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ORBITOFRONTAL CORTEX SULCOGYRAL PATTERNS IN FIRST EPISODE SCHIZOPHRENIA: PRELIMINARY FINDINGS
222
Abstracts
Poster 90 RETHINKING THE GENETIC ARCHITECTURE OF SCHIZOPHRENIA Kevin J. Mitchell1, David J. Porteous2 1 Trinity College Dublin Dublin Ireland; Edinburgh United Kingdom
2
University of Edinburgh
Background: For many years, the prevailing dogma has stated that schizophrenia (SZ) is caused, in each individual, by a combination of many genetic variants, each with small effect alone (the polygenic, common disease/common variants model). Recent empirical data are prompting a re-evaluation of this model. These include a lack of the expected number of strong positive findings from genome-wide association studies and the concurrent discovery of a rapidly increasing number of single mutations that strongly predispose to SZ and other psychiatric disorders. These have led to a recent shift towards a mixed model where separate proportions of cases are caused by polygenic or single-mutation mechanisms. However, models incorporating a significant contribution from single mutations run counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Methods: In light of recent empirical findings, we re-consider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them. Results: We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is quite consistent with observed familial recurrence risks (including for endophenotypes) and other population-wide parameters. Discussion: We argue for a more biologically consilient mixed model that involves interactions between single, disease-causing mutations and polygenic, modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms. doi:10.1016/j.schres.2010.02.318
Poster 91 A COMPARISON TO CONTROLS OF BRAIN STRUCTURE IN SUBJECTS WITH METHAMPHETAMINE PSYCHOSIS AND COMORBID HIV INFECTION Alasdair M. Barr, William G. Honer, G. William MacEwan, Willough Jenkins, Wayne Su, Tari Buchanan, Helen Craig, Donna J. Lang University of British Columbia Vancouver, BC, Canada
Background: Previous studies have reported that sustained use of high doses of the psychostimulant drug methamphetamine can induce transient psychosis. For many intravenous methamphetamine users, medical co-morbidity represents an additional problem, which may impact on mental health. In the present study, we investigated brain structure (using MRI), cognitive function and psychiatric symptomatology in subjects who had previously experienced an episode of psychosis related to methamphetamine use, and were concurrently infected with HIV. A matched control group was studied for comparison. Methods: Twenty one HIV-infected stimulant users were recruited, as well as 21 age, gender and IQ-matched non-HIV control subjects who did not use stimulants. Subjects were assessed for psychiatric symptomatology using various clinical screens, such as the MINI. All subjects completed a panel of cognitive tests, which included an evaluation of attention, memory and executive function. For HIV-infected subjects, viral
loads and antibody titers were measured. All subjects completed an MRI brain scan, that included SPGR, FLAIR and DTI sequences. Results: Compared to controls, the group with prior methamphetamine psychosis and HIV exhibited much higher rates of psychiatric symptoms, including substance dependence (85%), major depression (67%), anxiety disorder (24%) and hallucinations/delusions (70%). Analysis of the brain structure revealed no changes in volume of multiple sub-cortical structures, such as basal ganglia and hippocampus, but less frontal gray and white matter (p < 0.05). The number of minor structural abnormalities was also greater in the psychosis group. Analysis of white matter integrity with DTI noted that global fractional anisotropy values were lower in the psychosis group (p < 0.001). Discussion: In a study of intravenous stimulant drug users that had previously experienced methamphetamine-induced psychosis, and who were concurrently infected with HIV, we found a range of structural brain differences from controls. Rates of psychiatric symptomatology were also higher. doi:10.1016/j.schres.2010.02.319
Poster 92 ORBITOFRONTAL CORTEX SULCOGYRAL PATTERNS IN FIRST EPISODE SCHIZOPHRENIA: PRELIMINARY FINDINGS Cali F. Bartholomeusz1, Sarah Whittle1,2, Patrick McGorry2, Dennis Velakoulis1, Christos Pantelis1, Stephen J. Wood1 1 Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne Carlton South, Victoria, Australia; 2Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne Parkville, Victoria, Australia Background: The orbitofrontal cortex (OFC) is a region known to be involved in various higher order cognitive processes, in particular those associated with reward/punishment, moral judgement/decision-making and social cognition (Kringelbach and Rolls, 2004; Sabbagh, 2004). Three types of OFC sulcogyral patterns have been identified in the general population; Type I is most commonly found (56% of the time), Type II is less common (30%), while Type III is rare (14%) (Chiavaras and Petrides, 2000). Altered OFC sulcogyral patterns have been found in chronic schizophrenia, where Type III was more common and Type I less common (Nakamura et al., 2007). For patients, the Type III pattern was associated with poorer socio-economic status, worse verbal comprehension, having a 'negative emotionality' trait and more severe symptoms compared to patients without Type III expression. The aim of the current study was to replicate and extend this research by investigating whether OFC sulcogyral patterns are also altered in the early stage of the illness. Methods: 96 (71 male, 25 female) first episode schizophrenia (FES) patients (age M = 21.3, SD = 3.2; illness duration M = 66, SD = 107 days), with a diagnosis of either schizophrenia or schizophreniform disorder were recruited from Orygen Youth Health, a public outpatient service in Melbourne. 