Mechanisms of schizophrenia
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The mechanisms of schizophrenia that underlie the development of
schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social withdra ...
, a psychiatric disorder, are complex and not clearly understood. A number of
hypotheses A hypothesis (plural hypotheses) is a proposed explanation for a phenomenon. For a hypothesis to be a scientific hypothesis, the scientific method requires that one can test it. Scientists generally base scientific hypotheses on previous obser ...
including the dopamine hypothesis, and the glutamate hypothesis have been put forward in an attempt to explain the link between altered brain function and the symptoms and development of schizophrenia. Proposed models are separate from the proposed
causes Causes, or causality, is the relationship between one event and another. It may also refer to: * Causes (band), an indie band based in the Netherlands * Causes (company) Causes.com is a civic-technology app and website that enables users to orga ...
, which deal with the
risk factor In epidemiology, a risk factor or determinant is a variable associated with an increased risk of disease or infection. Due to a lack of harmonization across disciplines, determinant, in its more widely accepted scientific meaning, is often use ...
s that may lead to schizophrenia.


Pathophysiology

The exact pathophysiology of schizophrenia remains poorly understood. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. Other theories include the specific dysfunction of
interneuron Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. I ...
s, abnormalities in the immune system, abnormalities in
myelination Myelin is a lipid-rich material that surrounds nerve cell axons (the nervous system's "wires") to insulate them and increase the rate at which electrical impulses (called action potentials) are passed along the axon. The myelinated axon can be l ...
, and oxidative stress.


Dopamine dysfunction

The first formulations of the dopamine hypothesis of schizophrenia came from post-mortem studies finding increased numbers of D2/ D3 receptors in the
striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
, and elevated
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
levels of dopamine metabolites. Subsequently, most
antipsychotic Antipsychotics, also known as neuroleptics, are a class of Psychiatric medication, psychotropic medication primarily used to manage psychosis (including delusions, hallucinations, paranoia or disordered thought), principally in schizophrenia but ...
s were found to have affinity for D2 receptors. Later investigations have suggested a link between striatal dopamine synthesis and
positive symptoms Signs and symptoms are the observed or detectable signs, and experienced symptoms of an illness, injury, or condition. A sign for example may be a higher or lower temperature than normal, raised or lowered blood pressure or an abnormality showin ...
, as well as increased dopamine transmission in subcortical regions, and decreased transmission in cortical regions. A
meta-analysis A meta-analysis is a statistical analysis that combines the results of multiple scientific studies. Meta-analyses can be performed when there are multiple scientific studies addressing the same question, with each individual study reporting me ...
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 Amphetamine (contracted from alpha- methylphenethylamine) is a strong central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. It is also commonly used ...
release challenges observed significant differences between those with schizophrenia 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. 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. 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. 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, while dysregulated corticostriatal circuitry and reward circuitry in the form of
aberrant salience Salience (also called saliency) is that property by which some thing stands out. Salient events are an attentional mechanism by which organisms learn and survive; those organisms can focus their limited perceptual and cognitive resources on th ...
can give rise to delusions. 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. 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.


