Magnetic Resonance Imaging of Severely Disturbed ChildrenA Preliminary Study ROBERT L. HE NDREN , D.O. , JA.!'-.'ET E. HODDE-VARG AS , M .S . , LUIS A. VARGAS , PH.D ., WILLIAM W. ORRISON , M .D ., AND LANCE DELL , M.D. Abstract. This study investigates the relationship between brain pathology and psychiatric disturbance in 37 p sychiatric inpatients between 5 and 14 years of age referred for magnetic resonance imaging (MRI ). Of 37 images, 13 were' categorized as abnormal by neuroradiologists who were blind to the diagnoses of subjects. Three of six children with schizophrenia-related diagnoses had abnormal scans. In contrast, only one of 15 children with a primary disruptive behavior disorder diagnosis had an abnormal magnetic resonance image . A greater proportion of children with schizophrenia spectrum diagnoses had greater left than right frontal horns of the lateral ventricles than children with other diagnoses . I. Am. Acad. Child Adolesc. Psychiatry, 1991, 30, 3:466-470. Key Words: MRI, schizophrenia spectrum, structural abnormalities. Magnetic resonance -imaging' (M.,,"R..:I) is a well-established method for studying brain anatomy because of its high contrast resolution and absence of known biological hazards at currently used field strengths (Lee et al., 1986; lAMA 1988). MRI is useful in studying structural brain abnormalities in psychiatric patients (Gar ber et al., 1988). Variations in cerebral structure have been found, for example , in adult patients with schizophrenia (Andreasen et al. , 1986), manic depression (Rangel-Guerra et al., 1983), and Alzheimer's disease (Drayer, 1988 ). While theories proposing the presence of structural abnormalities in adult psychiatric populations have existed for a number of years, there is little information about the frequency of structural abnormalities present in children who exhibit different types of severe psychiatric problems . Recent studies have revealed structural abnormalities in children with schizophrenia (Schultz et al., 1983; Woody et al., 1987), severe developmental delays (Tatum et al.; 1989)', 'autism (Courchesne et al., 1988; Gaffney et al., 1987, 1989); and nonspecific psychiatric disturbances (Reiss et al., 1983). These studies have been limited in scope, have included only a few patients, and have not made comparisons between different psychiatric populations. Still other studies have failed to find structural abnormalities in children with psychiatric disturbances (Prior et al., 1984; Bauman and Kemper, 1985). The safety of the MRI techniques enables a broader investigation of children with psychiatric disorders. Such an investigation could provide data on whether any spe cific child psychiatric disturbances are more likely to be assoAccepted November 7. 1990. From the Division of Child and Adolescent Psych iatry. Department of Psychiatry. University of New Mex ico School of Medicine (Drs. Hendren and Vargas. Ms . Hodde-Vargas} ; University of New Mexico Center for Noninvas ive Diagnosis (Drs. Orrison and Dell). The authors thank Robert Kelln er, M.D .• Ph.D ., E. H . Uhlenhuth , M.D.• Kathryn Gordon . Ph .D .• and Daniel Kerlinsky , M .D.Jor their reviews of the manuscript. Reprint requests to Dr. Hendren , Division of Child and Adolescent Psychiatry. Department of Psychiatry. University of New Mexico School of Medicine. '2400 Tucker . NE. Albuquerque. NM 87131. 0890-8567/91/3003-0466$03 .00 /0© 199 J by the American Academy of Child and Adolescent Psychiatry.
466
ciated w ith structural deficits . In addition, the results could serve as a baseline for follow-up studies. Finally, the find ings could.be.used to.determine the degree to which cerebral pathology apparent in childhood predicts later development of psychiatric disorders. This study represents an initial investigation of the relationship between brain pathology and types of ps ychiatric disturbance in children.
Method Subjects Thirty-seven children (26 boys and 11 girls) who were inpatients at a university children's psychiatric hospital were referred for MRIs. Subjects were hospitalized during a period ranging from 1986 to 1988; their ages ranged from 5 to 14 years. This subject sample includes all children for whom an MRI was ind icated as part of a complete medical and neurological work-up based on the seriousness of their developmental, emotional, cognitive, and behavioral disturbance, and it included approximately one-third of the total number of children hospitalized during this period. DSMIII-R diagnoses were assigned by the treating clinician who worked closely with the children and were blind to the MRI .findings. Diagnoses were reviewed by the research team who were also blind to the :MRI findings for specific ch ildren to establish the primary diagnosis for each child and to assure compliance with criteria. (Children hospitalized before the use of DSM-III-R may have received a primary DSM-III Axis I diagnoses of pervasive developmental disorder (PDD) or schizoid disorder of childhood.)