24 (15 male, 9 female) healthy control participants were recruited from the general population. T1-weighted MR images were acquired with a 1.5T scanner. OFC pattern type was done by C.B. who was blinded to subject group. Classification was based on the method devised by Chaivaras and Petridies (2000), and involved viewing and tracing the sulci in the coronal and transverse planes and classifying according to visual inspection of the images (Cronbach's alpha for inter-rater reliability on an independent set of 50 brains was 0.82, and C.B.'s reliability for consistency was 0.88). Chi square statistics were performed on OFC pattern type and independent
Abstracts
samples t-tests were run to compare the number of intermediate and posterior sulci between groups. Results: Contrary to findings in chronic patients, there were no significant differences in the distribution of the three OFC Types between groups (FES patients: Type I = 46.4%, Type II = 26.6%, Type III = 27.1%; controls Type I = 56.3%, Type II = 16.7%, Type III = 27.1%). Similar percentages were found when left and right hemispheres were analyzed separately. However, significantly fewer intermediate rostral sulci were observed in the left hemisphere of patients compared to controls (t(117) = − 2.09, p < .05). Discussion: Our findings showed OFC Type III was not more common in FES patients in comparison to healthy controls, suggesting chronicity or stage of illness may be a dependent factor. However, given that OFC sulcogyral folding patterns are determined during early neurodevelopment, it is more likely that OFC Type III is a risk factor for poor social and functional outcome in general. The finding of fewer intermediate sulci in the left hemisphere may reflect underdevelopment of the neural system in that area, which is in line with findings of abnormal sulcal morphometry in the left cingulate of schizophrenia patients (Yücel et al., 2002). Further investigation into the relationship between social functioning and OFC pattern Type is needed and should encompass not only schizophrenia cohorts but other clinical populations as well.
doi:10.1016/j.schres.2010.02.320
Poster 93 BRAIN VOLUME CHANGES AFTER WITHDRAWAL OF ATYPICAL ANTIPSYCHOTICS IN FIRST-EPISODE SCHIZOPHRENIA PATIENTS Geartsje Boonstra1,3, Neeltje E.M. van Haren1, Hugo G. Schnack1, Wiepke Cahn1, Huibert Burger1,2,3, Maria Boersma1, Diederick E. Grobbee1,2, Hilleke E. Hulshoff Pol1, Rene S. Kahn1 1 UMCU Utrecht, Utrecht, Netherlands; 2UMCG Groningen, Groningen, Netherlands; 3Julius Centre Utrecht, Utrecht, Netherlands Background: The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time in patients. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients with a schizophrenic disorder. Methods: Sixteen remitted, stable first-episode patients with schizophrenia, schizoaffective or schizophreniform disorder and twenty healthy controls, group-matched for age and sex, were included. A Magnetic Resonance Imaging scan was obtained of all patients and controls at baseline and at one year follow-up. The patients either discontinued (n=8) their atypical antipsychotic medication (risperidone, olanzapine or quetiapine) or not (n=8) during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens and putamen were obtained. Multiple linear regression analyses were used to assess the influence of discontinuation of atypical antipsychotics on brain volume (change), while correcting for age, gender and intracranial volume. Main effect of group (patientcontrol) and effect of discontinuation (yes-no) were investigated. Results: Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls (p= 0.04 and p = 0.03, respectively). Additionally, nucleus accumbens volume increase over time was more pronounced in controls as compared to patients (p= 0.05). Furthermore, cerebral white matter volume in patients showed a larger increase over time as compared to controls (p= 0.02). Comparing patients on and off antipsychotic medication showed significant differences in change over time in volumes of the nucleus accumbens and putamen. The
223
nucleus accumbens and putamen volumes decreased during the interval in medication-free patients while increases were found in patients that continued their antipsychotics (nucleus accumbens: p = 0.04; putamen: p = 0.001). Discussion: We confirmed earlier findings of gray matter volume decrements in patients with schizophrenia in comparison to normal controls. Importantly, discontinuation of atypical antipsychotics was related to volume decrease over time in the putamen and nucleus accumbens. This suggests that increases seen in the basal ganglia as a result of starting typical antipsychotic medication, also occur in atypical medication and are reversed by medication discontinuation.