Glutamate dysfunction

Beside the dopamine hypothesis, interest has also focused on the neurotransmitter
glutamate Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
and the reduced function of the
NMDA glutamate receptor The ''N''-methyl-D-aspartate receptor (also known as the NMDA receptor or NMDAR), is a glutamate receptor and ion channel found in neurons. The NMDA receptor is one of three types of ionotropic glutamate receptors, the other two being AMPA and ...
in the pathophysiology of schizophrenia. This has largely been suggested by lower levels of
glutamate receptor Glutamate receptors are synaptic and non synaptic receptors located primarily on the membranes of neuronal and glial cells. Glutamate (the conjugate base of glutamic acid) is abundant in the human body, but particularly in the nervous system a ...
s found in postmortem brains of people previously diagnosed with schizophrenia and the discovery that glutamate blocking drugs such as phencyclidine and
ketamine Ketamine is a dissociative anesthetic used medically for induction and maintenance of anesthesia. It is also used as a recreational drug. It is one of the safest anesthetics, as, in contrast with opiates, ether, and propofol, it suppresses ne ...
can mimic the symptoms and cognitive problems associated with the condition. 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 Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic compound, organic chemical of the catecholamine and phenethylamine families. Dopamine const ...
function, all of which have been implicated in schizophrenia, have suggested an important mediating (and possibly causal) role of glutamate pathways in schizophrenia. Positive symptoms fail however to respond to glutamatergic medication. Reduced mRNA and protein expression of several NMDA receptor subunits has also been reported in postmortem brains from people with schizophrenia. In particular, the expression of mRNA for the NR1 receptor subunit, as well as the protein itself is reduced in the prefrontal cortex in post-mortem studies of those with schizophrenia. Fewer studies have examined other subunits, and results have been equivocal, except for a reduction in prefrontal NRC2. 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 Glutamate MDAreceptor subunit epsilon-1 is a protein that in humans is encoded by the ''GRIN2A'' gene. The canonical GluN2A subunit isoform encompasses 1464 amino acids. Alternative splicing can generate a primate-specific GluN2A-short isoform (12 ...
, GRIA1, SRR, and
GRM3 Metabotropic glutamate receptor 3 (mGluR3) is an inhibitory Gi/G0-coupled G-protein coupled receptor (GPCR) generally localized to presynaptic sites of neurons in classical circuits. However, in higher cortical circuits in primates, mGluR3 are lo ...
.


Interneuron dysfunction

Another hypothesis is closely related to the glutamate hypothesis, and involves the dysfunction of inhibitory
GABAergic In molecular biology and physiology, something is GABAergic or GABAnergic if it pertains to or affects the neurotransmitter GABA. For example, a synapse is GABAergic if it uses GABA as its neurotransmitter, and a GABAergic neuron produces GABA. A ...
interneuron Interneurons (also called internuncial neurons, relay neurons, association neurons, connector neurons, intermediate neurons or local circuit neurons) are neurons that connect two brain regions, i.e. not direct motor neurons or sensory neurons. I ...
s in the brain. They are local, and one type, the fast-spiking parvalbumin-positive interneuron, has been suggested to play a key role in schizophrenia pathophysiology. Early studies have identified decreases in
GAD67 Glutamate decarboxylase or glutamic acid decarboxylase (GAD) is an enzyme that catalyzes the decarboxylation of glutamate to gamma-aminobutyric acid (GABA) and carbon dioxide (). GAD uses pyridoxal-phosphate (PLP) as a cofactor. The reaction p ...
mRNA and protein in post-mortem brains from those with schizophrenia compared to controls. 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 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. Finally, excitatory synapse density is lower selectively on parvalbumin interneurons in schizophrenia and predicts the activity-dependent down-regulation of parvalbumin and GAD67. 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 those with schizophrenia, but these findings have remained inconclusive.
EEG Electroencephalography (EEG) is a method to record an electrogram of the spontaneous electrical activity of the brain. The biosignals detected by EEG have been shown to represent the postsynaptic potentials of pyramidal neurons in the neocortex ...
studies have indirectly also pointed to interneuron dysfunction in schizophrenia (see below). 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. 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 schizophrenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.


Myelination abnormalities

Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia. This theory originated from structural imaging studies, which found that white matter regions, in addition to grey matter regions, showed volumetric reductions in people with schizophrenia. In addition, gene expression studies have shown abnormalities in myelination and oligodendrocytes in the post-mortem brains. Furthermore, oligodendrocyte numbers appear to be reduced in several post-mortem studies. It has been suggested that myelination abnormalities could originate from impaired maturation of oligodendrocyte precursor cells, as these have been found to be intact in schizophrenia brains.


