- Email: [email protected]
Ventricular shape of monozygotic twins discordant for schizophrenia reflects vulnerability
194 anomalies of the CC. Although this gross developmental anomaly are not representative of schizophrenia, the higher incidence of schizophrenic symptoms in such patients may suggest that subtle structural or developmental anomalies of the CC might be present in other patients with schizophrenia. Most of these patients with grossly abnormalities at the CC showed prominent and severe positive symptoms (delusions and hallucinations) and poor response to traditional and atypical antipsychotic drugs. Our case and the literature suggest that patients with ACC may constitute a subgroup of patients in whom a more incisive psychopharmacotogical approach may be more beneficial, with clozapine been considered as soon as possible. The presence of schizophrenia on absence of CC may pose difficulties for theories that postulate excessive interhemispheric communication in the pathogenesis of psychosis.
BRAIN STRUCTURAL CORRELATES OF IQ IN HEALTHY AND SCHIZOPHRENIC ADOLESCENTS S. Frangou,* M. Hadjulis Section of Neurobiology of Psychosis, Institute of Psychiatry, London, United Kingdom Background: Previous MRI studies of brain development have found that significant changes occurring during adolescence such as reduction in the volume of cortical gray matter and basal ganglia and subfie increases in white matter volume. The aim of this study was to explore the possible correlations between brain structure and general intellectual ability in healthy and schizophrenic adolescents. Methods: Information about the general intellectual function of 40 adolescents with recent onset schizophrenia and an equal number of gender and age matched controls was obtained using the WISC-flI and WAIS-R. Structural MRI data were also obtained from all subjects. Full scale IQ index was used in a correlational analysis of the MRI data using SPM. Patients and controls were analysed separately. Results: There was a statistically significant group difference in mean full scale IQ, which was 81.88 (sd 19.38) for patients and 105.84 (sd 15.17) for controls. Within the control group, there was a positive correlation between full scale IQ score and the cerebellum, thalamus (more extensive on the left) anterior and posterior cingulate and a negative correlation with the caudate and putamen bilaterally. Further negative correlations were observed predominantly with frontal lobe white matter bilaterally. There were no significant correlations between IQ and brain structural data in the patient group. Conclusions: Our results suggest that brain maturational changes occurring in adolescence are closely correlated with general intellectual ability and that this pattern is disrupted by disease processes associated with the development of schizophrenia.
PSYCHOSIS IS ASSOCIATED WITH CHANGES IN MYELINATED WHITE MATTER D. L. Garver,* J. H o l c o m b , J. D. C h r i s t e n s e n
Mental Health Service, Louisville Veterans Affairs Medical Center, Louisville, KY, USA Previous reports have described accelerated toss o1" cerebral white matter volume in schizoprhenics(1). Others have reported changes of ventricle volumes in schizophrenics, with greatest increases following remission of psychotic symptoms(2). Twelve recently admitted neuroleptic-free DSM-IV schizophrenics and ten controls were assessed for change in cerebral white volumes during a 4 week period during which patients received antipsychotic medication. Eight of
13. Neuroimaging, Structural 10 patients showed reduction of psychotic symptoms (SAPS decrease of 25.5+10.5[SD]) during treatment. Psychoses worsened in two patients (increase in SAPS of 23.5+3.5). In responding patients, serial volumetric studies ot"cerebral white matter during the four week period showed a decrease of white matter volume (t=4.10; p=0.003). Patients whose psychosis further worsened showed an increase in white matter volume during the same period (t=8.30; p=0.076). In patients, change of white matter volumes during the four week period was positively correlated with changes in SAPS scores (rp=0.70; p<0.012). In ten controls assessed at similar intervals, no change in white matter volumes occurred (t=0.34; p=0.75). Swelling of myelin-containing oligodendrocytes, interference with the speed of neurotransmission through myelinated axons, and dyssynchrony of information processing by subcortical and cortical networks may be associated with psychosis exacerbation. Partial remission may be associated with reduction of a toxic process which interferes with myelination, and with such information processing. The nature of the toxic process is under further investigation. 1. Bartzokis G. (2002) Schizophrenia: Breakdown in the well regulated lifelong process of brain development and maturation. Neuropsychopharmacology (in press) 2. Garver DL, Nair TR, Christensen JD, ttolcomb JA, Kingsburg SJ (2000). Brain and ventricle instability during psychotic episodes of the schizoprhenias. Schizophrenia Research 44:11-23.