doi:10.1016/j.schres.2010.02.321
Poster 94 CORTICAL THICKNESS IN PATIENTS WITH SCHIZOPHRENIA AND THEIR SIBLINGS Heleen B.M. Boos, Wiepke Cahn, Neeltje E.M. Van Haren, Eske M. Derks, Rachel M. Brouwer, Hugo G. Schnack, Hilleke E. Hulshoff Pol, Rene S. Kahn Rudolf Magnus Institute of Neuroscience, Dept. of Psychiatry, University Medical Center Utrecht Utrecht, Utrecht, Netherlands Background: Brain imaging studies have consistently demonstrated brain abnormalities in patients with schizophrenia. However, it is unknown whether these are caused by genetic and/or disease related factors¹. As the heritability to develop the illness is around 80%, with first-degree relatives to share approximately 50% of their genetic variants, brain abnormalities may also be present in (healthy) first-degree relatives of patients with schizophrenia. This large MRI study examined cortical thickness in patients with schizophrenia as well as their non-psychotic siblings and compared them to healthy control subjects. Methods: From 193 patients with schizophrenia [age (mean/sd) = 26.90/5.58; male % = 81], 208 non-psychotic siblings [age (mean/ sd) = 27.54/6.76; male % = 46] and 136 healthy control subjects [age (mean/sd) = 27.53/8.24; male % = 50] whole brain scans were obtained on a 1.5 T Achieva scanner. In-house software2 was used to segment total brain (TB), gray matter (GM) and white matter (WM) of the cerebrum, lateral and third ventricle and cerebellum volumes. For each subject, cortical thickness (CortT) was calculated for every vertex3. Group differences in volumes were analysed by applying a Mixed Models approach. Differences in CortT were calculated using regression analyses with age, gender and handedness as covariates. Analyses were implemented in Mx. Results: Brain volume reductions in TB, GM and WM and increments in lateral and third ventricle volumes were found in patients with schizophrenia but not in non-psychotic siblings as compared with healthy control subjects. Moreover, in patients decreases in CortT were found in the frontal and temporal cortices and to a lesser extent in the occipital and parietal cortices. Nonpsychotic siblings of patients with schizophrenia were no different from healthy control subjects. Discussion: This study shows differences in cortical thickness in patients with schizophrenia but not in their non-psychotic siblings. This suggests that in schizophrenia cortical changes are mainly caused by disease-related factors. References: 1Hulshoff Pol et al., 2002. Am J Psychiatry 159(2): 244-50 2Schnack et al., 2001. Neuroimage (13): 230-7 3Software: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal. doi:10.1016/j.schres.2010.02.322
Abstracts
Poster 90 RETHINKING THE GENETIC ARCHITECTURE OF SCHIZOPHRENIA Kevin J. Mitchell1, David J. Porteous2 1 Trinity College Dublin Dublin Ireland; Edinburgh United Kingdom
2
University of Edinburgh
Background: For many years, the prevailing dogma has stated that schizophrenia (SZ) is caused, in each individual, by a combination of many genetic variants, each with small effect alone (the polygenic, common disease/common variants model). Recent empirical data are prompting a re-evaluation of this model. These include a lack of the expected number of strong positive findings from genome-wide association studies and the concurrent discovery of a rapidly increasing number of single mutations that strongly predispose to SZ and other psychiatric disorders. These have led to a recent shift towards a mixed model where separate proportions of cases are caused by polygenic or single-mutation mechanisms. However, models incorporating a significant contribution from single mutations run counter to a substantial body of theoretical literature that had supposedly conclusively rejected Mendelian inheritance with genetic heterogeneity. Methods: In light of recent empirical findings, we re-consider the methods and conclusions of early theoretical analyses and the explicit assumptions underlying them. Results: We show that many of these assumptions can now be seen to be false and that the model of genetic heterogeneity is quite consistent with observed familial recurrence risks (including for endophenotypes) and other population-wide parameters. Discussion: We argue for a more biologically consilient mixed model that involves interactions between single, disease-causing mutations and polygenic, modifying variants in each individual. We consider the implications of this model for moving SZ research beyond statistical associations to pathogenic mechanisms. doi:10.1016/j.schres.2010.02.318
