To explore gray (GM) and white matter (WM) abnormalities and the relationships with neuropsychopathology in first-episode schizophrenia (FES).
To explore gray (GM) and white matter (WM) abnormalities and the relationships with neuropsychopathology in first-episode schizophrenia (FES).
Nineteen patients with first episode of non-affective psychosis and 18 controls underwent a magnetic resonance voxel-based morphometry. Additionally, WM fractional anisotropy (FA) was calculated. For correlative analysis, symptoms and neuropsychological performances were scored by PANSS and by a comprehensive neuropsychological assessment respectively.
Patients showed significantly decreased volume of left temporal lobe and disarray of all major WM tracts. Disorganized PANSS factor was inversely related to left cerebellar GM volume (corrected P = 0.03) and to WM FA of the left cerebellum, inferior fronto-occipital fasciculi (IFOF), and inferior longitudinal fasciculi (corrected P < 0.05). PANSS negative factor was inversely related to FA in the IFOF and superior longitudinal fasciculi (corrected P < 0.05). Impairment in facial emotion identification showed associations with temporo-occipital GM volume decrease (corrected P = 0.003) and WM disarray of superior and middle temporal gyri, anterior thalamic radiation, and superior longitudinal fasciculi (corrected P < 0.05). Speed of processing and visual memory correlated with WM abnormalities in fronto-temporal tracts.
These results confirm how the structural development of key brain regions is related to neuropsychopathological dysfunction in FES, consistently with a neurodevelopmentally derived misconnection syndrome.
The limitations of the study are as follows:
In the past years, several researchers have investigated the possible associations between brain structural abnormalities and schizophrenia, even at the early phases of the disease [1-5].
Structural abnormalities of gray matter (GM) found in first-episode schizophrenia (FES) are supposed to be unbiased by secondary processes, such as duration of illness, long-term treatment, and different outcome variants, and therefore ideally reflecting only the primary pathological changes. If the whole pattern of GM abnormalities reflects an aberrant neuronal network, a concomitant alteration of white matter (WM) tissue might also be observed [6-8]. Previous diffusion tensor imaging (DTI) studies in chronic schizophrenia have shown decreased fractional anisotropy (FA) in frontal  and parietal lobes , while some authors found even no differences between patients and controls . Interestingly, recent studies suggested that WM abnormalities were present since the onset of the disease .
Both GM and WM abnormalities are thought to have clinical and neuropsychological correlates, which could characterize neurobiological models of the disorder.
A few pioneering studies have addressed the relationship between psychopathological dimensions and neuroanatomical changes in FES: Some authors provided evidence that morphology of the temporal cortex is associated with positive as well as with negative symptoms [13, 14], while others failed to detect any relationships between brain structural deviations and symptoms .
Even less investigated was the association between brain structure and cognitive performance. Disruptions of WM networks have been proposed as potential mechanisms for cognitive dysfunction in schizophrenia and other neurological disorders . Few studies suggested that WM abnormalities of the temporal regions may account for memory functioning impairment in the early course of schizophrenia , while deficits of executive and motor functioning might depend on WM disarray of the major tracts connecting fronto-temporal cortices . Unfortunately, GM volume and WM integrity have not been explored together in correlation with neuropsychological performances, so far.
It is becoming more evident that psychopathological and neuropsychological profiles are interrelated aspects of a complex behavioural expression. For instance, in non-affective psychosis, significant correlations between negative and disorganization symptom clusters and the majority of neuropsychological measures have been reported, while positive and depressive symptoms have shown no relations with cognition . Accordingly, different symptoms might show different patterns of relations with brain structure.
Over the years, functional neuroimaging techniques have provided a great body of evidence about cognitive functions, but unfortunately the tasks used for brain activation often do not explore the same functions and are generally less standardized than neuropsychological tests. Consequently, a pure volumetric approach such as voxel-based morphometry (VBM) might present less methodological caveats than functional neuroimaging .
We used VBM and tract-based spatial statistics to investigate GM volume and WM integrity in FES, correlating gray and WM structural changes with symptoms and neurocognitive scores.