VENTRICULAR SHAPE OF MONOZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA REFLECTS VULNERABILITY G. Gerig,* M. Styner, D. Jones, D. Weinberger, J. L i e b e r m a n
Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Enlarged ventricular size and/or asymmetry have been found markers for psychiatric illness, including schizophrenia. We studied ventricular size and shape in volumetric MRI (N=58) of dizygotic normal twin pairs (DZ, N=2* 10), monozygotic normal twin pairs (MZ, N=2* 10), and monozygotic twin pairs discordant for schizophrenia (DS, N=2"9). A fourth group of unrelated matched pairs (NR, N=2"10) was selected from the two normal groups. Left and right ventricles were segmented from high resolution T1 SPGR MRI using automatic classification and 3D connectivity analysis. Surfaces of segmented lateral ventricles were parameterized, represented by sets of corresponding points (point distribution model PDM), and spatially aligned using Procrustes fit. Pairwise global shape differences were measured as unsigned distances between corresponding surface points integrated across the objects. The statistical analysis included two tests with corrections for age and gender. First, we investigated pairwise shape similarity between ventricles of co-twins. The group difference of co-twin similarity between normal MZ and discordant DS was not significant, whereas both groups were significantly different from NR (MZ-NR: p<0.001 and DS-NR: p<0.008). Second, we examined the shape difference of the affected and unaffected DS subgroups in comparison to the normal control group. The average shape of normal co-twins not included in group tests served as a template for comparisons. Both the affected and unaffected DS groups showed significant shape difference from the normal population (CNTL vs. DS affected: p<0.049, CNTL vs. DS unaffected: p<0.007). The first test reveals pairwise co-twin shape similarity which seems equally large for healthy MZ and for DS, reflecting morphologic similarity due to heritability. The second test demonstrates ventricular shape alterations fi'om controls not only in the
International Congress on Schizophrenia Research 2003
i3. Neuroimaging, Structural
195
affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape change might reflect vulnerability for schizophrenia and hence be a marker for a neurodevelopmental aspect of the illness. Both statistical tests applied to volumes did not show any differences between MZ and DS groups, suggesting that shape analysis is more sensitive to subtle structural changes than volumetry.
EMOTIONAL MEMORY, THE AMYGDALA AND THE BASIS OF MOOD CONGRUENT DELUSIONS
conducted using high-resolution whole brain T1 weighted images. We also evaluated the degree of perinatal and birth complications (PBC) using maternal reports and hospital records wherever available. The high-risk offspring had a significantly higher frequency of perinatal and birth complications compared to controls (p=.01). When all subjects were included, there were significant negative correlations between PBC and gray matter volume as well as IQ. There were also significant positive correlations between PBC and cognitive deficits (as measured by Wisconsin Card Sorting Test errors) as well as neurological soft signs. When only the high-risk subjects were included, the correlations between PBC and both IQ and neurological soft signs remained significant. These findings suggest that perinatal and birth complications may be nonspeciflc etiopathogenic risk factors for psychopathology among young relatives at risk for schizophrenia.
