Resumen:

Actualmente existe gran cantidad de estudios y reportes sobre cambios cerebrales de pacientes con esquizofrenia. Los hallazgos obtenidos mediante estudios de imagen por resonancia magnética han aportado importantes conocimientos en relación con las diferencias estructurales en el cerebro de dichos pacientes.

Entre las anomalías estructurales reportadas con mayor frecuencia en pacientes con esquizofrenia crónica se encuentran un aumento en el tamaño de los ventrículos laterales, una disminu ción en el volumen cerebral total y disminuciones en el volumen de áreas temporales, frontales y parietales.

No obstante, aún resta definir si dichos cambios estructurales se presentan al inicio de la enfermedad o antes de la aparición de los síntomas psicóticos, si son producto de la cronicidad de la enfermedad o del empleo de medicamentos antipsicóticos, y si tales anomalías en la estructura cerebral muestran un comportamiento relativamente estático o sufren cambios conforme avanza la enfermedad.

La mayoría de los estudios de imagen por resonancia magnética realizados en etapas iniciales de la enfermedad, es decir en pacientes que cursan con un primer episodio de psicosis, han reportado un patrón de anomalías cerebrales muy similar al de los pacientes crónicos, aunque de menor magnitud. En el caso específico del lóbulo temporal, estructura cerebral que tradicionalmente se ha implicado en la fisiopatología de la esquizofrenia, la mayoría de los estudios reportan alteraciones de regiones temporales, sobre todo una reducción en el volumen de estructuras de la región temporo-mesial y el giro temporal superior. Otros estudios, sin embargo, han reportado resultados contrarios, como un aumento discreto en el volumen del lóbulo temporal o una ausencia de diferencias significativas al comparar los volúmenes con los del grupo de sujetos control, incluso en estudios longitudinales de seguimiento.

Debido a esta relativa ambigüedad en los resultados, decidimos realizar una búsqueda sistemática sobre estudios de imagen por resonancia magnética en pacientes con un PEP de esquizofrenia que evaluaran el volumen de estructuras del lóbulo temporal. Posteriormente, efectuamos un metanálisis de los resultados para examinar estadísticamente las pruebas publicadas sobre las alteraciones estructurales del lóbulo temporal en dichos pacientes.

Dieciocho estudios reunieron los criterios de inclusión para el presente análisis; en conjunto se incluyó a 575 pacientes que experimentaran un PEP y a 738 sujetos control. Asumiendo un volumen de 100% en el grupo control, encontramos que el volumen cerebral medio de las estructuras temporales fue menor en los pacientes con PEP (95%), al igual que el volumen regional de la amígdala izquierda (95%), el complejo hipocampo-amigdalino (derecho 94%, izquierdo 92%), el hipocampo (derecho 96%, izquierdo 85%) y el lóbulo temporal izquierdo (97%). El volumen del lóbulo temporal derecho fue discretamente mayor (104%) y no se encontró ninguna diferencia en el volumen de la amígdala derecha.

En conclusión, los resultados obtenidos después de haber realizado este análisis cuantitativo de las pruebas publicadas en la bibliografía sugieren que, durante la presentación de un primer episodio de psicosis, los pacientes con esquizofrenia presentan diferencias estructurales en los lóbulos temporales, y disminuciones particularmente discretas en el volumen de las estructuras de la porción mesial del lóbulo temporal, hallazgos que concuerdan con la concepción de la esquizofrenia como un trastorno neuropsiquiátrico con una marcada deficiencia en los lóbulos temporales.

Palabras clave: Esquizofrenia; primer episodio psicótico; resonancia magnética; imagen cerebral; lóbulo temporal

Abstract:

Magnetic resonance imaging (MRI) has been useful in revealing subtle structural differences in the brains of schizophrenic patients compared with healthy controls. MR structural analyses have revealed a number of brain abnormalities including ventricular enlargement, total brain volume reduction, and regional reductions in brain volume in frontal, parietal and temporal regions.

However, it is still unknown whether the brain abnormalities observed with MRI in schizophrenia are confounded by chronicity or whether there is a continual degenerative process. Evaluation of the brain structure during the first episode of psychosis (FEP) is a powerful strategy for investigating these fundamental questions. The first-episode design avoids the confusion of chronicity of illness, longstanding substance abuse, and the effects of treatment.