All consecutive patients referring to the acute psychiatric care and to the out-patient psychiatric service of Sant'Andrea Hospital of Rome between October 2010 and June 2011 were enrolled if fulfilling the following requirements: i) age between 18 and 30, ii) presenting their first episode of non-affective psychosis according to DSM-IV-TR criteria for schizophrenia, schizophreniform disorder, or brief psychotic disorder and iii) receiving adequate antipsychotic treatment for less than two weeks. Diagnosis was made using the Structured Clinical Interview for DSM-IV (SCID-I)  by two senior psychiatrists in consensus. Duration of untreated psychosis (DUP) was defined as the time from the first continuous (present most of the time) psychotic symptom to initiation of adequate antipsychotic treatment. The first identifiable positive symptom was determined using data gathered from multiple sources, including medical records and direct interviews with both patient and family members.
Mayor exclusion criteria were i) current or past diagnosis of autistic disorder or other pervasive developmental disorder, ii) history of severe head injury, iii) severe medical conditions or major neurological disorders, including mental retardation and dementia, that could prevent neuropsychological task performance or that could produce psychotic symptoms and iv) any current or past drug abuse.
Eighteen healthy volunteers were recruited as controls by word of mouth in the same catchment area. None had prior history of psychiatric disease, mental retardation, neurological or general medical illnesses, including substance dependence, as determined by using an abbreviated version of the Comprehensive Assessment of Symptoms and History . Controls were age-, gender-, handedness-, and education-matched with patients. The absence of psychosis in first-degree relatives was confirmed by clinical records and family interview. Written informed consent was obtained from all participants after providing complete description and explanation of the study. Ethical approval was obtained. The study followed the Declaration of Helsinki and Good Clinical Practice guidelines.
Patients’ clinical symptoms were rated using the Positive and Negative Syndrome Scale (PANSS)  by two specialists who were unaware of the purpose of the study. For statistical analysis, we used the five factors solution according to Emsley et al. . Handedness was assessed by the Edinburgh Inventory . Median time from admission to full psychopathological assessment was 14 days (range: 7–20 days).
Neuropsychological assessment was made according to the ‘Measurement and Treatment Research to improve Cognition in Schizophrenia’, including the exploration of seven domains, that is, speed of processing, sustained attention/vigilance, working memory, verbal memory, visual memory, reasoning and problem-solving, and social cognition . Median time from admission to neuropsychological assessment was four weeks (range: 17–35 days), which was deemed to be adequate for the acute state to be stabilized.
We here detail the tests used and the output considered for each domain: speed of processing: Stroop Word Test (Stroop W) – word reading (verbal), number of words read correctly in 30 seconds; sustained attention/vigilance: Wisconsin Card Sorting Test (WCST), number of non-perseverative errors (NPE); working memory: Trail Making, B-A subtest (TM B-A) – differential score between subtest B and subtest A (time in seconds); verbal memory: Buschke Verbal Selective Reminding Test (BVSRT) – delayed recall 15 min after six learning trials; visual memory: Rey-Osterrieth Complex Figure (ROCF) – delayed recall after 15 min; reasoning and problem-solving: Wisconsin Card Sorting Test (WCST), number of completed categories (CC); social cognition: Facial Emotion Identification Task (FEIT) – photographs of emotional faces and emotion labels were presented on a computer screen. Participants were asked to choose one of six emotions explicitly specified on the monitor for a given face. The scores used were the sums of named emotions. Other Executive Functions (Executive Control) were represented by Stroop Color-Word Test (Stroop CW) – number of color names printed in incongruously colored ink correctly pronounced in 30 s (inhibition of automatic responses).
MRI acquisition: median time elapsed from admission to MRI acquisition was 4 ± 1.5 days. A single MRI scan of all subjects was acquired on a 1.5-Tesla MRI scanner (Magnetom, Siemens, Erlangen, Germany). The imaging protocol comprised 3D T1-weighted magnetization-prepared rapid acquisition gradient echo (MP-RAGE) sequence (TR = 1110 ms; TE = 3.49 ms; matrix size = 256× 192; section thickness = 1 mm), FLAIR sequence (TR = 10000 ms; TE = 125 ms; matrix size = 256 × 192; section thickness = 5 mm), and DTI data acquired using a twelve-direction sequence (TR = 9400; TE = 9; matrix size = 128 × 128; section thickness = 1.9 mm).