A. Gibbs,* R Shaw, K. M o r g a n , R D a z z a n , R. Mun'ay, A. D a v i d
Division of Psychological Medicine, Institute of Psychiatry, King, London, United Kingdom Recent studies suggest that amygdala volumes in subjects with bipolar affective disorder are enlarged compared to schizophrenics and normal controls. The amygdala is known to be important in evaluating emotional stimuli and enhancing memory for emotionally arousing events. This study tests a model of mood congruent (MC) delusion formation that suggests that affective disturbance results in a state of emotional arousal in which excessive/abnormal emotional enhancement of stimuli (mediated by the amygdala) leads to biased recall and hence delusional beliefs. The hypothesis under investigation is that MC and mood incongruent (MI) groups will differ in their performance on emotional memory tasks and in amygdala volumes. Emotional memory of MC and MI groups was compared using the Cahill test (n=16 in each group). A separate group of subjects with delusions was recruited from a database of structural MRI scans of subjects with first onset psychosis. Volumetric analysis of the amygdala was carried out in this group and compared between MC and MI groups (n=15 in each group). Preliminary results support the hypothesis. These findings suggest that further investigation is warranted. It has been established from studies in normal populations that the effects of emotional arousal on memory can be attenuated by beta blockade. If emotional memory is shown to be important in the genesis and maintenance of mood congruent delusions this may represent a possible therapeutic intervention.
OBSTETRIC COMPLICATIONS CORRELATE WITH NEUROBEHAVIORAL AND BRAIN STRUCTURAL ALTERATIONS IN YOUNG RELATIVES AT RISK FOR SCHIZOPHRENIA A. R. Gilbert,* D. M. M o n t r o s e , M. S. K e s h a v a n
Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA There is growing evidence that complications of pregnancy and birth are risk factors for schizophrenia. Studies of young relatives at high risk for schizophrenia may further implicate perinatal and obstetric complications in the premorbid pathogenesis of the illness. Using Magnetic Resonance hnaging (MRI), we measured total brain and total gray matter volumes in child and adolescent high-risk relatives of schizophrenia patients (n=36), compared to healthy comparison subjects (n=25). Morphometric comparisons of brain volumes were
WHITE MATTER DEVELOPMENT IN NEWBORNS ASSESSED WITH DIFFUSION TENSOR IMAGING J. H. Gilmore,* G. Zhai, W. Lin, K. Wilber, G. Gerig
Psychiatry, University of North Carolina, Chapel Hill, NC, USA There is evidence that adults with schizophrenia have abnormalities of"white matter (WM). It is unclear when these abnormalities arise. While the neurodevelopmental hypothesis suggests that abnormalities of fetal and neonatal brain development contribute to risk for schizophrenia, most of the evidence has been circumstantial. There have been few attempts to directly study very early brain development in children and relate it to risk for schizophrenia. To determine the feasibility of studying neonatal WM development, we performed diffusion tensor imaging (DTI) in unsedated newborns. 20 normal newborns were studied unsedated in a Siemens 3T head-only scanner. 3 imaging sequences were performed: MP-RAGE, T2 weighted FSE, and an EPI single shot diffusion tensor sequence. Total scan time was approximately 15 minutes; most of the children slept during the scan. Apparent diffusion coefficient (ADC) and fractional diffusion anisotropy (FA) were determined using a region of interest approach in the internal capsule, the corpus collosum, gray matter, and in peripheral cortical WM. We obtained high quality scans without motion artifact in 13 children; results in neonates were compared to 8 normal adults. The neonates exhibited significantly higher ADC compared to adults in central W M (177+15.4 vs 77.9+12.8; p < 0.0001). In adults there was no difference in ADC between central and cortical white matter, while in newborns, a significantly higher ADC was observed in cortical WM vs central WM (15t_+21.8 vs 128.8_+16.1; p < 0.0001). FA in central W M was significantly lower in neonates compared to adults (0.47+_0.01 vs 0.74_+0.05; p < 0.0001); in neonates FA was lower in cortical WM compared to central WM (0.21_+0.06 vs 0.47_+0.01; p < 0.0001). This study indicates that it is feasible to study white matter development in unsedated newborns using DTI. Higher ADC and lower FA in neonates are consistent with higher water content and fewer membranes or physiologic restrictions to movement and less extensive myelination. The difference in central and cortical WM ADC and FA observed in neonates likely reflects differences in white matter maturation that is ongoing in the postnatal period. We have been successful with initial attempts to apply diffusion-tensor fiber tracking to these scans and are using this methodology to study developing white matter tracts. We are currently studying white matter development in newborns at high risk for schizophrenia.
