RAMI Psychiatry Registrars' Prize 2008

Thurs, 13th March 2008

Dr Frederick Sundram, Lecturer in Psychiatry,

Dept of Psychiatry, 1st Floor Smurfit Building,

RCSI Education & Research Centre,

Beaumont Hospital, Dublin 9

Email: fsundram@rcsi.ie

Telephone: 01-8093740

White matter microstructure in children with Velocardiofacial Syndrome: A Diffusion Tensor Imaging and Voxel Based Morphometry study.

Sundram F1, Murphy DG2, Murphy KC1.

1Dept of Psychiatry, RCSI Education & Research Centre, Beaumont Hospital, Dublin 9.2Dept of Psychological Medicine, Institute of Psychiatry, De Crespigny Park, London SE5 8AF, UK.

ContentsContents IntroductionIntroductionAimsAimsMethodsMethodsResultsResultsDiscussionDiscussionConclusionConclusion

IntroductionIntroduction To understand the developmental basis of To understand the developmental basis of

schizophreniaschizophrenia

Promising approach – Promising approach – abnormalities in young individuals who are likely to be abnormalities in young individuals who are likely to be at significantly elevated risk for the illnessat significantly elevated risk for the illness

permits discovery of possible neurobiological and permits discovery of possible neurobiological and neurodevelopmental mechanisms of risk for the illnessneurodevelopmental mechanisms of risk for the illness[1][1]

[1] Gottesman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic intentions. Am J Psychiatry 160, 636– 645.

Examples of high-risk groups:Examples of high-risk groups:Both parents with schizophreniaBoth parents with schizophreniaMonozygotic twinsMonozygotic twinsVelocardiofacial SyndromeVelocardiofacial SyndromeObstetric complicationsObstetric complicationsEtc.Etc.

Velocardiofacial Syndrome (VCFS) is the most common Velocardiofacial Syndrome (VCFS) is the most common genetic deletion syndromegenetic deletion syndrome[2][2] and is associated with and is associated with deletions in the chromosome 22q11 regiondeletions in the chromosome 22q11 region[3][3]. .

COMT and TBX1 genesCOMT and TBX1 genes

[2] Gothelf, D. and P. J. Lombroso (2001). "Genetics of childhood disorders: XXV. Velocardiofacial syndrome." J Am Acad Child Adolesc Psychiatry 40(4): 489-91.

[3] Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O'Leary LA, Wong LY, Elixson EM, Mahle WT, Campbell RM (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101-7

People with VCFS have much higher rates of schizophrenia spectrum disorders[4][4]

Up to 25-30%

[4] Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psych 1999; 56: 940–45.

Schizotypy characterized by peculiarities of Schizotypy characterized by peculiarities of thinking, odd beliefs, and eccentricities of thinking, odd beliefs, and eccentricities of appearance, behavior, interpersonal style and appearance, behavior, interpersonal style and thought thought

confers a much higher risk for the future confers a much higher risk for the future development of psychosisdevelopment of psychosis[5][5]..

[5] Arnold, P. D., J. Siegel-Bartelt, et al. (2001). "Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders." Am J Med Genet 105(4): 354-62.

VCFS provides a unique neurobiological template for understanding the evolution of psychosis[6].[6].

[6] Murphy, K. C. and M. J. Owen (2001). "Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia." Br J Psychiatry 179: 397-402.

People with VCFS also have significant abnormalities in white matter anatomy

White matter volume[7][7]

White matter integrity/connectivity[8][8] [9][9]

[7] Kates, W. R., C. P. Burnette, et al. (2001). "Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis." Biol Psychiatry 49(8): 677-84.

[8] Barnea-Goraly, N., V. Menon, B. Krasnow, A. Ko, A. Reiss and S. Eliez (2003). "Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study." Am J Psychiatry 160(10): 1863-9.

[9] Simon, T. J., L. Ding, J. P. Bish, D. M. McDonald-McGinn, E. H. Zackai and J. Gee (2005). "Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study." Neuroimage 25(1): 169-80.

However……..

only 2 previous studies in VCFS of white matter microstructural integrity as measured using Diffusion Tensor Imaging (DTI)

Ours is 3rd in the world

Also…..