Voxel-based morphometry was performed by using the Statistical Parametric Mapping package 8 (SPM8, Wellcome Trust Center for Neuroimaging, Oxford, England, http://www.fil.ion.ucl.ac.uk/spm) and the DARTEL registration method .
Brain segmentation was performed using Statistical Parametric Mapping 8 (SPM8, Wellcome Department of Imaging Neuroscience, University College, London, UK) running under MATLAB R2011a (The Mathworks, Sherborn, MA, USA). The segmented images were imported to DARTEL for warping procedure and then iteratively aligned to the average template. During DARTEL warping, the segmented images were modulated with Jacobian determinants to preserve volume changes. Normalized modulated GM was finally smoothed with an 8 mm full width at half maximum Gaussian kernel. GM, WM, and cerebrospinal fluid volumes were calculated using SPM 8.
Diffusion tensor imaging were corrected for the effects of head movements and eddy currents using the eddy-correct function (FSL, Oxford, UK) . The registered images (b0 and the twelve directions files) were skull-stripped using the FSL Brain Extraction Tool. FA maps were calculated using DTIFit (FMRIB Software Library's Diffusion Toolbox), which fits a diffusion tensor model at each voxel.
In order to perform a voxelwise analyses of FA images, we used tract-based spatial statistics (TBSS) v.1.2 . All FA images were coregistered to the Montreal Neurological Institute-152 space FA template using FNIRT (FMRIB's Nonlinear Registration Tool) and were fed into the FA skeletonization programme to create the mean FA skeleton.
Sociodemographic and neuropsychological statistical analyses were performed using the Statistical Package for the Social Sciences, version 16 (SPSS Inc, Chigaco, IL).
To analyze data from MRI scans, a general linear model through pre-processed images was set up. Two-sample t-test was applied to provide voxelwise group comparisons of GM volumes with age, gender, years of education, and total intracranial volume (TIV) as covariates of no interest. TIV was calculated as the sum of GM, WM, and cerebrospinal fluid (CSF) volumes. GM probability maps were filtered at uncorrected P < 0.005 and a minimum cluster size of 100 voxels. A family-wise error (FWE) correction was subsequently applied. The anatomical localization of significant clusters of GM analysis was detected using the tool FSL-view of FSL software and Talairach Demon Labels atlas (www.fmrib.ox.ac.uk/fsl).
Comparisons of FA between groups were tested by a two-sample t-test adjusted for patient's age and gender. The number of permutations was set at 500. Voxelwise FA statistical analysis was performed by using a permutation-based inference tool for non-parametric statistical thresholding (‘randomize’ program, part of FSL), at first using a statistical threshold of P < 0.005 and then using a threshold of P < 0.05 corrected for multiple comparisons by implementing threshold-free cluster enhancement (TFCE) . The anatomical location of significant clusters was detected using the Johns Hopkins University WM tractography atlas, part of FSL-view tool.
To determine the relationship between psychopathological domains, GM volume, and WM FA, several partial correlation analyses with PANSS negative and disorganized factors were performed. These symptoms have previously been related to brain volume and may represent a more stable psychopathological subset [14, 30]. Other domains were excluded from this analysis because they explore symptoms which are thought to be unstable, state dependent, and difficult to correlate with brain structure .
Differences in neuropsychological measures between patients and controls were analyzed by using the Mann–Whitney U-test. The partial correlation analyses were performed only on neuropsychological measures that retained their statistical significance in differentiating between patients and controls after Bonferroni correction. As previously described, age, gender years of education, and TIV were used as covariates of no interest and the same statistical threshold values were applied.
Twenty-five patients were enrolled. Despite our efforts to motivate them, five patients decided to quit the study because feeling not comfortable to undergo the MRI scan; three patients denied consent just prior to MRI scanning, while other two patients refused to complete the ongoing scan. Another patient, who was able to complete all sequences but obtained images of poor quality because of movement artifacts, was excluded from the final analysis. Therefore, a final set of 19 patients, with a high-quality MRI scan, was analyzed.
