In the preceding paragraphs we have discussed data suggesting dysfunction of white matter components and in diffusion weighted MRI in schizophrenia without a particular attention to specific white matter tracts. In general, FA is globally decreased (Douaud et al., 2007
; Kubicki et al., 2007
), but there are some tracts which present increased FA in schizophrenia patients in comparison to controls (Kubicki et al., 2007
). Also, although low FA is usually associated to poor cognitive performance in healthy as well as in some clinical populations (Turken et al., 2008
), in schizophrenia this is not always the case (Okugawa et al., 2006
). Since an exhaustive review of the white matter changes in schizophrenia is beyond the scope of this paper, over the next few paragraphs we will focus on those changes that have been shown to correlate specifically with models of symptom generation which may help understand the relationship between anisotropy and functional changes. We will pay particular attention in our comments to studies of subcortical white matter (Table ) which have not been specifically discussed in currently published reviews even though several original publications have become available (see below).
Fractional anisotropy in subcortical white matter of subjects with schizophrenia.
Schizophrenia is reportedly associated with reduced FA in frontal regions, which correlates with cognitive and motor deficits in patients (Walther et al., 2011
). In addition, better performance on attention and executive function tasks was associated with higher levels of FA in task-relevant regions in subjects with schizophrenia (Lim et al., 2006
). But contrary to the excessively simplistic postulate that more FA is always better, patients who hear conversing hallucinations have increased FA in interhemispheric auditory fibers compared to patients without this symptom or, to a lesser extent, to healthy controls (Mulert et al., 2012
). Moreover, higher FA in fibers connecting temporal regions (such as the arcuate fasciculus or the superior longitudinal fasciculus) was found to be associated with increased severity of hallucinations in schizophrenia patients (Hubl et al., 2004
; Seok et al., 2007
; Shergill et al., 2007
; Rotarska-Jagiela et al., 2009
The arcuate fasciculus connects the posterior temporal gyrus with the inferior frontal gyrus which underlies speech and vocal processing. Increased FA in the arcuate fasciculus bilaterally is likely to contribute to the pathophysiology underlying hallucinations in schizophrenia (Alba-Ferrara et al., 2012
); it combines with reduced functional connectivity between the posterior superior temporal gyrus and the anterior cingulate cortex resulting in difficulties to judge whether verbal stimuli are originated in the brain or come from an external source (Alba-Ferrara et al., 2012
). As a result of such changes, persons with schizophrenia would misidentify self-generated auditory objects as coming from external sources (Mechelli et al., 2007
), causing or contributing to hallucinations. Alternatively, but not necessarily in contradiction, diffusion abnormalities may decrease speed of axonal transmission speed resulting in neural timing abnormalities. Indeed, schizophrenia patients experience time-delayed corollary discharges to self-generated auditory stimuli, resulting in aberrant suppression of the sensory consequences of self-generated actions (Whitford et al., 2011
). Thus, schizophrenia patients have a combination of increased and decreased structural and functional connectivity in specific brain networks, and it is likely that different clinical profiles may explain differences in the reported findings on DTI studies.
Although a vast majority of DTI studies in schizophrenia have focused in the white matter tracts connecting between cortical structures, subcortical structures have recently started to draw the focus of attention. Connectivity of cortico-subcortical tracts has been found to be reduced (as measured by FA) in the posterior corona radiata of persons with schizophrenia in one study (Cui et al., 2011
), but not in another (Zhang et al., 2012
). Corona radiata contains reciprocal connecting fibers from the thalamus to the cerebral cortex and descending fibers from the frontoparietal cortex to the basal ganglia. Curiously, a strong negative correlation between motor activity and decreased FA was reported in schizophrenia patients (Walther et al., 2011
The shift to focusing on subcortical structures is in line with re-emergence of the dopaminergic hypothesis of schizophrenia. In brief, it has been proposed that striatal dopamine hyperfunction may contribute to the positive symptoms of schizophrenia (such as hallucinations or delusions), whereas decreased dopamine availability in the prefrontal cortex may underlie its negative symptoms (such as cognitive impairment, abulia or anhedonia) (de Erausquin et al., 1995
; Masciotra et al., 2005
; Howes and Kapur, 2009
). This hypothesis has received support from a variety of anatomical, functional and experimental sources (Masciotra et al., 2005
). In previous studies from our laboratory, an indigenous population of never-treated schizophrenics and their first-degree relatives were identified (Strejilevich et al., 2005
; Calvó de Padilla et al., 2006
). We recently reported preliminary DTI data on these medication free patients and their relatives focusing on dopaminergic fiber tracts. We found that FA was increased in dopaminergic tracts of both schizophrenia patients and their unaffected first degree relatives, when compared to healthy controls (Toranzo et al., 2011
). To the best of our knowledge, these data are the first reported free of the confounding effect of medications on DTI.
Recently, it was proposed that abnormal myelination in frontal regions may result in conduction delays in the efferent copies initiated by willed action. As a consequence, corollary discharges may be generated too late to suppress the sensory consequence of the willed action. Such anachronism would trigger prediction errors mechanisms underpinned by increased midbrain dopaminergic activity (Whitford et al., 2012
). Our data is also in line with the idea that overactivation of ascending dopamine pathways may underlie hyperkinetic movements in prodromal schizophrenia (Mittal et al., 2008
). Exacerbated activity of the dopamine receptors in the striatal pathway has been found in psychosis (Seeman and Kapur, 2000
). It could be thought that such neural overactivity may modulate synaptic maps resulting indeficient axonal pruning (Cohen-Cory, 2002
). Deficient axonal pruning may lead to redundant networks which may indicate decreased efficiency in information transmission reflected in increased FA in schizophrenia. Following this line, it has been hypothesized that forming and maintaining the brain's axonal wiring is metabolically costly (Laughlin and Sejnowski, 2003
). As it is assumed that the brain attempts to minimize wiring costs, perhaps the schizophrenia brain increased FA is an indicator of poor cost efficiency.