Neuropsychological effects of maintenance treatment with Clozapine in Treatment-Resistant Psychotic Disorder.

INTRODUCTION: Clozapine is a second-generation antipsychotic drug that is mainly prescribed for treatment-resistant psychotic disorder. It is known to have several undesirable side effects, including cognitive functional complaints, such as memory or attention. The aim of this work is to study if reduction of the dosage within the therapeutic margins could improve cognitive performance of Clozapine treated patients. To do so, a study was made of the relationship between Clozapine plasma levels and neuropsychological performance in patients undergoing Clozapine monotherapy. MATERIAL AND METHODS: This is a single-blind design study of the correlation between Clozapine plasma levels and neuropsychological testing in a sample of 19 patients with treatment-resistant psychotic disorder in whom Clozapine was the only psychotropic drug. Spearman correlations were carried out between neuropsychological variables and Clozapine plasma levels. Additionally, the sample was divided into two groups between patients with high Clozapine plasma drug levels (Clz pl≥300µg/L) and low ones (Clz pl<300 µg/L). MANOVA was performed to determine neuropsychological differences between the two groups. Subsequently, a linear regression model was carried out to predict neuropsychological performance. RESULTS: There was no significant Spearman correlation between neuropsychological scores and Clozapine plasma levels (p>0.1). MANOVA showed no significant differences between the two groups in any of the tests administered, although there was a trend towards significance in the number on attempts of the Card Sorting Test (WCST), where subjects with high levels of Clozapine showed worse performance (F=3.86; df=1.17; p=0.07). The linear regression model showed that only plasma levels significantly predicted executive performance, explaining 31% of the variance (F=3.62; df=2.16; p=0.05). CONCLUSION: No relationship between plasma levels of Clozapine and cognitive performance has been found. This result suggests that it is not desirable to reduce a relevant dose of Clozapine in patients with cognitive complaints.

Inferior frontal and insular cortical thinning is related to dysfunctional brain activation/deactivation during working memory task in schizophrenic patients.

Although working memory is known to be impaired in schizophrenia the anatomical and functional relationships underlying this deficit remain to be elucidated. A combined imaging approach involving functional and structural magnetic resonance techniques was used, applying independent component analysis and surface-based morphometry to 14 patients with schizophrenia and 14 healthy controls. Neurocognitive functioning was assessed by a neuropsychological test battery that measured executive function. It was hypothesized that working memory dysfunctional connectivity in schizophrenia is related to underlying anatomical abnormalities. Patients with schizophrenia showed cortical thinning in the left inferior frontal gyrus and insula, which explained 57% of blood oxygenation level-dependent signal magnitude in functional magnetic resonance imaging in the central executive network (lateral prefrontal and parietal cortex) over-activation and default mode network (anterior and posterior cingulate) deactivation. No structure-function relationship emerged in the healthy control group. The study provides evidence to suggest that dysfunctional activation/deactivation patterns in schizophrenia may be explained in terms of underlying gray matter deficits.

Brain effects of cognitive remediation therapy in schizophrenia: a structural and functional neuroimaging study.

BACKGROUND: Cognitive remediation therapy positively affects cognition and daily functioning in patients with schizophrenia. However, studies on the underlying neurobiological mechanisms of this treatment are scarce. The aim of the current study was to investigate functional and structural connectivity brain changes in schizophrenia patients after cognitive remediation therapy using a whole-brain approach that combined functional magnetic resonance imaging and diffusion tensor imaging. METHODS: A randomized controlled trial with 30 schizophrenia outpatients and 15 healthy volunteers. A strategy-learning-based treatment was used as a cognitive remediation therapy. A social skills training that provides useful information about illness management was used as an active control. We investigated changes in the pattern of functional connectivity assessed during an n-back task by tensorial independent component analysis as implemented in the multivariate exploratory linear decomposition into independent components and in the fractional anisotropy index of white matter integrity using tract-based spatial statistics. RESULTS: Brain networks activation pattern significantly changed in patients exposed to the cognitive treatment in the sense of normalizing toward the patterns observed in healthy control subjects. Additionally, in white matter, they showed an increase in fractional anisotropy index in the anterior part of the genu of the corpus callosum. Cognitive improvement, functional, and also structural changes showed statistically significant correlations. CONCLUSIONS: Improvement in brain functioning detected after cognitive remediation therapy in schizophrenia patients might be based on an increase of the interhemispheric information transfer between the bilateral prefrontal cortexes via the corpus callosum.