At the time of first clinical assessment, all patients were under one atypical antipsychotic medication (seven patients olanzapine, 10 patients risperidone, two patients aripiprazole). Mean dosages (mg/day) were 11.4 (DS: 2.8) and 4.6 (DS: 0.9) for olanzapine and risperidone respectively. Both patients on aripiprazole were taking 15 mg/day. On average, these treatments corresponded to 13.2 (DS: 3.5) and 398 (DS: 105) olanzapine and chlorpromazine equivalents (mg/day) respectively . At the time of first clinical assessment, mean treatment duration was less than 14 days (mean: 9.4; SD: 1.61). Mean DUP was 8 (SD: 3.31) months. Six months after enrollment in the study, all Axis I diagnoses were schizophrenia. All subjects were Caucasian and right handed. Sociodemographic characteristics and main psychopathological domains of PANSS are shown in Table 1. Patients did not differ from controls for general features (all P > 0.3). The six patients excluded from the final analysis did not differ for any of the abovementioned features, including mean antipsychotics dosages (data not shown).
|Males, N, (%)||Age (years)||Years of education||Civil status (% single)||Intracranial volume (ml)||DUP (mo.)||PANSS pos/scl||PANSS neg/scl||PANSS gen/scl||PANSS tot/scl||PANSS neg/fct||PANSS dis/fct||PANSS pos/fct||PANSS exc/fct||PANSS anx/fct|
|FES (N = 19)||12 (63)||22.2 (3.7)||12.1 (3.1)||84.2||1407 (115.1)||8 (3.3)||26.2 (9.3)||24.3 (6.7)||49.1 (14.4)||103.3 (15.1)||25.1 (7.7)||21.8 (5.7)||24.8 (8.2)||12.5 (4.8)||18.3 (5.5)|
|HC (N = 18)||11 (61)||23.4 (3.3)||13.3 (1.2)||78.9||1362.6 (74.1)||N/A||N/A||N/A||N/A||N/A||N/A||N/A||N/A||N/A||N/A|
Complete results of neuropsychological tests are shown in Table 2.
|Cognitive domains||First-episode patients (n = 19)||Healthy subjects (n = 18)|
Speed of processing
|64.9 ± 9.5||80.2 ± 9.1|
|19.4 ± 15.6||9.6 ± 10.5|
|120.0a ± 143.1||25.7 ± 7.6|
Buschke delayed recall
|6.2 ± 3.0||9.3 ± 1.0|
ROCF delayed recallb
|15.4 ± 6.6||26.0 ± 5.7|
Reasoning and problem-solving
|4.5 ± 2.0||5.2 ± 1.7|
|26.0 ± 8.5||34.6 ± 4.1|
|25.0 ± 4.4||31.8 ± 3.7|
The following neuropsychological measures retained statistical significance after Bonferroni correction (all P < 0.005) and entered the subsequent correlative analyses: i) social cognition (FEIT); ii) speed of processing (Stroop W) and iii) visual memory (ROCF).
Relative to controls, patients showed significantly decreased GM volume in the superior, middle, inferior, and fusiform gyrus of the left temporal lobe [Brodmann area 37] at uncorrected cluster level (P = 0.003). As shown by Table 3, a trend toward significance was found for the decrease in right cerebellum and right cuneus [Brodmann area 17] volumes (P < 0.03 and P < 0.09 respectively). No significant increases in GM volume were found in patients compared to healthy controls. Figure 1 depicts regions of GM volume reduction in FES.
|MNI coordinates||K-value||P-value (unc)||P-value (FWE)||Z-value||Side||Anatomical region|
|959||0.003||0.10||4.46||L||Fusiform gyrus (BA 37)|
|21||−79||−8||260||0.09||0.96||3.67||R||Cuneus (BA 17)|
White matter analysis revealed significantly decreased FA values in patients compared to controls in all major WM tracts (Fig. 2), including thalamic radiations, cortico-cortical association tracts (uncinate, inferior and superior longitudinal fasciculus, inferior fronto-occipital fasciculus), interhemispheric tract (splenium of the corpus callosum), and cortico-spinal tracts (uncorrected P < 0.005).