International Congress on Schizophrenia Research 2003
BRAIN STRUCTURAL CORRELATES OF IQ IN HEALTHY AND SCHIZOPHRENIC ADOLESCENTS S. Frangou,* M. Hadjulis Section of Neurobiology of Psychosis, Institute of Psychiatry, London, United Kingdom Background: Previous MRI studies of brain development have found that significant changes occurring during adolescence such as reduction in the volume of cortical gray matter and basal ganglia and subfie increases in white matter volume. The aim of this study was to explore the possible correlations between brain structure and general intellectual ability in healthy and schizophrenic adolescents. Methods: Information about the general intellectual function of 40 adolescents with recent onset schizophrenia and an equal number of gender and age matched controls was obtained using the WISC-flI and WAIS-R. Structural MRI data were also obtained from all subjects. Full scale IQ index was used in a correlational analysis of the MRI data using SPM. Patients and controls were analysed separately. Results: There was a statistically significant group difference in mean full scale IQ, which was 81.88 (sd 19.38) for patients and 105.84 (sd 15.17) for controls. Within the control group, there was a positive correlation between full scale IQ score and the cerebellum, thalamus (more extensive on the left) anterior and posterior cingulate and a negative correlation with the caudate and putamen bilaterally. Further negative correlations were observed predominantly with frontal lobe white matter bilaterally. There were no significant correlations between IQ and brain structural data in the patient group. Conclusions: Our results suggest that brain maturational changes occurring in adolescence are closely correlated with general intellectual ability and that this pattern is disrupted by disease processes associated with the development of schizophrenia.
PSYCHOSIS IS ASSOCIATED WITH CHANGES IN MYELINATED WHITE MATTER D. L. Garver,* J. H o l c o m b , J. D. C h r i s t e n s e n
Mental Health Service, Louisville Veterans Affairs Medical Center, Louisville, KY, USA Previous reports have described accelerated toss o1" cerebral white matter volume in schizoprhenics(1). Others have reported changes of ventricle volumes in schizophrenics, with greatest increases following remission of psychotic symptoms(2). Twelve recently admitted neuroleptic-free DSM-IV schizophrenics and ten controls were assessed for change in cerebral white volumes during a 4 week period during which patients received antipsychotic medication. Eight of
13. Neuroimaging, Structural 10 patients showed reduction of psychotic symptoms (SAPS decrease of 25.5+10.5[SD]) during treatment. Psychoses worsened in two patients (increase in SAPS of 23.5+3.5). In responding patients, serial volumetric studies ot"cerebral white matter during the four week period showed a decrease of white matter volume (t=4.10; p=0.003). Patients whose psychosis further worsened showed an increase in white matter volume during the same period (t=8.30; p=0.076). In patients, change of white matter volumes during the four week period was positively correlated with changes in SAPS scores (rp=0.70; p<0.012). In ten controls assessed at similar intervals, no change in white matter volumes occurred (t=0.34; p=0.75). Swelling of myelin-containing oligodendrocytes, interference with the speed of neurotransmission through myelinated axons, and dyssynchrony of information processing by subcortical and cortical networks may be associated with psychosis exacerbation. Partial remission may be associated with reduction of a toxic process which interferes with myelination, and with such information processing. The nature of the toxic process is under further investigation. 1. Bartzokis G. (2002) Schizophrenia: Breakdown in the well regulated lifelong process of brain development and maturation. Neuropsychopharmacology (in press) 2. Garver DL, Nair TR, Christensen JD, ttolcomb JA, Kingsburg SJ (2000). Brain and ventricle instability during psychotic episodes of the schizoprhenias. Schizophrenia Research 44:11-23.