Immune system abnormalities

Inflammation Inflammation (from la, wikt:en:inflammatio#Latin, inflammatio) is part of the complex biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or Irritation, irritants, and is a protective response involving im ...
and immune system abnormalities are seen to be key mechanisms for the development of schizophrenia. A number of causes and consequences of inflammation have been implicated many of which are stress-related. Evidence suggests that early stress may contribute to the development of schizophrenia through alterations in the functioning of the immune system. Adverse childhood experiences (ACEs) for example can give
toxic stress Early childhood is a critical period in a child's life that includes ages from conception to five years old.Poulsen, Marie K., and Karen M. Finello. "Foundations of Early Childhood Mental Health: Public Health & Life Course Perspectives." Preventi ...
. ACEs and trauma can disrupt the control of immune responses and give rise to lasting inflammatory dysregulation throughout the nervous system. Chronic trauma can promote chronic immune system activation. Persistent systemic inflammation may lead to damage of the peripheral tissue and a subsequent breach of the blood-brain-barrier. If this happens
microglia Microglia are a type of neuroglia (glial cell) located throughout the brain and spinal cord. Microglia account for about 7% of cells found within the brain. As the resident macrophage cells, they act as the first and main form of active immune de ...
can be activated and cause
neuroinflammation Neuroinflammation is inflammation of the nervous tissue. It may be initiated in response to a variety of cues, including infection, traumatic brain injury,Ebert SE, Jensen P, Ozenne B, Armand S, Svarer C, Stenbaek DS ''et al.'' Molecular imaging of ...
. Inflammation can result in oxidative stress in schizophrenia which has damaging consequences for brain cells. The immune hypothesis is supported by findings of high levels of immune markers in the blood of people with schizophrenia. High levels of immune markers have also been associated with having more severe psychotic symptoms. Furthermore, a meta-analysis of genome-wide association studies discovered that 129 out of 136
single-nucleotide polymorphism In genetics, a single-nucleotide polymorphism (SNP ; plural SNPs ) is a germline substitution of a single nucleotide at a specific position in the genome. Although certain definitions require the substitution to be present in a sufficiently lar ...
s significantly associated with schizophrenia were located in the
major histocompatibility complex The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. These cell surface proteins are calle ...
region of the genome. A 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.


Oxidative stress

Another theory that has gained support is that a large role is played in the disease by oxidative stress. 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. Oxidative stress has been shown to affect maturation of oligodendrocytes, 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, which have also been found to be dysregulated in schizophrenia (see above). Evidence that oxidative stress and
oxidative DNA damage DNA oxidation is the process of oxidative damage of deoxyribonucleic acid. As described in detail by Burrows et al., 8-oxo-2'-deoxyguanosine (8-oxo-dG) is the most common oxidative lesion observed in duplex DNA because guanine has a lower one-e ...
are increased in various tissues of people with schizophrenia has been reviewed by Markkanen et al. The presence of increased oxidative DNA damage may be due, in part, to insufficient repair of such damages. Several studies have linked polymorphisms in
DNA repair DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA dam ...
genes to the development of schizophrenia. In particular, the
base excision repair Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from t ...
protein
XRCC1 DNA repair protein XRCC1, also known as X-ray repair cross-complementing protein 1, is a protein that in humans is encoded by the ''XRCC1'' gene. XRCC1 is involved in DNA repair, where it complexes with DNA ligase III. Function XRCC1 is invol ...
has been implicated.


Neuropathology

The most consistent finding in post-mortem examinations of brain tissue is a lack of neurodegenerative lesions or
gliosis Gliosis is a nonspecific reactive change of glial cells in response to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, ...
. Abnormal neuronal organization and orientation ( dysplasia) has been observed in the
entorhinal cortex The entorhinal cortex (EC) is an area of the brain's allocortex, located in the medial temporal lobe, whose functions include being a widespread network hub for memory, navigation, and the perception of time.Integrating time from experience in the ...
, 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. The reductions in prefrontal and increase in striatal spine densities seem to be independent of antipsychotic drug use.


