Vicente Molina

Influence of the normalization template on the outcome of statistical parametric mapping of PET scans

Spatial normalization is an essential preprocessing step in statistical parametric mapping (SPM)-based analysis of PET scans. The standard template provided with the SPM99 software package was originally constructed using (15)O-H(2)O PET scans and is commonly applied regardless of the tracer actually used in the scans being analyzed. This work studies the effect of using three different normalization templates in the outcome of the statistical analysis of PET scans: (1) the standard SPM99 PET template; (2) an (18)F-FDG PET template, constructed by averaging PET scans previously normalized to the standard template; and (3) an MRI-aided (18)F-FDG PET template, constructed by averaging PET scans normalized according to the deformation parameters obtained from MRI scans. A strictly anatomical MRI normalization of each PET was used as a reference, under the rationale that a normalization based only upon MRI should provide higher spatial accuracy. The potential bias involved in the normalization process was estimated in a clinical SPM study comparing schizophrenic patients with control subjects. For each between-group comparison, three SPM maps were obtained, one for each template. To evaluate the influence of the template, these SPM maps were compared to the reference SPM map achieved using the anatomical normalization. SPMs obtained by MRI-aided normalization showed the highest spatial specificity, and also higher sensitivity when compared to the standard normalization using the SPM99 (15)O-H(2)O template. These results show that the use of the standard template under inappropriate conditions (different tracer or mental state) may lead to inconsistent interpretations of the statistical analysis.

Increase in gray matter and decrease in white matter volumes in the cortex during treatment with atypical neuroleptics in schizophrenia

The effects of atypical antipsychotic treatment on the brain volume deficits associated with schizophrenia are poorly understood. We assessed the brain volumes of eleven healthy controls and 29 patients with schizophrenia, using magnetic resonance imaging at baseline and at follow-up after two years of treatment with atypical neuroleptics. Two groups of patients were analyzed: treatment-naïve patients (n = 17) and chronic treatment-resistant patients (n = 12). Treatment-naïve patients received risperidone during the follow-up period, whereas chronic patients received clozapine. Gray matter (GM) and white matter (WM) volumes in the frontal, parietal, occipital, and temporal lobes were measured. Contrary to the controls, both groups of patients presented GM increases and WM decreases in the parietal and occipital lobes (p < .005). Frontal GM also increased in the chronic group with clozapine. There was a significant (p < .001) inverse relationship between the baseline volumes (GM deficit/WM excess) and the longitudinal change. These GM and WM changes were not related to changes in weight. Thus, treatment with risperidone and clozapine in schizophrenia may have an effect on gray and white matter volume and needs further exploration.

The Wisconsin Card Sorting Test and the assessment of frontal function: A validation study with event-related potentials

The Wisconsin Card Sorting Test (WCST) is generally regarded as the prototype of abstract reasoning task and has been routinely used to assess frontal lobe function in a variety of clinical and research contexts. However, there are growing concerns that the WCST fails to discriminate frontal patients from those with lesions in other brain regions or from normals. Event-related potentials (ERP) from frontal, fronto-temporal, temporal, parietal and occipital areas were recorded during the performance of a computerized version of the WCST in order to explore frontal versus non-frontal ERP indexes during WCST activation. The task protocol was contrived to focus on the differences between early and late trials of each WCST series. Cognitive processes underlying these two task conditions have been described as extradimensional and intradimensional shifts in attention, respectively. Differences between early and late WCST trials appeared as soon as 120 msec poststimulus and were associated with a negative field potential centred at the fronto-temporal region of the left hemisphere. Significantly larger amplitudes of the posterior P3b wave for late as compared with early WCST trials also lent support to claims of a strong involvement of working memory mechanisms during WCST performance. Results are discussed in terms of the implications for the utility of ERP measures in clinical neuropsychology.

