Mechanisms of 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, the most important of which are the dopamine hypothesis and the glutamate hypothesis. Note that these theories are separate from the causes of schizophrenia, which deal with actual starting points of the illness instead, e.g. genetic and environmental factors. The current theories attempt to explain how changes in brain functioning can contribute to symptoms of the disease.
The exact pathophysiology of schizophrenia remains poorly understood. Since the coining of schizophrenia by Eugene Bleuler in 1908, a variety of theories have been proposed concerning its underlying pathophysiology. The most commonly supported theories are the dopamine hypothesis and the glutamate hypothesis. More recent theories center around specific dysfunction of interneurons, abnormalities in the immune system, abnormalities in myelination, and oxidative stress.
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 amphetamines, which trigger the release of dopamine, may exacerbate the psychotic symptoms in schizophrenia.
The theory proposes that excess activation of D2 receptors underlies (the positive symptoms of) schizophrenia. Although postulated for about 20 years based on the D2 blockade effect common to all antipsychotics, it was not until the mid-1990s that 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.
Evidence for this theory includes findings that the potency of many antipsychotics is correlated with their affinity to dopamine D2 receptors; and the exacerbatory effects of a dopamine agonist (amphetamine) and a dopamine beta hydroxylase inhibitor (disulfiram) on schizophrenia; and post-mortem studies initially suggested increased density of dopamine D2 receptors in the striatum. Such high levels of D2 receptors intensify brain signals and can exacerbate positive symptoms (i.e. hallucinations and paranoia) in schizophrenia. Impaired glutamate (a neurotransmitter which directs neuron to pass along an impulse) activity appears to be another source of schizophrenia symptoms.
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.
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 can give rise to delusions.
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 and the discovery that the glutamate blocking drugs such as phencyclidine and ketamine 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 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 patients with schizophrenia.
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.
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. 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. 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. 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 the patients with schizophrenia, but these findings have remained inconclusive.
EEG 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). Interestingly, 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 schizophenia, published in 2015, was the first genetic evidence for the broad involvement of GABAergic neurotransmission.
Another hypothesis states that abnormalities in myelination are a core pathophysiology of schizophrenia. 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.
Immune system abnormalities
Another hypothesis postulates that inflammation and immune system abnormalities could play a central role in the disease. 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. The immune hypotheses is supported by findings of high levels of immune markers in the blood of schizophrenia patients. 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 polymorphisms (SNP) significantly associated with schizophrenia were located in the major histocompatibility complex region of the genome.
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.
A theory that has gained more support in recent years 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).
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.
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. 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. 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, 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. 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.
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.
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. 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.
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 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.
Diffusion tensor imaging (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 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.
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.
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.
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. Decreased PFC connectivity has also been observed. DOPA PET studies have confirmed an altered synthesis capacity of dopamine in the nigrostriatal system demonstrating a dopaminergic dysregulation.
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