Procedure All subjects received the Wechsler Intelligence Scale for Children-Revised (WISC-R) and cranial MRIs . Both were performed in conjunction with treatment, and consent was obtained from the parent(s) or legal guardian . The MRI scans were performed on a 1.5 Tesla superconducting magnet. Tj-weighted images were obtained with spin-echo techniques using a repetition time (fR) of 600 ms and an echo time (TE) of 20 ms. Proton den sity and T 2 -weighted images were performed using spin-echo pulse sequences with a TR of 2,000 or 2 ,500 ms and TE of 30 and 80 ms. Images were I.Am.Acad. Child Adolesc , Psychiatry. 30 :3. May 1991
MAGNETIC RESONANCE IMAGING TABLE 1. Characteristics of Subjects with Abnormal MRls Age (Yrs-Mos) Sex
Handedness
14-11
M
Rt
8-7
F
Both
13-7
M
10-6
Schizotypal? WISC-R SCORES Borderlin e? VIQ PIQ FSIQ
Primary Diagnosi s Schizophrenia
No
82
98
Atypic al organi c brain syndrome
No
68
54
Lt
Major depression
No
97
129
M
Rt
Organic personality syndrome
No
92
114
10-6
F
Rt
Post-traumatic stress disorder
No
77
104
12-5
M
Rt
Pervasive development al disorder
No
72
72
13-6
F
Rt
Atypical psychosis
No
81
78
9-1
M
Rt
Pervas ive developmental disorder
No
66
101
12-3
M
Rt
Majo r depress ion
No
94
108
8-0
F
Rt
Pervasive developmental disorder
Yes
50
65
12-4
M
Rt
Conduct disorder
No
113
126
12-3
F
Rt
Pervasive developmental disorder
Yes
78
86
14-11
M
Rt
Schizophrenia
No
81
98
Note: VIQ
=
Verbal IQ; PIQ
= Performance IQ; FSIQ
Top normal size pituitary; decreased signal intensity on It 58 Enlarged fourth ventricle; atrophy inferior cerebellar vermi s; enlarged posterior fossa 112 Asymmetrical lateral ventricle, rt>lt with mass shift 102 Enlarged fourth ventricle; hypoplasia inferior cerebellar vermis ; enlarged cisterna magna 88 Focal cortical encephalomalacia , anterior It temporal lobe 70 Sing le, nonspecific area of abnormal signal intensity, It semi-ovaIe region 88 Abnormal focal area of increased signal intensity in It peri ventricular white matter 81 Diffuse delayed maturation of white matter in basa l gang lia bilaterally 100 Small area of abnormal signal inten sity in area of It anterior basal gangli a or medial temporal lobe 53 Loss of large portion of brain parenchyma, rt temporal lobe 121 Tonsillar posi tion suggests Chiari I malformation 80 Mild to modera te hydrocephalus-probably comm unica ting type 88 Nonspecific focal areas of abnormal white matter
= Full-scale IQ.