GI tract dysfunction

It has been hypothesized that in some people, development of schizophrenia is related to
intestinal tract The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans and ...
dysfunction such as seen with non-celiac gluten sensitivity or abnormalities in the
gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut m ...
. A subgroup of persons with schizophrenia present an immune response to gluten differently from that found in people with celiac, with elevated levels of certain serum biomarkers of gluten sensitivity such as anti-gliadin IgG or anti-gliadin IgA antibodies. A link has been made between the
gut microbiota Gut microbiota, gut microbiome, or gut flora, are the microorganisms, including bacteria, archaea, fungi, and viruses that live in the digestive tracts of animals. The gastrointestinal metagenome is the aggregate of all the genomes of the gut m ...
and the development of TRS. The most prevalent cause put forward for TRS is that of mutation in the genes responsible for drug effectiveness. These include liver enzyme genes that control the availability of a drug to brain targets, and genes responsible for the structure and function of these targets. In the colon the bacteria encode a hundred times more genes than exist in the human genome. Only a fraction of ingested drugs reach the colon, having been already exposed to small intestinal bacteria, and absorbed in the
portal circulation In the circulatory system of animals, a portal venous system occurs when a capillary bed pools into another capillary bed through veins, without first going through the heart. Both capillary beds and the blood vessels that connect them are co ...
. This small fraction is then subject to the metabolic action of many communities of bacteria. Activation of the drug depends on the composition and enzymes of the bacteria and of the specifics of the drug, and therefore a great deal of individual variation can affect both the usefulness of the drug and its tolerability. It is suggested that parenteral administration of antipsychotics would bypass the gut and be more successful in overcoming TRS. The composition of gut microbiota is variable between individuals, but they are seen to remain stable. However, phyla can change in response to many factors including ageing, diet, substance use, and medications – especially antibiotics, laxatives, and antipsychotics. In FEP, schizophrenia has been linked to significant changes in the gut microbiota that can predict response to treatment.


Sleep disorders

It has been suggested that
sleep problems A sleep disorder, or somnipathy, is a medical disorder of an individual's sleep patterns. Some sleep disorders are severe enough to interfere with normal physical, mental, social and emotional functioning. Polysomnography and actigraphy are test ...
may be a core component of the pathophysiology of schizophrenia.


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.


Morphometry

Structural imaging studies have consistently reported differences in the size and structure of certain brain areas in schizophrenia. The largest combined neuroimaging study with over 2000 subjects and 2500 controls focused on subcortical changes. Volumetric increases were found in the lateral ventricles (+18%),
caudate nucleus The caudate nucleus is one of the structures that make up the corpus striatum, which is a component of the basal ganglia in the human brain. While the caudate nucleus has long been associated with motor processes due to its role in Parkinson's di ...
and pallidum, and extensive decreases in the
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
(-4%),
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
,
amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
and
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
. Together, this indicates that extensive changes do occur in the brains of people with schizophrenia. A 2006 meta-analysis of MRI studies found that whole brain and hippocampal volume are reduced and that ventricular volume is increased in those 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. In first episode psychosis typical antipsychotics like haloperidol were associated with significant reductions in gray matter volume, whereas atypical antipsychotics like olanzapine were not. Studies in non-human primates found gray and white matter reductions for both typical and atypical antipsychotics. Abnormal findings in the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...
,
temporal cortex The temporal lobe is one of the four major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe is involved in proc ...
and
anterior cingulate cortex In the human brain, the anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex that resembles a "collar" surrounding the frontal part of the corpus callosum. It consists of Brodmann areas 24, 32, and 33. It is involved ...