Poster 91 A COMPARISON TO CONTROLS OF BRAIN STRUCTURE IN SUBJECTS WITH METHAMPHETAMINE PSYCHOSIS AND COMORBID HIV INFECTION Alasdair M. Barr, William G. Honer, G. William MacEwan, Willough Jenkins, Wayne Su, Tari Buchanan, Helen Craig, Donna J. Lang University of British Columbia Vancouver, BC, Canada
Background: Previous studies have reported that sustained use of high doses of the psychostimulant drug methamphetamine can induce transient psychosis. For many intravenous methamphetamine users, medical co-morbidity represents an additional problem, which may impact on mental health. In the present study, we investigated brain structure (using MRI), cognitive function and psychiatric symptomatology in subjects who had previously experienced an episode of psychosis related to methamphetamine use, and were concurrently infected with HIV. A matched control group was studied for comparison. Methods: Twenty one HIV-infected stimulant users were recruited, as well as 21 age, gender and IQ-matched non-HIV control subjects who did not use stimulants. Subjects were assessed for psychiatric symptomatology using various clinical screens, such as the MINI. All subjects completed a panel of cognitive tests, which included an evaluation of attention, memory and executive function. For HIV-infected subjects, viral
loads and antibody titers were measured. All subjects completed an MRI brain scan, that included SPGR, FLAIR and DTI sequences. Results: Compared to controls, the group with prior methamphetamine psychosis and HIV exhibited much higher rates of psychiatric symptoms, including substance dependence (85%), major depression (67%), anxiety disorder (24%) and hallucinations/delusions (70%). Analysis of the brain structure revealed no changes in volume of multiple sub-cortical structures, such as basal ganglia and hippocampus, but less frontal gray and white matter (p < 0.05). The number of minor structural abnormalities was also greater in the psychosis group. Analysis of white matter integrity with DTI noted that global fractional anisotropy values were lower in the psychosis group (p < 0.001). Discussion: In a study of intravenous stimulant drug users that had previously experienced methamphetamine-induced psychosis, and who were concurrently infected with HIV, we found a range of structural brain differences from controls. Rates of psychiatric symptomatology were also higher. doi:10.1016/j.schres.2010.02.319
Poster 92 ORBITOFRONTAL CORTEX SULCOGYRAL PATTERNS IN FIRST EPISODE SCHIZOPHRENIA: PRELIMINARY FINDINGS Cali F. Bartholomeusz1, Sarah Whittle1,2, Patrick McGorry2, Dennis Velakoulis1, Christos Pantelis1, Stephen J. Wood1 1 Melbourne Neuropsychiatry Centre, Department of Psychiatry, The University of Melbourne Carlton South, Victoria, Australia; 2Orygen Youth Health Research Centre, Centre for Youth Mental Health, The University of Melbourne Parkville, Victoria, Australia Background: The orbitofrontal cortex (OFC) is a region known to be involved in various higher order cognitive processes, in particular those associated with reward/punishment, moral judgement/decision-making and social cognition (Kringelbach and Rolls, 2004; Sabbagh, 2004). Three types of OFC sulcogyral patterns have been identified in the general population; Type I is most commonly found (56% of the time), Type II is less common (30%), while Type III is rare (14%) (Chiavaras and Petrides, 2000). Altered OFC sulcogyral patterns have been found in chronic schizophrenia, where Type III was more common and Type I less common (Nakamura et al., 2007). For patients, the Type III pattern was associated with poorer socio-economic status, worse verbal comprehension, having a 'negative emotionality' trait and more severe symptoms compared to patients without Type III expression. The aim of the current study was to replicate and extend this research by investigating whether OFC sulcogyral patterns are also altered in the early stage of the illness. Methods: 96 (71 male, 25 female) first episode schizophrenia (FES) patients (age M = 21.3, SD = 3.2; illness duration M = 66, SD = 107 days), with a diagnosis of either schizophrenia or schizophreniform disorder were recruited from Orygen Youth Health, a public outpatient service in Melbourne. 