A significant correlation between PANSS disorganized/cognitive factor score and GM decrease was found in the left cerebellum (corrected P = 0.03). Table 4 shows the complete results of the statistical correlation between PANSS scores and morphometric GM analysis.
|Neuropsychological and psychopathological domains||Regions of decreased gray matter volume|
|MNI coordinates||K-value||P-value (unc.)||P-value (FWE)||Z-value||Side||Anatomical region|
|PANSS cognitive/disorganized factor||−33||−54||−46||1182||0.001||0.03||3.23||L||Cerebellum|
|PANSS negative factor||36||−85||5||364||0.04||0.80||3.92||R||Middle occipital gyrus|
|Social cognition (identification task)||23||−78||−5||1720||<0.001||0.003||4.42||R||Fusiform gyrus [BA 37]|
|Speed of processing (Stroop word)||−48||−54||−21||3484||0.03||0.89||3.60||L||Cerebellum|
|Visual memory (ROCF delayed recall)||9||−72||−28||3596||0.02||0.87||3.54||R||Cerebellum|
A significant inverse correlation between PANSS disorganized/cognitive factor score and FA was found in the left cerebellum, the inferior fronto-occipital fasciculus bilaterally, the inferior longitudinal fasciculus bilaterally, and part of the commissural fibers (body and splenium of the corpus callosum) (corrected P < 0.05). Furthermore, a significant inverse correlation between PANSS negative factor and FA was found in the inferior fronto-occipital fasciculus bilaterally, superior longitudinal fasciculus bilaterally, and splenium of the corpus callosum (corrected P < 0.05).
In patients, FEIT score (i.e., social cognition) significantly correlated with a GM decrease in the right temporal–occipital cortex [Brodmann area 37]. A correlation was found between i) speed of processing and decreased left cerebellar GM volume and ii) visual memory and GM decrease in right cerebellum, without reaching statistical significance (See Table 4).
Patients displayed a significant correlation between FEIT score and WM disarray of the superior and middle temporal gyrus bilaterally, anterior thalamic radiation, superior longitudinal fasciculi, genu and body of the corpus callosum (corrected P < 0.05).
Speed of processing and visual memory showed a similar pattern of associated WM disarray: Both correlated with FA of frontal (i.e., parts of the anterior thalamic radiation and inferior fronto-occipital fasciculus, bilaterally) and left temporal WM areas (i.e., superior longitudinal fasciculus, inferior longitudinal fasciculus, and inferior fronto-occipital fasciculus) (uncorrected P < 0.001).
In recent years, schizophrenia has been proposed as a neurodevelopmentally derived ‘misconnection syndrome’ involving connections between cortical regions and the cerebellum mediated through the thalamus (the cortico-cerebellar-thalamic-cortical circuit, CCTCC) . Abnormal CCTCC leads to misconnection in many aspects of mental activity, or to ‘cognitive dysmetria’, which is substantially a pattern of disorganization. Following this theory, significant correlations between symptoms, cognitive performances, and cerebral anatomy might be detected in schizophrenia. Inherently with the concept of ‘neurodevelopment’, it appears likely to find such correlations since the onset of the disease.
In the present study, whole-brain, rater-independent VBM was carried out to investigate GM and WM volume abnormalities at the onset of schizophrenia (FES), addressing possible neuroanatomical underpinnings of symptoms and cognitive impairment.
First, our results suggest the presence of a reduction in left temporal GM volume in patients as compared to controls, which has been advocated as a trait feature of chronic schizophrenia. Our findings are consistent with those of some authors , while others showed GM reduction in different regions [1, 2]. Factors that may underlie the differing patterns of morphological changes in FES are numerous, rendering difficult any comparison with previous studies. Because sociodemographic and clinical characteristics of our series were comparable with the previous investigations applying VBM in FES, differences between other reports may be due to different definition of first episode, duration of illness before assessment, and type of medication. We hypothesized that the influence of antipsychotic treatment in GM volume of our population was unlikely, as we had only patients treated for less than 14 days. Variations in VBM methodology, such as normalization parameters, may affect the sensitivity of the study to detect changes in some brain regions, particularly in medio-temporal regions; differences in image smoothing may affect the number of areas of volume reduction detected . The SPM8 model and the DARTEL registration method used in our study allow for the identification of structural changes with a more accurate intersubject alignment, obtaining a correct realignment of small inner structure .