Cortical thickness in untreated transsexuals.

Sex differences in cortical thickness (CTh) have been extensively investigated but as yet there are no reports on CTh in transsexuals. Our aim was to determine whether the CTh pattern in transsexuals before hormonal treatment follows their biological sex or their gender identity. We performed brain magnetic resonance imaging on 94 subjects: 24 untreated female-to-male transsexuals (FtMs), 18 untreated male-to-female transsexuals (MtFs), and 29 male and 23 female controls in a 3-T TIM-TRIO Siemens scanner. T1-weighted images were analyzed to obtain CTh and volumetric subcortical measurements with FreeSurfer software. CTh maps showed control females have thicker cortex than control males in the frontal and parietal regions. In contrast, males have greater right putamen volume. FtMs had a similar CTh to control females and greater CTh than males in the parietal and temporal cortices. FtMs had larger right putamen than females but did not differ from males. MtFs did not differ in CTh from female controls but had greater CTh than control males in the orbitofrontal, insular, and medial occipital regions. In conclusion, FtMs showed evidence of subcortical gray matter masculinization, while MtFs showed evidence of CTh feminization. In both types of transsexuals, the differences with respect to their biological sex are located in the right hemisphere.

Effects of androgenization on the white matter microstructure of female-to-male transsexuals. A diffusion tensor imaging study.

Diffusion tensor imaging (DTI) can sensitively detect white matter sex differences and the effects of pharmacological treatments. Before cross-sex hormone treatment, the white matter microstructure of several brain bundles in female-to-male transsexuals (FtMs) differs from those in females but not from that in males. The purpose of this study was to investigate whether cross-sex hormone treatment (androgenization) affects the brain white matter microstructure. Using a Siemens 3 T Trio Tim Magneton, DTI was performed twice, before and during cross-sex hormonal treatment with testosterone in 15 FtMs scanned. Fractional anisotropy (FA) was analyzed on white matter of the whole brain, and the latter was spatially analyzed using Tract-Based Spatial Statistics. Before each scan the subjects were assessed for serum testosterone, sex hormone binding globulin level (SHBG), and their free testosterone index. After at least seven months of cross-gender hormonal treatment, FA values increased in the right superior longitudinal fasciculus (SLF) and the right corticospinal tract (CST) in FtMs compared to their pre-treatment values. Hierarchical regression analyses showed that the increments in the FA values in the SLF and CST are predicted by the free testosterone index before hormonal treatment. All these observations suggest that testosterone treatment changes white matter microstructure in FtMs.

Clinical utility of the Bem Sex Role Inventory (BSRI) in the Spanish transsexual and nontranssexual population.

The aim of the study is to evaluate the usefulness of the Bem Sex Role Inventory (BSRI; Bem, 1974), an overall measurement of the cultural construct of masculinity and femininity, in the psychological assessment of Spanish transsexuals. Seventy male-to-female transsexuals (MF), 51 female-to-male transsexuals (FM), 77 control men, and 79 control women completed the Spanish version of the BSRI. Statistically significant differences between groups were only found on the femininity scale, on which MF transsexuals and control women scored significantly higher than FM transsexuals and control men. The results indicate that (a) only the femininity scale of the BSRI appears to be useful today for evaluating differences in the sex-role identification in Spanish controls and transsexuals; and (b) MF and FM transsexuals score as a function of their gender identity instead of their anatomical sex on the BSRI femininity scale.

The microstructure of white matter in male to female transsexuals before cross-sex hormonal treatment. A DTI study.

BACKGROUND: Diffusion tensor imaging (DTI) has been shown to be sensitive in detecting white matter differences between sexes. Before cross-sex hormone treatment female to male transsexuals (FtM) differ from females but not from males in several brain fibers. The purpose of this paper is to investigate whether white matter patterns in male to female (MtF) transsexuals before commencing cross-sex hormone treatment are also more similar to those of their biological sex or whether they are more similar to those of their gender identity. METHOD: DTI was performed in 18 MtF transsexuals and 19 male and 19 female controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics. RESULTS: MtF transsexuals differed from both male and female controls bilaterally in the superior longitudinal fasciculus, the right anterior cingulum, the right forceps minor, and the right corticospinal tract. CONCLUSIONS: Our results show that the white matter microstructure pattern in untreated MtF transsexuals falls halfway between the pattern of male and female controls. The nature of these differences suggests that some fasciculi do not complete the masculinization process in MtF transsexuals during brain development.