VENTRICULAR SHAPE OF MONOZYGOTIC TWINS DISCORDANT FOR SCHIZOPHRENIA REFLECTS VULNERABILITY G. Gerig,* M. Styner, D. Jones, D. Weinberger, J. L i e b e r m a n
Psychiatry, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA Enlarged ventricular size and/or asymmetry have been found markers for psychiatric illness, including schizophrenia. We studied ventricular size and shape in volumetric MRI (N=58) of dizygotic normal twin pairs (DZ, N=2* 10), monozygotic normal twin pairs (MZ, N=2* 10), and monozygotic twin pairs discordant for schizophrenia (DS, N=2"9). A fourth group of unrelated matched pairs (NR, N=2"10) was selected from the two normal groups. Left and right ventricles were segmented from high resolution T1 SPGR MRI using automatic classification and 3D connectivity analysis. Surfaces of segmented lateral ventricles were parameterized, represented by sets of corresponding points (point distribution model PDM), and spatially aligned using Procrustes fit. Pairwise global shape differences were measured as unsigned distances between corresponding surface points integrated across the objects. The statistical analysis included two tests with corrections for age and gender. First, we investigated pairwise shape similarity between ventricles of co-twins. The group difference of co-twin similarity between normal MZ and discordant DS was not significant, whereas both groups were significantly different from NR (MZ-NR: p<0.001 and DS-NR: p<0.008). Second, we examined the shape difference of the affected and unaffected DS subgroups in comparison to the normal control group. The average shape of normal co-twins not included in group tests served as a template for comparisons. Both the affected and unaffected DS groups showed significant shape difference from the normal population (CNTL vs. DS affected: p<0.049, CNTL vs. DS unaffected: p<0.007). The first test reveals pairwise co-twin shape similarity which seems equally large for healthy MZ and for DS, reflecting morphologic similarity due to heritability. The second test demonstrates ventricular shape alterations fi'om controls not only in the
International Congress on Schizophrenia Research 2003
i3. Neuroimaging, Structural
195
affected but-also in the unaffected DS group. This leads to the conclusion that ventricular shape change might reflect vulnerability for schizophrenia and hence be a marker for a neurodevelopmental aspect of the illness. Both statistical tests applied to volumes did not show any differences between MZ and DS groups, suggesting that shape analysis is more sensitive to subtle structural changes than volumetry.
EMOTIONAL MEMORY, THE AMYGDALA AND THE BASIS OF MOOD CONGRUENT DELUSIONS
conducted using high-resolution whole brain T1 weighted images. We also evaluated the degree of perinatal and birth complications (PBC) using maternal reports and hospital records wherever available. The high-risk offspring had a significantly higher frequency of perinatal and birth complications compared to controls (p=.01). When all subjects were included, there were significant negative correlations between PBC and gray matter volume as well as IQ. There were also significant positive correlations between PBC and cognitive deficits (as measured by Wisconsin Card Sorting Test errors) as well as neurological soft signs. When only the high-risk subjects were included, the correlations between PBC and both IQ and neurological soft signs remained significant. These findings suggest that perinatal and birth complications may be nonspeciflc etiopathogenic risk factors for psychopathology among young relatives at risk for schizophrenia.
A. Gibbs,* R Shaw, K. M o r g a n , R D a z z a n , R. Mun'ay, A. D a v i d
Division of Psychological Medicine, Institute of Psychiatry, King, London, United Kingdom Recent studies suggest that amygdala volumes in subjects with bipolar affective disorder are enlarged compared to schizophrenics and normal controls. The amygdala is known to be important in evaluating emotional stimuli and enhancing memory for emotionally arousing events. This study tests a model of mood congruent (MC) delusion formation that suggests that affective disturbance results in a state of emotional arousal in which excessive/abnormal emotional enhancement of stimuli (mediated by the amygdala) leads to biased recall and hence delusional beliefs. The hypothesis under investigation is that MC and mood incongruent (MI) groups will differ in their performance on emotional memory tasks and in amygdala volumes. Emotional memory of MC and MI groups was compared using the Cahill test (n=16 in each group). A separate group of subjects with delusions was recruited from a database of structural MRI scans of subjects with first onset psychosis. Volumetric analysis of the amygdala was carried out in this group and compared between MC and MI groups (n=15 in each group). Preliminary results support the hypothesis. These findings suggest that further investigation is warranted. It has been established from studies in normal populations that the effects of emotional arousal on memory can be attenuated by beta blockade. If emotional memory is shown to be important in the genesis and maintenance of mood congruent delusions this may represent a possible therapeutic intervention.