Relationship between white matter anatomy and schizotypy in VCFS[10][10] never been specifically investigated in children before.

[10] Gruzelier, J. H. (2003). "Theory, methods and new directions in the psychophysiology of the schizophrenic process and schizotypy." Int J Psychophysiol 48(2): 221-45.

AimsAimsWe planned to assess within VCFS children and controls:

differences in whole brain white matter microstructure using DTI through DTI group mapping analysis

differences in whole brain white matter volume through structural MRI imaging using Voxel based Morphometry analysis

the relationship of the anatomy of those brain regions which significantly differed in the analyses above to schizotypy scores

MethodsMethods

Ethics ApprovalEthics ApprovalProvided through the Institute of Psychiatry Provided through the Institute of Psychiatry

Research Ethics CommitteeResearch Ethics Committee

SubjectsSubjectsRecruited through 22qDS support groupRecruited through 22qDS support groupBehavioural Genetics Clinic, Maudsley Behavioural Genetics Clinic, Maudsley

HospitalHospital

DNA Extracted from blood samples collected on all subjects Fluorescence in situ hybridisation (FISH) (Oncor Inc,

Gaithersburg, MD, USA) confirmed 3Mb 22q11 deletion in VCFS cases

Chromosome 22q11 deletion excluded in all controls.

Exclusion criteria VCFS clinical phenotype but without the large 3Mb 22q11.2 deletion, a clinically detectable medical disorder known to affect brain structure (e.g. epilepsy), a history of head injury or contraindications to MRI scanning

VCFS cases 11 children (5 male and 6 female) with clinical features of

VCFS, established genetic 22q11 deletion (mean age: 12years, SD±2.2, range 9-17years;

mean FSIQ: 66, SD±8.0, range 56-84).

Controls 12 healthy controls (8 male and 4 female) with a non-deleted

22q11 region, of whom 7 were sibling and 5 non-sibling (mean age: 13years, SD±2.5, range 9-17years;

mean FSIQ: 116, SD±15.9, range 90–141). None had genetic disorder and all were free of clinical

disorders affecting brain anatomy or function.

DTI and structural MRI data were acquired atthe same scanning session

1.5T MRI scanner Measures of interest were the fractional anisotropy

(FA) and volume of white matter

As brain changes are likely to extend over a number of contiguous voxels, non-parametric test statistics incorporating spatial information such as 3D cluster mass (the sum of suprathreshold voxel statistics) were used for both DTI group mapping and Voxel Based Morphometry

Locally developed software at the Institute of Psychiatry - XBAM (http://www.brainmap.co.uk/) measured between group differences at each intracerebral voxel in standard space using an analysis of covariance model (ANCOVA)

Finally, we carried out a post hoc analysis to determine if differences in white matter FA or volume were associated with schizotypy (measured using a previously published scale designed for young people with VCFS[11][11]) within subjects with VCFS.

[11] Campbell, L. E., E. Daly, F. Toal, A. Stevens, R. Azuma, M. Catani, et al. (2006). "Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study." Brain 129(Pt 5): 1218-28.

ResultsResultsDTI group mapping:DTI group mapping:

FA reductionFA reduction FA in VCFS subjects was significantly reduced in the FA in VCFS subjects was significantly reduced in the

frontal, parietal and temporal lobes of the left frontal, parietal and temporal lobes of the left hemisphere hemisphere

Changes localised to the: Changes localised to the: ascending projections from the thalamus to the post-central ascending projections from the thalamus to the post-central

gyrus of the parietal lobe via the posterior limb of the internal gyrus of the parietal lobe via the posterior limb of the internal capsule and posterior thalamic radiation; capsule and posterior thalamic radiation;

descending projections from the motor cortex of the frontal lobedescending projections from the motor cortex of the frontal lobevia the superior region of the corona radiata; via the superior region of the corona radiata;

tapetum lateral to the posterior horn of the lateral ventricle; tapetum lateral to the posterior horn of the lateral ventricle; fronto-parietal course of the arcuate fasciculus (AF)fronto-parietal course of the arcuate fasciculus (AF)

DTI group mapping:DTI group mapping:

FA increasesFA increases However, people with VCFS also had a However, people with VCFS also had a

significantly increased FA significantly increased FA exclusively in the left hemisphere againexclusively in the left hemisphere again in regions that were anatomically more anterior in regions that were anatomically more anterior

and inferior to the FA decreases described and inferior to the FA decreases described previouslypreviously

especially in the genu/anterior limb of the internal capsule especially in the genu/anterior limb of the internal capsule anterior and superior portions of the corona radiata and anterior and superior portions of the corona radiata and terminal corpus callosumterminal corpus callosum

Fig. 1: Control group vs. VCFS subject group FA. Fig. 1: Control group vs. VCFS subject group FA. Ascending 2mm transverse sections; Ascending 2mm transverse sections; (Radiological convention: L=R, R=L). (Radiological convention: L=R, R=L). Orange: FA in controls significantly > VCFS subjects. Orange: FA in controls significantly > VCFS subjects. Blue: FA in VCFS subjects significantly > controls. Blue: FA in VCFS subjects significantly > controls.

Voxel Based MorphometryVoxel Based Morphometry Mean global white matter volume did not Mean global white matter volume did not

differ significantly between VCFS children differ significantly between VCFS children and controls (mean=383ml, SD±35.0ml vs. and controls (mean=383ml, SD±35.0ml vs. mean=418ml, SD±62.2ml; p=0.114). mean=418ml, SD±62.2ml; p=0.114).

However, significant differences in regional However, significant differences in regional distribution of white matter distribution of white matter

People with VCFS had a significant reduction bilaterally People with VCFS had a significant reduction bilaterally in the: in the:

middle cerebellar peduncle of the cerebellum and middle cerebellar peduncle of the cerebellum and brainstem; brainstem;

optic radiation and lingual, middle and inferior optic radiation and lingual, middle and inferior occipital gyri; occipital gyri;

cuneus and precuneus; cuneus and precuneus; posterior thalamic radiation; posterior thalamic radiation; body, genu and tapetum of the corpus callosum; body, genu and tapetum of the corpus callosum; hippocampus and hippocampus and paracentral lobuleparacentral lobule

Also….. Also….. they had a significantly greater proportionthey had a significantly greater proportion

of white matter bilaterally in the: of white matter bilaterally in the: anterior limb of the internal anterior limb of the internal

capsulecapsule basal gangliabasal ganglia cingulum and cingulum and body and splenium of the corpus body and splenium of the corpus

callosumcallosum

White Matter Volume in VCFS subjects vs. Controls. White Matter Volume in VCFS subjects vs. Controls. (Radiological convention L=R, R=L).(Radiological convention L=R, R=L).Red/Yellow: Volumetric excesses in VCFS.Red/Yellow: Volumetric excesses in VCFS.Blue/Purple: Volumetric deficits in VCFS.Blue/Purple: Volumetric deficits in VCFS.

Schizotypy correlationsSchizotypy correlations Within VCFS Within VCFS Analysis of schizotypy correlation with Analysis of schizotypy correlation with

white matter FA and white matter volumewhite matter FA and white matter volume Significant positive correlation (r=0.759, n=7, Significant positive correlation (r=0.759, n=7,

p=0.048) between increased white matter FA in p=0.048) between increased white matter FA in the left internal capsulethe left internal capsule

DiscussionDiscussion FA reduction - regions that may have important effects on

the connectivity of a number of neural systems

E.g.tapetum, corona radiata and AF which respectively connect the 1) inferior temporal lobes; 2) corticospinal, corticobulbar and corticopontine tracts and 3) frontal, parietal and temporal lobes within each hemisphere

may underpin some of the cognitive impairments classically reported in the disorder e.g. visuo-spatial, attentional and language deficits

Another factor contributing to these Another factor contributing to these cognitive deficits in VCFS - simultaneous cognitive deficits in VCFS - simultaneous decrease in regional white matter volume at decrease in regional white matter volume at non-frontal sites non-frontal sites

e.g. the cerebellum, brainstem, occipital e.g. the cerebellum, brainstem, occipital lobes and corpus callosum (body, genu and lobes and corpus callosum (body, genu and tapetum) suggesting dysmaturation of the tapetum) suggesting dysmaturation of the posterior structures of the brain.posterior structures of the brain.

