause of (the positive symptoms of) schizophrenia, with a particular focus on the function of [[dopamine]] in the [[mesolimbic pathway]] of the brain. This focus largely resulted from the accidental finding that a drug group which blocks dopamine function, known as the [[phenothiazines]], could reduce psychotic symptoms. It is also supported by the fact that [[amphetamine]]s, which trigger the release of dopamine, may exacerbate the psychotic symptoms in schizophrenia.<ref name="Laruelle1996">{{vcite journal |author=Laruelle M, Abi-Dargham A, van Dyck CH, ''et al'' |title=Single photon emission computerized tomography imaging of amphetamine-induced dopamine release in drug-free schizophrenic subjects |journal=Proc. Natl. Acad. Sci. U.S.A |volume=93 |issue=17 |pages=9235–40 |year=1996 |month=August |pmid=8799184 |pmc=38625 |doi=10.1073/pnas.93.17.9235}}</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|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 : the journal of mental science|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>
The theory proposes that excess activation of [[Dopamine receptor D2|D<sub>2</sub> receptors]] underlies the positive symptoms of schizophrenia. Although postulated for about 20 years based on the D<sub>2</sub> blockade effect common to all antipsychotics, it was not until the mid-1990s that [[Positron emission tomography|PET]] and [[SPET]] imaging studies provided supporting evidence. This explanation is now thought to be simplistic, partly because newer antipsychotic medication (called [[atypical antipsychotic]] medication) can be equally effective as older medication (called [[typical antipsychotic]] medication), but also affects [[serotonin]] function and may have slightly less of a [[dopamine]] blocking effect.<ref name="JonesPilowsky2002">{{vcite journal |author=Jones HM, Pilowsky LS |title=Dopamine and antipsychotic drug action revisited |journal=Br J Psychiatry |volume=181 |pages=271–5 |year=2002 |month=October |pmid=12356650 |doi=10.1192/bjp.181.4.271}}</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>
Evidence for this theory includes the observation that dopamine [[Dopamine receptor D2|dopamine D<sub>2</sub> receptors]] agonists and releasing agents exacerbate symptoms of schizophrenia, while many antipsychotics block [[Dopamine receptor D2|dopamine D<sub>2</sub> receptors]] <ref>{{vcite book |author=Martin S |title=An Atlas of Schizophrenia |publisher=Taylor & Francis |location=Washington, DC |year=2002 |isbn=1-85070-074-5 |page= 54}}</ref><ref>{{vcite journal |author=Creese I, Burt DR, Snyder SH |title=Dopamine receptor binding predicts clinical and pharmacological potencies of antischizophrenic drugs |journal=Science |volume=192 |issue=4238 |pages=481–3 |year=1976 |month=April |pmid=3854 |doi=10.1126/science.3854}}</ref><ref>{{vcite journal | doi = 10.1016/S0166-2236(84)80062-4 | author = Angrist B, van Kammen DP | year = 1984 | title = CNS stimulants as a tool in the study of schizophrenia | url = | journal = Trends in Neurosciences | volume = 7 | pages = 388–90 }}</ref><ref>{{vcite journal |author=Lieberman JA, Kane JM, Alvir J |title=Provocative tests with psychostimulant drugs in schizophrenia |journal=Psychopharmacology |volume=91 |issue=4 |pages=415–33 |year=1987 |pmid=2884687 |doi= 10.1007/BF00216006}}</ref> Furthermore, post-mortem studies have suggested increased density of dopamine D<sub>2</sub> receptors in the [[striatum]].


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 though 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>
The importance of the dopamine theory has been further strengthened by the finding for common variant in the dopamine D2 receptor as candidate loci for the disease, as identified by the large genome-wide association study which included over 35,000 cases and over 110,000 controls.<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>

⚫
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>


=== Glutamate abnormalities ===
=== Glutamate abnormalities ===

Revision as of 04:21, 10 September 2017

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

Main article: Dopamine hypothesis of schizophrenia

The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased striatal availability of [[Dopamine D2 receptor|D2]/D3s 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 though to lead to improper formation of beliefs.[17]

Glutamate abnormalities

Main article: Glutamate hypothesis of schizophrenia

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 the 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]

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.[23]

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.[24] Interestingly, 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.[25] Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67.[26] 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).[27] These studies have pointed to abnormalities in oscillatory activity in schizophrenia, particularly in the gamma band (30–80 Hz). Interestingly, gamma band activity appears to originate from intact functioning parvalbumin-positive interneuron.[28] 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.[29]

Myelination abnormalities

Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia.[30][31][32] 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.[33]

It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells,[34] 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.[35] The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients.[36] High levels of immune markers have also been associated with having more severe psychotic symptoms.[37][38] 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.[39]

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.[40]

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][41][42] 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.[43]

Oxidative stress has been shown to affect maturation of oligodendrocytes,[44] 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,[45] which have also been found to be dysregulated in schizophrenia (see above).

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.[46]

MRI

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.[47] 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.[48] In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not.[49] Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics.[50]

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.[51] 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.[51]

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.[52]

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.[53] 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.[54]

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[55][56] and somewhat less widespread cortical thinning in occipital and parietal regions[56] 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.[57]

DTI

Diffusion tensor imaging (DTI) allows for the investigation of white matter more closely than traditional MRI.[52] Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia.[58][59] 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.

CT

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.[52][60]

Functional abnormalities

PET

Data from a PET study[61] suggests that the less the frontal lobes are activated (red) during a working memory task, the greater the increase in abnormal dopamine activity in the striatum (green), thought to be related to the neurocognitive deficits in schizophrenia.

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.[52]

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.[62] Decreased PFC connectivity has also been observed.[63] DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.[64][65]

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