White matter microstructure in female to male transsexuals before cross-sex hormonal treatment. A diffusion tensor imaging study.

BACKGROUND: Some gray and white matter regions of the brain are sexually dimorphic. The best MRI technique for identifying subtle differences in white matter is diffusion tensor imaging (DTI). The purpose of this paper is to investigate whether white matter patterns in female to male (FtM) transsexuals before commencing cross-sex hormone treatment are more similar to that of their biological sex or to that of their gender identity. METHOD: DTI was performed in 18 FtM transsexuals and 24 male and 19 female heterosexual controls scanned with a 3 T Trio Tim Magneton. Fractional anisotropy (FA) was performed on white matter fibers of the whole brain, which was spatially analyzed using Tract-Based Spatial Statistics. RESULTS: In controls, males have significantly higher FA values than females in the medial and posterior parts of the right superior longitudinal fasciculus (SLF), the forceps minor, and the corticospinal tract. Compared to control females, FtM showed higher FA values in posterior part of the right SLF, the forceps minor and corticospinal tract. Compared to control males, FtM showed only lower FA values in the corticospinal tract. CONCLUSIONS: Our results show that the white matter microstructure pattern in untreated FtM transsexuals is closer to the pattern of subjects who share their gender identity (males) than those who share their biological sex (females). Our results provide evidence for an inherent difference in the brain structure of FtM transsexuals.

Anterior cingulate and paracingulate sulci morphology in patients with schizophrenia.

The anterior cingulate cortex is a cerebral region engaged in several emotional and cognitive functions. The aim of this study was to investigate possible anterior cingulate and paracingulate sulcal abnormalities in schizophrenia. Twenty-three patients with DSM-IV diagnoses of schizophrenia were compared with 23 healthy subjects matched for age, gender, and parental socioeconomic status. Magnetic resonance images were used to explore the morphology of these regions, with volume and maximum depth being measured by an automated method of sulcal recognition. Additionally, voxel-based morphometry (VBM) was performed to analyze possible reduction in gray and white matter of the anterior cingulate region. A smaller volume of the left anterior cingulate sulcus (ACS) was observed in patients with schizophrenia when compared with healthy controls. Furthermore, female patients showed a reduction in volume of the left ACS and an increase of the right paracingulate sulcus (PCS) compared to female controls. There was also a significant relationship between the depth of right PCS and neuroleptic exposure. VBM analysis showed a reduction in left anterior cingulate gray matter. These findings provide further evidence of left anterior middle frontal cortex abnormalities in schizophrenia. In addition, the results suggest gender differences in the structural abnormalities of the illness.

Cortical activation during mental rotation in male-to-female and female-to-male transsexuals under hormonal treatment.

There is strong evidence of sex differences in mental rotation tasks. Transsexualism is an extreme gender identity disorder in which individuals seek cross-gender treatment to change their sex. The aim of our study was to investigate if male-to-female (MF) and female-to-male (FM) transsexuals receiving cross-sex hormonal treatment have different patterns of cortical activation during a three-dimensional (3D) mental rotation task. An fMRI study was performed using a 3-T scan in a sample of 18 MF and 19 FM under chronic cross-sex hormonal treatment. Twenty-three males and 19 females served as controls. The general pattern of cerebral activation seen while visualizing the rotated and non-rotated figures was similar for all four groups showing strong occipito-parieto-frontal brain activation. However, compared to control males, the activation of MF transsexuals during the task was lower in the superior parietal lobe. Compared to control females, MF transsexuals showed higher activation in orbital and right dorsolateral prefrontal regions and lower activation in the left prefrontal gyrus. FM transsexuals did not differ from either the MF transsexual or control groups. Regression analyses between cerebral activation and the number of months of hormonal treatment showed a significant negative correlation in parietal, occipital and temporal regions in the MF transsexuals. No significant correlations with time were seen in the FM transsexuals. In conclusion, although we did not find a specific pattern of cerebral activation in the FM transsexuals, we have identified a specific pattern of cerebral activation during a mental 3D rotation task in MF transsexuals under cross-sex hormonal treatment that differed from control males in the parietal region and from control females in the orbital prefrontal region. The hypoactivation in MF transsexuals in the parietal region could be due to the hormonal treatment or could reflect a priori cerebral differences between MF transsexual and control subjects.

