Structural neuroimaging studies have multiplied over the last 20 years to try and advance our understanding of the pathophysiology that underlies schizophrenia and other psychoses. What these studies seem to have established is that there are indeed differences in the volume of certain brain areas between individuals affected by psychoses and those non-affected, with smaller volumes of medial temporal and frontal regions, and larger cerebral ventricles in affected individuals. Furthermore, they suggest that these differences are already evident at illness onset and possibly even in never-treated individuals in the prodromal stage, before full-blown psychotic symptoms emerge . This evidence has suggested that the brain alterations seen in psychosis may be long-standing, possibly resulting from an altered development of the central nervous system, and that they are not solely the result of antipsychotic treatment. While most of these studies evaluated grey matter, the more recent availability of techniques such as diffusion tensor imaging has also allowed the evaluation of the putative integrity (most often expressed as fractional anisotropy) of the white matter tracts connecting these grey matter regions. Studies that have used this approach additionally found the presence of a disrupted integrity, particularly in the white matter tracts connecting frontal and temporal areas, suggesting the presence of a ‘disconnection’ between grey matter areas that they link . It follows that the concomitant evaluation of both grey and white matter offers an advantageous approach, as it provides complementary information on multiple aspects of brain pathophysiology. This approach becomes even more informative when it is used to explore the correlation between brain alterations and specific clinical manifestations of the disease. Among these, negative symptoms and cognitive deficits are particularly interesting, as their presence has been associated with a less favourable response to treatment and with poorer clinical and functional outcomes. Understanding more about what neuroanatomical changes are associated with predictors of poor outcome, early in the illness, is the next step in the application of neuroimaging if this has to provide not only a basis for patient stratification in treatment trials in psychiatry, but also potentially inform the individualized treatment and management of psychiatric disorders.
The article ‘Anatomical substrates of cognitive and clinical dimensions in first episode schizophrenia’ , published in this edition of the Journal, has followed exactly this approach. The authors have recruited a sample of individuals at their first episode of a non-affective psychosis and compared them to a group of healthy individuals. The clinical sample included in the study is noticeable in that it was composed by patients with a relatively brief duration of untreated illness (an average of 8 months), who had received only few days of treatment with antipsychotic drugs, and who had no history or current drug use. These are in fact all factors that could potentially affect brain structure. In these patients, the authors evaluated both grey and white matter structure, as well as symptom profile and cognitive function. They then explored whether or not there was a correlation between grey and white matter structure and specific symptom profiles evaluated with the Positive and negative syndrome scale (PANSS) (disorganized/cognitive and negative), and cognitive performance in tasks in which the patients performed significantly worse than the healthy controls, namely social cognition, speed of processing and verbal memory.
The study found that the presence of disorganized/cognitive symptoms was associated with both smaller volume and altered white matter integrity of the cerebellum. This is a region reported as important in the pathophysiology of schizophrenia, and in the cognitive impairments observed in this disorder. The finding of changes in both grey and white matter in this structure suggests a major alteration in its neuroanatomy.
Interestingly, the presence of more negative symptoms was associated with altered integrity of white matter tracts connecting for example frontal and temporal brain regions. This finding links nicely with the hypothesis that the pathophysiology of psychosis involves a disconnection between frontal and temporal brain regions, additionally suggesting that this disconnection may be associated with a different symptom profile. It is also interesting that these symptoms were not associated with grey matter volume reductions, which may reflect either a lack of power due to the relatively small sample size, or the fact that in this early illness stage negative symptoms and grey matter volume reductions are not particularly marked.
In terms of the cognitive tasks evaluated, the main finding of this article was that the presence of an impairment in social cognition, evaluated as the ability to recognize the emotion of a face presented on a computer screen, was associated with a reduction in both volume and integrity of temporal regions, and in white matter tracts reported as altered in schizophrenia, such as the anterior thalamic radiation and the superior longitudinal fasciculus . As the authors discuss, these brain areas are relevant to both the visual analysis of faces, and also to the derivation of meaning from face perception. The finding of grey and white matter alterations in these brain areas proposes a neural basis for the functional social cognition impairments found in schizophrenia, which are often proposed as key factors in poor functional outcome.
Taken together, the findings of this study suggest that there are indeed certain clinical manifestations, in terms of both symptoms and cognition, which have specific association with some of the neuroanatomical brain alterations seen in psychosis, and which most importantly are already evident at illness onset. It is of note that in this study the patients had been exposed to minimal treatment with antipsychotics, hence the structural changes observed are not likely to be due to differences in treatment in patients with these clinical and cognitive signs. It is also noticeable that patients had no current or past use of illicit drugs, another important confounder often present in neuroimaging studies of individuals with psychosis. Therefore, the findings lend further support to the hypothesis that at least some brain changes in psychosis have a neurodevelopmental origin, and possibly characterize a subgroup of patients who present with particularly marked disorganized and negative symptoms, as well as with cognitive impairments.
The presence of brain changes that may have a neurodevelopmental origin, and that as such are already present at illness onset, is particularly important in the application of structural neuroimaging to the clinical diagnosis and management of psychiatric disorders. For example, the recent use of methods of analysis that take into consideration the distributed nature of brain volumes changes observed in psychosis, has shown that structural neuroimaging data obtained at illness onset can be used to predict, with significant accuracy, subsequent clinical outcome . This evidence suggests that there may be a subgroup of patients that could potentially be identified already at the time of first presentation to services, who are less likely to benefit from standard treatment. For example, we know that about 60% of patients do not show a good response to their first antipsychotic drug, with no or only partial amelioration of symptoms. We also know that patients presenting with more negative and disorganized symptoms, and with cognitive impairment are those less likely to respond to medication and less likely to have a good prognosis. It is possible that these individuals represent a group with a different underlying pathophysiological substrate, characterized by more marked neuroanatomical grey and white matter changes, already evident at illness onset.
Studying neuroanatomical markers together with clinical and cognitive measures could potentially help in the early identification of those patients less likely to respond to pharmacological treatment and less likely to have a good outcome, ultimately allowing early individualized patient management. Furthermore, if brain connectivity is indeed involved in the presentation of more resistant clinical symptoms, treatments that restore connectivity may help individuals who do not currently respond to standard antipsychotic treatment.