24 (15 male, 9 female) healthy control participants were recruited from the general population. T1-weighted MR images were acquired with a 1.5T scanner. OFC pattern type was done by C.B. who was blinded to subject group. Classification was based on the method devised by Chaivaras and Petridies (2000), and involved viewing and tracing the sulci in the coronal and transverse planes and classifying according to visual inspection of the images (Cronbach's alpha for inter-rater reliability on an independent set of 50 brains was 0.82, and C.B.'s reliability for consistency was 0.88). Chi square statistics were performed on OFC pattern type and independent
Abstracts
samples t-tests were run to compare the number of intermediate and posterior sulci between groups. Results: Contrary to findings in chronic patients, there were no significant differences in the distribution of the three OFC Types between groups (FES patients: Type I = 46.4%, Type II = 26.6%, Type III = 27.1%; controls Type I = 56.3%, Type II = 16.7%, Type III = 27.1%). Similar percentages were found when left and right hemispheres were analyzed separately. However, significantly fewer intermediate rostral sulci were observed in the left hemisphere of patients compared to controls (t(117) = − 2.09, p < .05). Discussion: Our findings showed OFC Type III was not more common in FES patients in comparison to healthy controls, suggesting chronicity or stage of illness may be a dependent factor. However, given that OFC sulcogyral folding patterns are determined during early neurodevelopment, it is more likely that OFC Type III is a risk factor for poor social and functional outcome in general. The finding of fewer intermediate sulci in the left hemisphere may reflect underdevelopment of the neural system in that area, which is in line with findings of abnormal sulcal morphometry in the left cingulate of schizophrenia patients (Yücel et al., 2002). Further investigation into the relationship between social functioning and OFC pattern Type is needed and should encompass not only schizophrenia cohorts but other clinical populations as well.
doi:10.1016/j.schres.2010.02.320
Poster 93 BRAIN VOLUME CHANGES AFTER WITHDRAWAL OF ATYPICAL ANTIPSYCHOTICS IN FIRST-EPISODE SCHIZOPHRENIA PATIENTS Geartsje Boonstra1,3, Neeltje E.M. van Haren1, Hugo G. Schnack1, Wiepke Cahn1, Huibert Burger1,2,3, Maria Boersma1, Diederick E. Grobbee1,2, Hilleke E. Hulshoff Pol1, Rene S. Kahn1 1 UMCU Utrecht, Utrecht, Netherlands; 2UMCG Groningen, Groningen, Netherlands; 3Julius Centre Utrecht, Utrecht, Netherlands Background: The influence of antipsychotic medication on brain morphology in schizophrenia may confound interpretation of brain changes over time in patients. We aimed to assess the effect of discontinuation of atypical antipsychotic medication on change in brain volume in patients with a schizophrenic disorder. Methods: Sixteen remitted, stable first-episode patients with schizophrenia, schizoaffective or schizophreniform disorder and twenty healthy controls, group-matched for age and sex, were included. A Magnetic Resonance Imaging scan was obtained of all patients and controls at baseline and at one year follow-up. The patients either discontinued (n=8) their atypical antipsychotic medication (risperidone, olanzapine or quetiapine) or not (n=8) during the follow-up period. Intracranial volume and volumes of total brain, cerebral gray and white matter, cerebellum, third and lateral ventricle, nucleus caudatus, nucleus accumbens and putamen were obtained. Multiple linear regression analyses were used to assess the influence of discontinuation of atypical antipsychotics on brain volume (change), while correcting for age, gender and intracranial volume. Main effect of group (patientcontrol) and effect of discontinuation (yes-no) were investigated. Results: Decrease in cerebral gray matter and caudate nucleus volume over time was significantly more pronounced in patients relative to controls (p= 0.04 and p = 0.03, respectively). Additionally, nucleus accumbens volume increase over time was more pronounced in controls as compared to patients (p= 0.05). Furthermore, cerebral white matter volume in patients showed a larger increase over time as compared to controls (p= 0.02). Comparing patients on and off antipsychotic medication showed significant differences in change over time in volumes of the nucleus accumbens and putamen. The
223
nucleus accumbens and putamen volumes decreased during the interval in medication-free patients while increases were found in patients that continued their antipsychotics (nucleus accumbens: p = 0.04; putamen: p = 0.001). Discussion: We confirmed earlier findings of gray matter volume decrements in patients with schizophrenia in comparison to normal controls. Importantly, discontinuation of atypical antipsychotics was related to volume decrease over time in the putamen and nucleus accumbens. This suggests that increases seen in the basal ganglia as a result of starting typical antipsychotic medication, also occur in atypical medication and are reversed by medication discontinuation.
doi:10.1016/j.schres.2010.02.321
Poster 94 CORTICAL THICKNESS IN PATIENTS WITH SCHIZOPHRENIA AND THEIR SIBLINGS Heleen B.M. Boos, Wiepke Cahn, Neeltje E.M. Van Haren, Eske M. Derks, Rachel M. Brouwer, Hugo G. Schnack, Hilleke E. Hulshoff Pol, Rene S. Kahn Rudolf Magnus Institute of Neuroscience, Dept. of Psychiatry, University Medical Center Utrecht Utrecht, Utrecht, Netherlands Background: Brain imaging studies have consistently demonstrated brain abnormalities in patients with schizophrenia. However, it is unknown whether these are caused by genetic and/or disease related factors¹. As the heritability to develop the illness is around 80%, with first-degree relatives to share approximately 50% of their genetic variants, brain abnormalities may also be present in (healthy) first-degree relatives of patients with schizophrenia. This large MRI study examined cortical thickness in patients with schizophrenia as well as their non-psychotic siblings and compared them to healthy control subjects. Methods: From 193 patients with schizophrenia [age (mean/sd) = 26.90/5.58; male % = 81], 208 non-psychotic siblings [age (mean/ sd) = 27.54/6.76; male % = 46] and 136 healthy control subjects [age (mean/sd) = 27.53/8.24; male % = 50] whole brain scans were obtained on a 1.5 T Achieva scanner. In-house software2 was used to segment total brain (TB), gray matter (GM) and white matter (WM) of the cerebrum, lateral and third ventricle and cerebellum volumes. For each subject, cortical thickness (CortT) was calculated for every vertex3. Group differences in volumes were analysed by applying a Mixed Models approach. Differences in CortT were calculated using regression analyses with age, gender and handedness as covariates. Analyses were implemented in Mx. Results: Brain volume reductions in TB, GM and WM and increments in lateral and third ventricle volumes were found in patients with schizophrenia but not in non-psychotic siblings as compared with healthy control subjects. Moreover, in patients decreases in CortT were found in the frontal and temporal cortices and to a lesser extent in the occipital and parietal cortices. Nonpsychotic siblings of patients with schizophrenia were no different from healthy control subjects. Discussion: This study shows differences in cortical thickness in patients with schizophrenia but not in their non-psychotic siblings. This suggests that in schizophrenia cortical changes are mainly caused by disease-related factors. References: 1Hulshoff Pol et al., 2002. Am J Psychiatry 159(2): 244-50 2Schnack et al., 2001. Neuroimage (13): 230-7 3Software: McConnell Brain Imaging Centre, Montreal Neurological Institute, McGill University, Montreal. doi:10.1016/j.schres.2010.02.322