Magnetic resonance imaging study of cerebral sulci in low-risk preterm children.

Premature birth is associated with several brain dysfunctions including changes in the normal pattern of sulcal development. Previous studies on sulcal abnormalities were performed in subjects with perinatal brain complications. We selected a sample of preterm subjects with a low risk of neurodevelopmental abnormalities with the aim of investigating the effects of prematurity per se. Surface and maximum depth measures of four sulci that develop at different gestational ages were obtained using Anatomist/Brain Visa 3.0.2 software. The sulci measured were the olfactory sulcus (16 weeks), the parieto-occipital sulcus (22-23 weeks), the superior temporal sulcus (32 weeks) and the orbitofrontal sulcus (36-39 weeks). The sample comprised 17 low-risk preterms (mean gestational age: 32 weeks) and 16 full-term children who were matched for age at scan, gender, handedness and socio-cultural status. Analysis of surface variance showed a significant group effect (P<0.015), as well as an interaction between the type of sulcus and group (P<0.001). The superior temporal sulcus surface was inferior in the low-risk preterm group compared to controls. Our findings suggest that even without perinatal complications, premature birth affects sulcal morphology.

A voxel-based diffusion tensor imaging study of temporal white matter in patients with schizophrenia.

Diffusion tensor imaging (DTI) is a relatively new technique used to detect changes in the anisotropic diffusion of white matter. The study of the disruption of brain connectivity may increase our understanding of cognitive deficits associated with schizophrenia. Here we analysed DTI data in 25 patients with DSM-IV schizophrenia and 24 healthy controls. Two complementary measures, fractional anisotropy (FA) and the apparent diffusion coefficient (ADC), were considered and analysed using voxel-based morphometry. Declarative memory functions were also investigated and their associations with DTI data were analysed. FA was significantly reduced, and the ADC increased in the left sub-gyral white matter of the temporal lobe, which involves the posterior part of the fornix. In the schizophrenic group, females had lower FA than males in the genu of the corpus callosum. Memory functions correlate with FA values. These data provide further evidence for the disruption of white matter connectivity in the left medial temporal lobe, and for its contribution to the declarative memory deficit in schizophrenia.

Hippocampal underactivation in an fMRI study of word and face memory recognition in schizophrenia.

Schizophrenia is a major mental disorder which is characterized by several cognitive deficits. Investigations of the neural basis of memory dysfunctions using neuroimaging techniques suggest that the hippocampus plays an important role in declarative memory impairment. The goal of this study was to investigate possible dysfunctions in cerebral activation in schizophrenic patients during both word and face recognition memory tasks. We tested 22 schizophrenics and 24 controls matched by gender, age, handedness and parental socioeconomic status. Compared to healthy volunteers, patients with schizophrenia showed decreased bilateral hippocampal activation during word and face recognition tasks. The whole brain analysis also showed a pattern of cortical and subcortical hypoactivation for both verbal and non-verbal recognition. This study provides further evidence of hippocampal involvement in declarative memory impairments of schizophrenia.

Left posterior hippocampal density reduction using VBM and stereological MRI procedures in schizophrenia.

Structural deficits in the hippocampus have been implicated in the pathophysiology of schizophrenia. However the role played by structural impairments in the hippocampus in the memory deficits of schizophrenic patients remains unclear. Magnetic resonance imaging was used in this study to investigate left, right, anterior and posterior hippocampal volume and density in 28 schizophrenic patients and 33 normal controls. Voxel-based morphometry analysis showed that schizophrenics had significantly lower density in the right and posterior hippocampus than controls. MRI stereological analysis revealed significant differences in left posterior hippocampus than controls. MRI stereological analysis revealed significant differences in anterior and posterior on both sides, with the left posterior region predominating. Schizophrenics showed significant impairments in verbal learning and long term retention (P<0.001). The correlation analyses between hippocampal density and memory variables yielded a significant correlation between forgetting and density of the anterior hippocampus. These findings support the hypothesis of a regional atrophy within the hippocampus in schizophrenic patients.