Structural MRI studies of patients experiencing a first-episode psychosis have revealed a similar pattern of brain abnormalities as in samples of chronic patients, although deficits may be less extensive. The temporal lobe, a brain structure traditionally implicated in the pathophyisiology of schizophrenia, has been examined often in first-episode studies. Many studies have reported significant abnormalitites in the medial areas and superior temporal gyri. However, most studies examining the whole temporal lobe have been unable to show such significant abnormalities.

In the light of the increasing amount of ambiguous findings regarding structural temporal lobe abnormalities in patients with schizophrenia experiencing their first-episode of psychosis, a quantitative review of the existing literature was needed to better characterize the temporal lobe deficits observed with MRI in those patients.

Thus we conducted a systematic review of structural MRI studies of patients with first-episode schizophrenia in which volume measurements of temporal lobe structures were reported. Using meta-analytical methods, we carried out an analysis of the temporal lobe volumes in these FEP patients and the comparison subjects. In addition to solving the problems of traditional narrative reviews, a meta-analysis provides tools for integrating quantitative data from multiple studies, improving the overall effect size of variables of interest, and increasing statistical power.

Eighteen studies were identified as suitable for the present analysis. These studies included 575 FEP patients and 738 control subjects. The average number of patients across studies was 32. The majority of patients in the studies were male (62%) and the average age of patients was 27 years old. In terms of structural brain findings, and assuming a volume of 100% in the comparison group, we found that the mean temporal volume of subjects with FEP was smaller (95%), as well as the analysis of regional structures such as left amygdala (95%), hippocampus-amygdala (left 92%, right 94%), hippocampus (left 85%, right 96%), and left temporal lobe (97%). Right temporal lobe volume was slightly greater (104%) and there was no difference in the volume of the right amygdala.

Although this review was focused on evaluating the findings on temporal lobe deficits in patients with a first episode of psychosis, other brain region volumes were analyzed. The whole brain volume (95%) and frontal lobe volume (right 98%, left 99%) were lower in patients than in the comparison subjects.

It is important to consider several potential limitations of this study. The first one has to do with the methodology employed to analyze structural MRI data. The method of choice in investigating the distribution of subtle cerebral pathology in schizophrenia has been an examination of anatomically defined regions of interest (ROI) within the brain. This method has some limitations, including the manual tracing of ROI on successive brain slices, a time consuming process that does not easily allow for the comparison of many brain regions or for the examination of volume differences in large samples of subjects. Furthermore, the question of validity is relevant as the ROI is investigator-determined and depends on the complex interindividual variability of the brain.

The other method used in two studies included in this review is the voxel-based morphometry (VBM). This is an automated statistical method for examining structural MR images of the brain. VBM methodology makes voxel-wise comparisons of the local concentrations of grey matter between two groups of subjects and offers a more rapid and extensive survey of grey matter abnormalities in patients than ROI analysis. An important limitation of this methodology is that it has less regional sensitivity compared to the ROI technique and that these differences have to be considered in the interpretation of the results.

Secondly, although our review only considered studies with patients experiencing a first episode of psychosis in schizophrenia (and not affective psychotic disorders), the fact that different investigators used somewhat different criteria when making their diagnoses could have introduced a potential bias in our inclusion process. Thus, it is possible that our results can not be generalized to the full population of first-episode patients. For instance, although most of the studies included used either DSM-IV diagnostic criteria (16 studies) or the Research Diagnostic Criteria (2 studies), variability may arise because many authors did not consider previous psychotic episodes in which patients were treated with antipsychotic medications for less than 30 days.

In conclusion, this meta-analysis suggests that schizophrenic patients present temporal lobe differences, mainly diminished volume values in mesial temporal lobe structures during the initial presentation of a first episode of their illness. However, our results indicated that there was also evidence of global volume changes and regional volume decreases in the frontal lobes of these patients. This data, derived from patients in the early courses of their illness, is compatible with developmental hypotheses of schizophrenic abnormalities and with the view of schizophrenia as a neuropsychiatric disorder with marked deficits in the temporal lobes.

However, the central questions in schizophrenia research regarding which brain abnormalities are independent of psychosis and which evolve before and after psychosis begins still remain unanswered. We think that these questions can be addressed by longitudinal neuroimaging studies beginning in the prodromal phase of the illness or by evaluating high-risk subjects during the critical period of transition to first-episode psychosis.

Key words: Schizophrenia; first-episode of psychosis; magnetic resonance imaging; brain imaging; temporal lobe