Anatomical and functional brain variables associated with clozapine response in treatment-resistant schizophrenia

Clozapine alleviates the symptoms of a significant proportion of treatment-resistant schizophrenic patients. Previous studies suggest that the response to clozapine may be associated with prefrontal and temporal anatomy as well as with prefrontal, basal ganglia and thalamic metabolism. A sample of 25 treatment-resistant (TR) schizophrenic patients underwent magnetic resonance imaging (MRI) and 18F-deoxyglucose positron emission tomography (PET) before and after treatment with clozapine. We investigated the association between changes in positive, disorganized, and negative schizophrenic syndromes with clozapine treatment and a set of cerebral variables that included total intracranial volume (ICV); hippocampal, dorsolateral prefrontal (DLPF) and temporal gray-matter volume and metabolism; and metabolic activity of the thalamus, pallidum/putamen, and caudate head. Improvement in positive symptoms with clozapine was directly related to temporal gray-matter volume, whereas improvement of disorganization symptoms was inversely related to ICV and hippocampal volume. Patients with high baseline DLPF cortical volume and metabolic activity were more likely to experience improvement in their negative symptoms. We conclude that clinical improvement with clozapine may be related with the anatomy and metabolic activity of specific brain areas, with the structural integrity of the DLPF and temporal regions showing the maximum predictive capacity.

Cerebral metabolic changes induced by clozapine in schizophrenia and related to clinical improvement

RationaleThe study of the different effects on brain metabolism between typical and atypical antipsychotics would aid in understanding their mechanisms of action. Clozapine is of special interest, since it is one of the most effective antipsychotic drugs and demonstrates a distinctive mechanism of action in pre-clinical studies with respect to typical neuroleptics.ObjectiveTo study the differences in cerebral activity induced by clozapine as compared to those produced by haloperidol.Methods[18F]Fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) scans were obtained in the resting condition before and after 6 months of treatment with clozapine in 22 treatment-resistant patients with schizophrenia. Before inclusion, patients had been chronically treated with classical drugs, and all of them received haloperidol during the last month. Data were analyzed with statistical parametric mapping (SPM′99) methods, comparing pre-treatment and post-treatment conditions. The association between the changes in symptom scores and metabolism was also assessed to corroborate the functional relevance of possible metabolic changes.ResultsClozapine decreased prefrontal and basal ganglia activity, and increased occipital metabolism, including primary and association visual areas. The change in negative symptoms was related with the decrease of basal ganglia activity; the improvement in disorganization related to the metabolic decrease in the motor area, and the change in positive symptoms was associated to the increase of activity in the visual area.ConclusionsThese results show that haloperidol and clozapine produce different patterns of metabolic changes in schizophrenia. Compared to the haloperidol baseline, clozapine inhibited the metabolic activity of the prefrontal and motor cortical regions and basal ganglia and induced a higher activation of the visual cortex. The improvement in disorganization, negative and positive syndromes with clozapìne may be respectively associated with metabolic changes in the motor area, basal ganglia, and visual cortex.

Ventricular enlargement in schizophrenia is associated with a genetic polymorphism at the interleukin-1 receptor antagonist gene

Magnetic resonance imaging (MRI) studies have shown some morphological and volumetric peculiarities in brains of schizophrenic patients. The authors explored the influence of genetic polymorphisms at interleukin-1beta (IL-1B) and interleukin-1 receptor antagonist (IL-1RN) genes on these abnormalities. Hippocampus, lateral ventricles, and dorsolateral prefrontal cortex gray matter volumes were measured in a sample of 23 DSM-IV diagnosed schizophrenic patients of Spanish origin using MRI scans; MRI data were adjusted for age and brain volume using regression parameters from a healthy control group (n = 45). IL-1B and IL-1RN genes, involved in neurodevelopment and neurodegenerative processes, were analyzed in the patient sample. Patients carrying VNTR-allele*2 of IL-1RN gene showed a significant enlargement of both left (P = 0.002) and right (P = 0.01) ventricles. Sex and illness duration were controlled for in the analyses. Our results, though preliminary, suggest that IL-1RN gene might contribute to the ventricular volumetric changes observed in schizophrenic patients.