are found before the first onset of schizophrenia symptoms. These regions are the regions of structural deficits found in schizophrenia and first-episode subjects. Positive symptoms, such as thoughts of being persecuted, were found to be related to the medial prefrontal cortex,
amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
, and
hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...
region. Negative symptoms were found to be related to the
ventrolateral prefrontal cortex The ventrolateral prefrontal cortex (VLPFC) is a section of the prefrontal cortex located on the inferior frontal gyrus, bounded superiorly by the inferior frontal sulcus and inferiorly by the lateral sulcus. It is attributed to the ana ...
and
ventral striatum The striatum, or corpus striatum (also called the striate nucleus), is a nucleus (a cluster of neurons) in the subcortical basal ganglia of the forebrain. The striatum is a critical component of the motor and reward systems; receives glutamate ...
. Ventricular and third ventricle enlargement, abnormal functioning of the amygdala, hippocampus, parahippocampal gyrus, neocortical temporal lobe regions, frontal lobe, prefrontal gray matter, orbitofrontal areas, parietal lobs abnormalities and subcortical abnormalities including the
cavum septi pellucidi The cave of septum pellucidum (CSP), cavum septi pellucidi, or cavity of septum pellucidum is a slit-like space in the septum pellucidum that is present in fetuses but usually fuses during infancy. The septum pellucidum is a thin, laminated transl ...
, basal ganglia, corpus callosum, thalamus and cerebellar abnormalities. Such abnormalities usually present in the form of loss of volume. Most schizophrenia studies have found average reduced volume of the left medial
temporal lobe The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe ...
and left
superior temporal gyrus The superior temporal gyrus (STG) is one of three (sometimes two) gyri in the temporal lobe of the human brain, which is located laterally to the head, situated somewhat above the external ear. The superior temporal gyrus is bounded by: * the lat ...
, and half of studies have revealed deficits in certain areas of the
frontal gyrus The frontal gyri are four gyri of the frontal lobe in the brain. These are four horizontally oriented, parallel convolutions, of the frontal lobe. The other main gyrus of the frontal lobe is the precentral gyrus which is vertically oriented, and ...
,
parahippocampal gyrus The parahippocampal gyrus (or hippocampal gyrus') is a grey matter cortical region of the brain that surrounds the hippocampus and is part of the limbic system. The region plays an important role in memory encoding and retrieval. It has been inv ...
and temporal gyrus. However, at variance with some findings in individuals with chronic schizophrenia significant group differences of
temporal lobe The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe ...
and
amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
volumes are not shown in first-episode people on average. 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 and somewhat less widespread cortical thinning in occipital and parietal regions in people 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.
CT scan A computed tomography scan (CT scan; formerly called computed axial tomography scan or CAT scan) is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers ...
s of the brains of people with schizophrenia show several pathologies. The brain ventricles are enlarged as compared to normal brains. The ventricles hold
cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the bra ...
(CSF) and enlarged ventricles indicate a loss of brain volume. Additionally, the brains have widened sulci as compared to normal brains, also with increased CSF volumes and reduced brain volume. Using
machine learning Machine learning (ML) is a field of inquiry devoted to understanding and building methods that 'learn', that is, methods that leverage data to improve performance on some set of tasks. It is seen as a part of artificial intelligence. Machine ...
, two neuroanatomical subtypes of schizophrenia have been described. Subtype 1 shows widespread low grey matter volumes, particularly in the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
,
nucleus accumbens The nucleus accumbens (NAc or NAcc; also known as the accumbens nucleus, or formerly as the ''nucleus accumbens septi'', Latin for "nucleus adjacent to the septum") is a region in the basal forebrain rostral to the preoptic area of the hypotha ...
, medial temporal, medial prefrontal,
frontal Front may refer to: Arts, entertainment, and media Films * ''The Front'' (1943 film), a 1943 Soviet drama film * ''The Front'', 1976 film Music *The Front (band), an American rock band signed to Columbia Records and active in the 1980s and ea ...
, and insular cortices. Subtype 2 shows increased volume in the
basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...
and internal capsule, with otherwise normal brain volume.