Schizotypy correlation Schizotypy correlation internal capsule internal capsule large collection of white matter composed of axons thatlarge collection of white matter composed of axons that

project chiefly from the thalamus to the cerebral cortex and project chiefly from the thalamus to the cerebral cortex and vice versavice versa

anterior limb especially involved in connectivity with anterior limb especially involved in connectivity with the frontal lobe through fronto-thalamic, thalamo-the frontal lobe through fronto-thalamic, thalamo-frontal and cortico-pontine pathwaysfrontal and cortico-pontine pathways

Schizophrenia studies Schizophrenia studies reduced FA in these circuits reduced FA in these circuits[12][12] schizotypy schizotypy like schizophrenia, may arise from abnormalities like schizophrenia, may arise from abnormalities

in fronto-temporal connectivityin fronto-temporal connectivity

[12] Shergill, S. S., R. A. Kanaan, X. A. Chitnis, O. O'Daly, D. K. Jones, S. Frangou, et al. (2007). "A diffusion tensor imaging study of fasciculi in schizophrenia." Am J Psychiatry 164(3): 467-73.

ConclusionConclusion As neuroimaging techniques have matured –

shift to examining abnormalities in the ‘connectivity’ of neural systems instead of traditional assessment of ‘lesion of a region’

Disconnectivity between critical regions in VCFS notonly results in cognitive impairment but also apredisposition to psychosis which is mediated through changes in fronto-temporal circuitry

These abnormalities may also be relevant to psychosis in the wider population

References[1] Ottoman, I.I., Gould, T.D., 2003. The endophenotype concept in psychiatry: etymology and strategic

intentions. Am J Psychiatry 160, 636– 645.[2] Gothelf, D. and P. J. Lombroso (2001). "Genetics of childhood disorders: XXV. Velocardiofacial

syndrome." J Am Acad Child Adolesc Psychiatry 40(4): 489-91.[3] Botto LD, May K, Fernhoff PM, Correa A, Coleman K, Rasmussen SA, Merritt RK, O'Leary LA, Wong

LY, Elixson EM, Mahle WT, Campbell RM (2003) A population-based study of the 22q11.2 deletion: phenotype, incidence, and contribution to major birth defects in the population. Pediatrics 112:101-7

[4] Murphy KC, Jones LA, Owen MJ. High rates of schizophrenia in adults with velo-cardio-facial syndrome. Arch Gen Psych 1999; 56: 940–45.

[5] Arnold, P. D., J. Siegel-Bartelt, et al. (2001). "Velo-cardio-facial syndrome: Implications of microdeletion 22q11 for schizophrenia and mood disorders." Am J Med Genet 105(4): 354-62.

[6] Murphy, K. C. and M. J. Owen (2001). "Velo-cardio-facial syndrome: a model for understanding the genetics and pathogenesis of schizophrenia." Br J Psychiatry 179: 397-402.

[7] Kates, W. R., C. P. Burnette, et al. (2001). "Regional cortical white matter reductions in velocardiofacial syndrome: a volumetric MRI analysis." Biol Psychiatry 49(8): 677-84.

[8] Barnea-Goraly, N., V. Menon, B. Krasnow, A. Ko, A. Reiss and S. Eliez (2003). "Investigation of white matter structure in velocardiofacial syndrome: a diffusion tensor imaging study." Am J Psychiatry 160(10): 1863-9.

[9] Simon, T. J., L. Ding, J. P. Bish, D. M. McDonald-McGinn, E. H. Zackai and J. Gee (2005). "Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study." Neuroimage 25(1): 169-80.

[10] Gruzelier, J. H. (2003). "Theory, methods and new directions in the psychophysiology of the schizophrenic process and schizotypy." Int J Psychophysiol 48(2): 221-45.

[11] Campbell, L. E., E. Daly, F. Toal, A. Stevens, R. Azuma, M. Catani, et al. (2006). "Brain and behaviour in children with 22q11.2 deletion syndrome: a volumetric and voxel-based morphometry MRI study." Brain 129(Pt 5): 1218-28.

[12] Shergill, S. S., R. A. Kanaan, X. A. Chitnis, O. O'Daly, D. K. Jones, S. Frangou, et al. (2007). "A diffusion tensor imaging study of fasciculi in schizophrenia." Am J Psychiatry 164(3): 467-73.