N-acetyl-aspartate levels in the dorsolateral prefrontal cortex in the early years of schizophrenia are inversely related to disease duration

Magnetic resonance spectroscopy studies in schizophrenia have revealed consistently reduced N-acetyl aspartate (NAA) levels in chronic patients, but not in recent-onset patients. Studies on the relationship between this marker and disease duration have commonly been negative, although it is also true that they have been conducted in patients with long-standing disease. We compared NAA levels in the dorsolateral prefrontal cortex in 16 recent-onset patients (duration: 1.8+/-0.6 years), 19 chronic patients (duration: 9.7+/-6.1 years), and 20 healthy controls. We studied the NAA/creatine and choline/creatine ratios in the dorsolateral prefrontal cortex in both hemispheres, controlling for the effect of age. Chronic patients had significantly lower NAA/Cr ratios in the left hemisphere compared to recent-onset patients and healthy controls, with no difference in Cho/Cr ratio. There were no differences between controls and recent-onset patients. There was a significant inverse relationship between left-side NAA/Cr and disease duration, suggesting that prefrontal NAA levels may progressively decrease in schizophrenia. Taken within the context of the existing literature, these results indicate that this process may be limited to the early years following the onset of the disease. Therefore, reduced prefrontal levels of NAA may be limited to chronic schizophrenia patients.

P300 amplitude as a possible correlate of frontal degeneration in schizophrenia

The existence of neurodegeneration is a debated issue in schizophrenia research. The P300 component of event-related electrical potentials (ERP) has been related to the different degree of damage to gray and white matter. This study explores the possible relationship between P300 amplitude and/or latency and the existence of degenerative processes in schizophrenia, by assessing its correlation with volume of sulcal CSF and duration of illness, as transversal indicators of neurodegeneration. Nineteen patients (14 males, 5 females) and 13 controls (6 males, 7 females) were studied with MRI and electrophysiological records (P300). The possible influence of sex and age at the time of the exploration was statistically controlled in both groups. The results show a significant negative correlation between P300 amplitude and prefrontal CSF volume in the patient group. A lower though still significant correlation was also found between P300 amplitude and duration of illness, whereas no correlation was found in the control group. These results support the hypothesis that P300 amplitude may be interpreted as a marker of neurodegeneration in schizophrenia.

Multimodality image quantification using the Talairach grid

We present an application of the widely accepted anatomical reference of the Talairach atlas as a system for semiautomatic segmentation and analysis of MRI and PET images. The proposed methodology can be seen as a multimodal application where the anatomical information of the MRI is used to build the Talairach grid and a co-registered PET image is superimposed on the same grid. By doing so, the Talairach-normalized tessellation of the brain is directly extended to PET images, allowing for a convenient regional analysis of volume and activity rates of brain structures, defined in the Talairach Atlas as sets of cells. This procedure requires minimal manipulation of brain geometry, thus fully preserving individual brain morphology. To illustrate the potential of the Talairach method for neurological research, we applied our technique in a comparative study of volume and activity rate patterns in MRI and PET images of a group of 51 schizophrenic patients and 24 healthy volunteers. With regard to previous applications of the Talairach grid as an automatic segmentation system, the procedure presented here features two main improvements: the enhanced possibility of measuring metabolic activity in a variety of brain structures including small ones like the caudate nucleus, hippocampus or thalamus; and its conception as an easy-to-use tool developed to work in standard PC Windows environment.

Anatomical and functional cerebral variables associated with basal symptoms but not risperidone response in minimally treated schizophrenia

In schizophrenia, structural and functional cerebral variables show an unclear association with clinical features and their value as predictors of response to a typical antipsychotic agents has yet to be determined. The goal of this study was to investigate the relationships between clinical variables (baseline syndromes and response to risperidone) and anatomo-functional brain variables. We studied 19 minimally treated patients with schizophrenia of recent onset using magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) under resting conditions. The following brain variables were studied: volume of the cerebrospinal fluid (CSF) and gray matter (GM) of the dorsolateral prefrontal cortex (DLPFC) and temporal lobe; hippocampal metabolic activity and volume; and metabolic activity of the DLPFC, temporal lobe, putamen and caudate. Anatomical volume measurements were corrected for age and intracranial size using regression parameters determined from a matched sample of control subjects. Using stepwise multiple regression, we assessed the relation between these brain measures and basal scores of symptom dimensions (positive, disorganization, negative and total), as well as their change in response to risperidone. We found that positive and disorganization symptoms improved with risperidone treatment and that hippocampal metabolism, DLPFC CSF volume, and temporal CSF volume predicted baseline symptoms. However, none of the brain measures predicted response to treatment. We conclude that there is evidence of a significant association between basal symptoms and DLPFC atrophy and limbic hyperactivity at rest in recent-onset schizophrenic patients.