White matter

Diffusion tensor imaging Diffusion-weighted magnetic resonance imaging (DWI or DW-MRI) is the use of specific MRI sequences as well as software that generates images from the resulting data that uses the diffusion of water molecules to generate contrast in MR images. It ...
(DTI) allows for the investigation of white matter more closely than traditional MRI. Over 300 DTI imaging studies have been published examining white matter abnormalities in schizophrenia. Although quite some variation has been found pertaining to the specific regions affected, the general consensus states a reduced
fractional anisotropy Fractional anisotropy (FA) is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A ...
in brains from people with schizophrenia versus controls. Importantly, these differences between subjects and controls could potentially be attributed to lifestyle effects, medication effects etc. Other studies have looked at people with first-episode schizophrenia that have never received any medication, so-called medication-naive subjects. These studies, although few in number, also found reduced
fractional anisotropy Fractional anisotropy (FA) is a scalar value between zero and one that describes the degree of anisotropy of a diffusion process. A value of zero means that diffusion is isotropic, i.e. it is unrestricted (or equally restricted) in all directions. A ...
in subject brains compared to control brains. As with earlier findings, abnormalities can be found throughout the brain, although the corpus callosum seemed to be most commonly effected.


Functional abnormalities

During
executive function In cognitive science and neuropsychology, executive functions (collectively referred to as executive function and cognitive control) are a set of cognitive processes that are necessary for the cognitive control of behavior: selecting and succe ...
tasks in people with schizophrenia, studies using
functional magnetic resonance imaging Functional magnetic resonance imaging or functional MRI (fMRI) measures brain activity by detecting changes associated with blood flow. This technique relies on the fact that cerebral blood flow and neuronal activation are coupled. When an area o ...
(fMRI) demonstrated decreased activity relative to controls in the bilateral
dorsolateral prefrontal cortex The dorsolateral prefrontal cortex (DLPFC or DL-PFC) is an area in the prefrontal cortex of the primate brain. It is one of the most recently derived parts of the human brain. It undergoes a prolonged period of maturation which lasts until adultho ...
(dlPFC), right
anterior cingulate cortex In the human brain, the anterior cingulate cortex (ACC) is the frontal part of the cingulate cortex that resembles a "collar" surrounding the frontal part of the corpus callosum. It consists of Brodmann areas 24, 32, and 33. It is involved ...
(ACC), and left mediodorsal nucleus of the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
. Increased activation was observed in the left ACC and left inferior parietal lobe. During emotional processing tasks, reduced activations have been observed in the medial prefrontal cortex, ACC, dlPFC and amygdala. A meta-analysis of facial emotional processing observed decreased activation in the
amygdala The amygdala (; plural: amygdalae or amygdalas; also '; Latin from Greek, , ', 'almond', 'tonsil') is one of two almond-shaped clusters of nuclei located deep and medially within the temporal lobes of the brain's cerebrum in complex verteb ...
, parahippocampus, lentiform nuclei, fusiform gyrus and right superior frontal gyrus, as well as increased activation in the left insula. One meta-analysis of fMRI 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. 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.


PET

PET scan Positron emission tomography (PET) is a functional imaging technique that uses radioactive substances known as radiotracers to visualize and measure changes in metabolic processes, and in other physiological activities including blood flow, r ...
findings in people with schizophrenia indicate
cerebral blood flow Cerebral circulation is the movement of blood through a network of cerebral arteries and veins supplying the brain. The rate of cerebral blood flow in an adult human is typically 750 milliliters per minute, or about 15% of cardiac output. Arterie ...
decreases in the left parahippocampal region. A reduced ability to metabolize glucose in the
thalamus The thalamus (from Greek θάλαμος, "chamber") is a large mass of gray matter located in the dorsal part of the diencephalon (a division of the forebrain). Nerve fibers project out of the thalamus to the cerebral cortex in all directions, ...
and
frontal cortex The frontal lobe is the largest of the four major lobes of the brain in mammals, and is located at the front of each cerebral hemisphere (in front of the parietal lobe and the temporal lobe). It is parted from the parietal lobe by a groove betwe ...
is also shown. PET scans show developmental abnormality in the medial part of the left
temporal lobe The temporal lobe is one of the four Lobes of the brain, major lobes of the cerebral cortex in the brain of mammals. The temporal lobe is located beneath the lateral fissure on both cerebral hemispheres of the mammalian brain. The temporal lobe ...
, and the
limbic The limbic system, also known as the paleomammalian cortex, is a set of brain structures located on both sides of the thalamus, immediately beneath the medial temporal lobe of the cerebrum primarily in the forebrain.Schacter, Daniel L. 2012. ''Ps ...
, and frontal systems. PET scans show that
thought disorder A thought disorder (TD) is any disturbance in cognition that adversely affects language and thought content, and thereby communication. A variety of thought disorders were said to be characteristic of people with schizophrenia. A content-thought ...
s stem from increased blood 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 carried out during active auditory hallucinations revealed increased blood flow in the thalamus, left hippocampus, right striatum, parahippocampus, orbitofrontal, and cingulate areas. In addition, a decrease in
NAA NAA or Naa may refer to: People * Naa Ashorkor (born 1988), Ghanaian actress and radio/ TV broadcaster * Naa Govindasamy (1946–1999), Singaporean Tamil-language writer and computer font developer * Naa Someswara, Indian science writer and T ...
uptake has been reported in the hippocampus and both the grey and white matter of the
prefrontal cortex In mammalian brain anatomy, the prefrontal cortex (PFC) covers the front part of the frontal lobe of the cerebral cortex. The PFC contains the Brodmann areas BA8, BA9, BA10, BA11, BA12, BA13, BA14, BA24, BA25, BA32, BA44, BA45, BA46, ...
. NAA may be an indicator of neural activity of number of viable neurons. However, given methodological limitations and variance it is not possible to use this as a diagnostic method. Decreased prefrontal cortex connectivity has also been observed. DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.


References


External links

*{{Commons category-inline Neuroscience of schizophrenia