Positive symptoms and white matter microstructure in never-medicated first episode schizophrenia

Abstract

Background. We investigated cerebral structural connectivity and its relationship to symptoms in never-medicated individuals with first-onset schizophrenia using diffusion tensor imaging (DTI).Method. We recruited subjects with first episode DSM-IV schizophrenia who had never been exposed to antipsychotic medication (n=34) and age-matched healthy volunteers (n=32). All subjects received DTI and structural magnetic resonance imaging scans. Patients' symptoms were assessed on the Positive and Negative Syndrome Scale. Voxel-based analysis was performed to investigate brain regions where fractional anisotropy (FA) values significantly correlated with symptom scores.Results. In patients with first-episode schizophrenia, positive symptoms correlated positively with FA scores in white matter associated with the right frontal lobe, left anterior cingulate gyrus, left superior temporal gyrus, right middle temporal gyrus, right middle cingulate gyrus, and left cuneus. Importantly, FA in each of these regions was lower in patients than controls, but patients with more positive symptoms had FA values closer to controls. We found no significant correlations between FA and negative symptoms.Conclusions. The newly-diagnosed, neuroleptic-naive patients had lower FA scores in the brain compared with controls. There was positive correlation between FA scores and positive symptoms scores in frontotemporal tracts, including left fronto-occipital fasciculus and left inferior longitudinal fasciculus. This implies that white matter dysintegrity is already present in the pre-treatment phase and that FA is likely to decrease after clinical treatment or symptom remission.

Patterns of Brain Structural Changes in First-Contact, Antipsychotic Drug-Naïve Patients with Schizophrenia

“…[4][5][6][7][8] Different from other studies of first-episode antipsychotic drug-naïve patients with schizophrenia, [4][5][6][7][8][9] we observed that patients also showed regions of increased FA and decreased MD values, likely reflecting structural "hyperconnectivity," 18 mainly in the brain stem, cerebellum, and in the interhemispheric and cortico-cortical WM connections. Some studies of patients with schizophrenia have found a similar pattern of DTI changes.…”

“…In addition, we also found a negative correlation between MD of some cerebellar and cerebral regions and the severity of the clinical positive manifestations. A relationship between increased FA values of the fronto-occipital and temporolimbic tracts and more severe positive symptoms has been previously observed in nevermedicated patients with schizophrenia 5,10 and in medicated patients with schizophrenia with a history of auditory hallucinations and other positive symptoms. [26][27][28] Overall, these findings suggest that the observed pattern of structural WM changes in patients with schizophrenia is already present before treatment initiation and is associated with the occurrence of positive clinical manifestations.…”

“…It is clear that studies based on untreated patients enrolled at an early stage of the disease represent the easiest and most rewarding strategy to overcome such an issue. To date, however, only a few studies [4][5][6][7][8][9] have adopted this strategy showing WM changes compared with healthy participants in a variable pattern of brain regions including the splenium of the corpus callosum, 4,6 superior longitudinal fasciculus, 7,8 anterior 9 and posterior 4 limbs of the internal capsule, and fronto-occipital fasciculus. 4 The relevance of DTI abnormalities in the early phase of schizophrenia is further supported by the positive association between positive symptoms and fractional anisotropy (FA) values of the superior and inferior longitudinal fasciculi and inferior fronto-occipital fasciculus in never-medicated patients with schizophrenia.…”

“…4 The relevance of DTI abnormalities in the early phase of schizophrenia is further supported by the positive association between positive symptoms and fractional anisotropy (FA) values of the superior and inferior longitudinal fasciculi and inferior fronto-occipital fasciculus in never-medicated patients with schizophrenia. 5,10 In addition, most studies [4][5][6][7][8] have investigated FA only, and none of them have assessed GM volumes in the same sample.…”

Frontal fasciculi and psychotic symptoms in antipsychotic-naive patients with schizophrenia before and after 6 weeks of selective dopamine D2/3 receptor blockade

“…[40][41][42] Moreover, recent functional MRI studies have indicated that functional connectivity in the prefrontal cortex increases with the severity of psychotic symptoms, especially in the early stage of schizophrenia. 43,44 As functional hyperconnectivity may be reflected in regional FA increases, [40][41][42] our findings of both positive and negative associations with positive symptoms in 2 closely linked anatomical structures (AF and SLF) support the idea that psychotic symptoms arise from regional irregularities in white matter rather than deficits per se.…”