Results
The pneumoencephalography studies in the 1920s and ’30s, and the CT research carried out in the 1970s and ’80s, showed already that patients with schizophrenia have larger brain ventricles than healthy control subjects at group level, and more recent MRI research has confirmed this (4) . Cohen’s d can be used as a measure of the effect size when measuring differences between groups. d < 0.4 is considered a small effect, d = 0.4 – 0.8 medium, and d > 0.8 large. Meta-analyses show a moderately enlarged lateral ventricular volume in chronic schizophrenia (d = 0.49) (5) and in first-episode schizophrenia (d = 0.61 (left) and 0.47 (right)) (6) . In a Norwegian subject sample we found a moderately enlarged ventricular volume (d = 0.41 (right) and d = 0.38 (left)) (7) . One hypothesis is that an enlarged ventricular volume may be associated with volume diminution in other brain structures (8) . It may be that when the volume of grey and white matter is smaller, the ventricular volume will be greater in order to «fill up» the intracranial volume.
Total brain volume has been used as an indirect measurement of structural integrity. Smaller total brain volume has been found in patients with schizophrenia compared with healthy control subjects (9) , but subjected to meta-analysis the effect size is small (d = – 0.25) (5) . Similarly, in another meta-analysis a smaller total volume (of 2.7 %) was reported in first-episode schizophrenia compared with healthy control subjects (10) .
When the total volume is smaller and the ventricles enlarged, the question is whether there are certain regions or structures where the volume reduction is more pronounced. The following is a brief review of the best replicated findings (for illustration, see Figs. 1 and 2):
Fig. 1 Coronal section of T1-weighted MR image, automatic volume estimation using MRI post-processing tool FreeSurfer. R = right, S = superior
Fig. 2 Three-dimensional illustration of subcortical structures based on a template from the MRI post-processing tool FreeSurfer. Illustration © Ørjan Bergmann
The hippocampus is located medially in the temporal lobe of the brain and is important for verbal learning and memory. It is generally reported to be smaller in patients with schizophrenia than in healthy control subjects (4, 9) , a finding we have also reported from two Scandinavian cohorts (7, 11, 12) . In a recently published meta-analysis of 44 MRI studies, the effect size was found to be medium (d = – 0.48 and – 0.53 for the left and right hippocampus respectively) (13) , and there was no difference between first-episode and chronic schizophrenia. That the changes were present at onset of the illness may indicate that the hippocampal volume reduction in schizophrenia is developmentally related. The hippocampal volume reduction may represent a loss of grey matter, which may be significant for cognitive functions like learning and memory, which have been shown to be impaired in schizophrenia (14) .
A number of studies, including our own (7, 11, 15) , as well as several meta-analyses (5, 16, 17) , have demonstrated in cases of schizophrenia an enlarged volume of the basal ganglia, especially pronounced in the globus pallidus. The basal ganglia are rich in dopamine fibres, and changes may therefore be difficult to interpret since the structures are affected by antidopaminergic antipsychotics (18) .
The thalamus, a mid-line structure that borders on the ventricles, has proved to be smaller in patients with schizophrenia (19) . In one meta-analysis, an effect size has been found of d = – 0.32 (right) and d = – 0.33 (left) in chronic schizophrenia and d = – 0.45 (right) and d = – 0.48 (left) in first-episode schizophrenia (20) . The thalamus functions as a key node in the brain’s cognitive processes, and one hypothesis is that the flow of information between different areas of the brain is disrupted in schizophrenia (21) .
The cortex is a complex structure with sulci and gyri. The neurons in the cortex are among other things involved in volitionally controlled and complex cognitive processes. The first MRI studies found a smaller cortical volume, particularly in the frontal and temporal lobes (4) . This volume loss has been replicated in a number of later studies and may reflect a reduction of neuropil (unmyelinated nerve cells, synapses and glial cells), as has been found in neuropathological post mortem studies of schizophrenia patients (22) . A smaller volume may be caused by a reduction in thickness and/or area (volume = thickness x area). In our group’s study from Oslo, we found a thinner cortex and a smaller area and volume in schizophrenia, where the changes in volume were «driven» by the reduction in thickness (23) . This finding is consistent with several other studies that show a thinner cortex, most pronounced in the frontal and temporal areas, in schizophrenia (24) – (26) .
Reduced cortical folding (gyrification) in schizophrenia has been found in a number of studies, but it has also been shown and replicated in other studies that one area in the right frontal lobe has increased gyrification (27) – (30) . This is particularly interesting because the cortex folds naturally so that communicating areas come closer to one another (reducing the distance for nerve signals) (31) . It is also known that gyrification takes place prenatally (31) , which points towards the changes in cortical folding representing early developmental disorders. This in turn supports the theory that schizophrenia has an aetiology related to abnormal neurodevelopment.
Whether or not the anatomy of the brain changes over time in schizophrenia may say something about the underlying pathophysiology. Longitudinal changes in cortical thickness, but not in area, have been shown in schizophrenia (32) , and it has been found that a reduction in cortical thickness over time correlates with the severity of the disorder (33) . In first-episode schizophrenia, longitudinal reductions have been shown in the grey matter in the frontal lobe and thalamus and in the white matter in frontal, temporal and parietal areas. The changes were most evident in the first few years following onset of the disorder and were consistent with impaired cognitive function, but not with other symptoms (34) . In one meta-analysis of 27 studies, longitudinal changes were found in both grey and white matter (35) . It has been suggested that progressive changes may be related to the use of antipsychotics or may represent degenerative processes, but this is controversial. There is also some uncertainty as to whether there are real longitudinal changes or whether the findings represent methodological weaknesses.