The second finding of our study was a disarray of all major WM tracts in patients compared to controls. Although obtained in a small sample, this finding suggests the presence of WM disarray since the onset of the disease, sustaining that neurological aberrations lead to intra- and interhemispheric deregulated connectivity, which may explain the global nature and heterogeneity of cognitive deficits in schizophrenia . As far as imaging correlates are concerned, to the best of our knowledge this is the first study examining the relationship between GM volume, WM integrity, and both psychopathological and neuropsychological measures in FES. The psychopathological factorial model itself – which is the best model enabling to study the relationship between specific symptoms and underlining neural substrates – has been rarely applied to correlative analysis in schizophrenia [34-37].
First, the disorganized/cognitive PANSS factor was associated with decrease in GM volume and FA disarray in the left cerebellum. Cerebellum is involved in basic neurocognitive functions such as timing and associative learning and plays a significant role in cognition . It is activated in a variety of mental activities including facial recognition, emotion attribution, directed attention, and memory. To the best of our knowledge, this is the first study identifying, in the early course of schizophrenia, the disorganized psychopathological pattern related to volume deficits and microstructural disarray in that region, thus replicating findings from chronic population .
Second, negative symptoms displayed a significant inverse correlation with FA of the major WM cortico-cortical association tracts. This is consistent with previous studies and may be explained by the ‘functional disconnection’ hypothesis, according to which a disconnection between fronto-temporal WM areas might be related to negative symptoms of schizophrenia [17, 39]. Unfortunately, we failed to detect a correlation between negative symptoms and cortical GM volume. One possible interpretation is that disturbed neural circuits, rather than structural alterations per se, may play a role in the development of symptoms in FES . Interestingly, a disarray of WM seems to be specifically associated with the expression of negative symptoms in chronic patients . Unfortunately, the small sample size of the present study did not allow more definitive conclusions.
Correlative neuropsychological analysis showed additional interesting results. Social cognition impairment was related to a GM decrease in right temporo-occipital cortex and to a concurrent WM disarray of superior and middle temporal gyrus bilaterally, anterior thalamic radiation, and superior longitudinal fasciculus. The correlation with GM volume is in line with a previous study in first-episode psychosis . On the other hand, WM abnormalities could be partially included in the revised face-perception circuitry, composed of a core system (temporo-occipital regions) mediating the visual analysis of faces, and of an extended pathway (frontal-limbic system) deriving meaning from face perception . As supported by recent literature, impaired social cognition is a core feature of schizophrenia, representing a specific deficit rather than a result of a generalized cognitive dysfunction . Interestingly, it appears to be present even before the onset of psychosis  and to be significantly related to brain structural abnormalities .
The results at uncorrected cluster levels are also discussed below; low statistical power may represent a possible caveat, but is perhaps allowed by the preliminary nature of our study.
Both speed of processing and visual memory impairment were related to a fronto-temporal WM disarray. This common pattern of underlining anatomical abnormalities could possibly reflect the clinical association between them . However, we failed to detect a significant concurrent GM volume decrease, which is not surprising as some authors suggested that WM pathology may play a primary role in cognitive deficits .
In summary, this is an original exploratory study of anatomical underpinnings of neuropsychopathology in FES. While the small number of patients is of course a weakness of the study, one strength is represented by the selection of patients. All patients included had an untreated psychosis for less than 12 months before admission, and all had diagnostic confirmation of schizophrenia six months after study entry. This supports the accuracy of our diagnoses of FEP. Moreover, a possible confounding factor in the evaluation of cognitive function, such as the history of prior drug abuse, has been excluded in all our patients. Of note, controls were matched for age, gender, and education, which could be confounding factors when inferring cognitive function from brain structure.
Consistently with a neurodevelopmentally derived ‘misconnection syndrome’ , our results suggest how the structural development of key brain regions may relate to neuropsychopathological dysfunction even at the very early stages of schizophrenia. Overall, confirmatory longitudinal studies are needed.
We are grateful to all subjects who participated in this study. We thank Dr. Eleonora De Pisa and Dr. Giovanni Manfredi, Pysichiatry Unit, Sant'Andrea Hospital, Rome, for their help with recruitment of subjects. Finally, we would like to thank the anonymous reviewers who, with their invaluable suggestions, significantly helped to improve the quality of the paper.