OBSTETRIC COMPLICATIONS CORRELATE WITH NEUROBEHAVIORAL AND BRAIN STRUCTURAL ALTERATIONS IN YOUNG RELATIVES AT RISK FOR SCHIZOPHRENIA A. R. Gilbert,* D. M. M o n t r o s e , M. S. K e s h a v a n
Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA There is growing evidence that complications of pregnancy and birth are risk factors for schizophrenia. Studies of young relatives at high risk for schizophrenia may further implicate perinatal and obstetric complications in the premorbid pathogenesis of the illness. Using Magnetic Resonance hnaging (MRI), we measured total brain and total gray matter volumes in child and adolescent high-risk relatives of schizophrenia patients (n=36), compared to healthy comparison subjects (n=25). Morphometric comparisons of brain volumes were
WHITE MATTER DEVELOPMENT IN NEWBORNS ASSESSED WITH DIFFUSION TENSOR IMAGING J. H. Gilmore,* G. Zhai, W. Lin, K. Wilber, G. Gerig
Psychiatry, University of North Carolina, Chapel Hill, NC, USA There is evidence that adults with schizophrenia have abnormalities of"white matter (WM). It is unclear when these abnormalities arise. While the neurodevelopmental hypothesis suggests that abnormalities of fetal and neonatal brain development contribute to risk for schizophrenia, most of the evidence has been circumstantial. There have been few attempts to directly study very early brain development in children and relate it to risk for schizophrenia. To determine the feasibility of studying neonatal WM development, we performed diffusion tensor imaging (DTI) in unsedated newborns. 20 normal newborns were studied unsedated in a Siemens 3T head-only scanner. 3 imaging sequences were performed: MP-RAGE, T2 weighted FSE, and an EPI single shot diffusion tensor sequence. Total scan time was approximately 15 minutes; most of the children slept during the scan. Apparent diffusion coefficient (ADC) and fractional diffusion anisotropy (FA) were determined using a region of interest approach in the internal capsule, the corpus collosum, gray matter, and in peripheral cortical WM. We obtained high quality scans without motion artifact in 13 children; results in neonates were compared to 8 normal adults. The neonates exhibited significantly higher ADC compared to adults in central W M (177+15.4 vs 77.9+12.8; p < 0.0001). In adults there was no difference in ADC between central and cortical white matter, while in newborns, a significantly higher ADC was observed in cortical WM vs central WM (15t_+21.8 vs 128.8_+16.1; p < 0.0001). FA in central W M was significantly lower in neonates compared to adults (0.47+_0.01 vs 0.74_+0.05; p < 0.0001); in neonates FA was lower in cortical WM compared to central WM (0.21_+0.06 vs 0.47_+0.01; p < 0.0001). This study indicates that it is feasible to study white matter development in unsedated newborns using DTI. Higher ADC and lower FA in neonates are consistent with higher water content and fewer membranes or physiologic restrictions to movement and less extensive myelination. The difference in central and cortical WM ADC and FA observed in neonates likely reflects differences in white matter maturation that is ongoing in the postnatal period. We have been successful with initial attempts to apply diffusion-tensor fiber tracking to these scans and are using this methodology to study developing white matter tracts. We are currently studying white matter development in newborns at high risk for schizophrenia.
International Congress on Schizophrenia Research 2003