obtained in 5 mm slice thicknesses in sagittal, axial, and coronal planes . Neuroradiologists, who were blind to the subjects' diagnoses, categorized the images as either "normal" or " abnormal" for each child (Table I). A variety of indicators classified images as "abnormal," including focal variable signal intensities, encephalomalacia, ventricular enlargement, atrophy, and abnormal white matter signal. In addition, the neuroradiologists, who were blind to the subjects' psychiatric diagnoses, rated scans according to apparent asymmetry between the left and right frontal horns of the lateral ventricles. The coronal slice from the head of the caudate nucleus was used for this rating. Each scan was rated as either displaying: (1) the left ventricle larger than the right, (2) equal size or minimal asymmetry, or (3) the right ventricle larger than the left, using a qualitative scale from 0 (symmetry) to 3 (extreme asymmetry). Two neuroradiologists agreed upon the asymmetry rating for each subject. Asymmetry ratings were available for 34 of the 37 subjects. Analyses of the scans proceeded in a two-step process . First, subjects were grouped according to their primary Axis I diagnoses (Table 2). DSM-llI and DSM-llI-R diagnostic groupings were used as a basis for delineating categories of diagnoses. PDD (N = 8) and schizophrenia -related disorders (N = 6) were distinguished as separate diagnostic I. Am .Aca d. Child Adolesc . Psychiatry , 30:3 , Ma y 199 1
MR I Finding
89
categories , since neither could be combined with other diagnostic groups . The disruptive behavior disorder category (N = 15) consisted of subjects with a primary diagnosis of either conduct disorder (N = 14) or oppositional defiant disorder (N = 1). Subjects diagnosed with either dysthymia or major depression were grouped under a mood disorder category (N = 3). The "other" category (N = 5) grouped together subjects with the remaining diagnoses (identity disorder , post-traumatic stress disorder, atypical brain syndrome, organic personality disorder, separation anxiety disorder), whose frequencies did not merit separate categories. The frequencies of abnormal MRls occurring between diagnostic categories were compared . In addition, WISC-R verbal, performa nce, and full-scale IQs of subjects with abnormal MRls were compared with those with normal MRls . The second step in the analyses was to determine if particular differences in the asymmetry ratings among particular types of disorde rs provided any indication of specific brain regions of pathology . For this purpose, the diagnoses were recategorized into two groups. The first group was comprised of the schizophrenia-related disorders (schizophrenia, schizoid disorder of childhood, schizophreniform disorder, or atypical psychosis) plus schizotypal and borderline personality disorders. In this recategorization, an
467
HENDR EN ET A L. T AB L E 2. Incidence of Normal and Abnormal MRIs and Primary Axis I Diagnosis for 37 Severely Disturbed Children
3. Comparison" of the Lateral Ventricle Asymmetry Ratings of Schizophrenia Spectrum Diagnoses versus All Other Diagnoses
T ABLE
MRI Finding
Asymmetry Rating
Diagnosi s
Norm al
Abnor mal
Diagnosis
Left > Right
Equal or Right > Left
Pervasive developmen tal disorde r Schizophrenia-related disorder' Disruptive behavior disorder Mood disorder Other
4 3
4
Schizophren ia spectrum Other diagnoses
8 4
6 16
14
3 I
I
2
2
3
"Includes schizophrenia, schizop hreniform, schizo id disorder of childhood, and other psychosis .
Axis II diagnosis of schizotypal or borderline personalit y disorder preempted any other diagnosis on Axis I that was not schizophrenia related . The second group was comprised of all other diagnoses combined. This comparison was chosen because research on schizophrenia has produced more specific hypotheses concerning the focus of dysfunction . "Schizophrenia spectrum " disorder, therefore, reflects inclusion of subjects who displayed DSM-III -R schizotypal and borderline features , since research suggests that schizotypal (Baron et aI., 1985; Siever, 1985) and borderline (Kutcher et al., 1987) personality disorders may be related etiologically to schizophrenia, and the full range of schizophrenic symptom atology is less likely to be exhibited in children (Bettes and Walker, 1987). Although there is also research suggesting that borderline personality disorder, as seen in adults, is not linked genetically to schizophrenia (Lorenger et al., 1982; Chapin et aI. , 1987), a decis ion was made to include children with suspected borderline personality disorder , as (1) a sufficient number of studies have suggested that the DSM -Il/ diagnosis of borderline personality disorder is often concomitant with one of schizotypal personality disorder in adult psychiatric populations (Spitzer et aI., 1979; Gunderson et aI. , 1983; George and Soloff, 1986), suggesting the lack of differentiation between the two diagnoses; and (2) it is felt that differentiation between schizotypal and borderline personality disorder diagnoses is even more tenuous within child psychiatric population s. Those subjects who had definit e or suspected diagnoses of schizotypal or borderline personalit y disorder were included in this category, regardles s of additional Axis I diagnoses from other categories . Ventricular asymmetry ratings for subjects with schizophrenia spectrum disorder were compared against all other diagnostic categories combined. The frequency of those with the left ventricle larger than the right was compared to the frequency of those with equal size or the right ventricle larger than the left.
Results Characteristics of Abnormal versus Normal Scans Of the 37 series of images, 13 were categorized as abnormal (Table 1). Table 2 shows the frequency of abnormal MRls within each diagnostic category. Four of eight children with primary diagnoses of PDD had abnormal images. Three out of the six children diagnosed with schizophrenia, schizoid disorder of childhood , schizophreniform, or other
468
"Fisher's exact p = 0.0356 (two-tailed).
psychosis had abnormal images. In contrast , only one out of the 15 children with a primary disruptive behavior disorder diagnosis had an abnormal MRI. Althou gh three of the five children with "other" diagnoses obtained abnormal scans, two of these three children with abnormal scans had "organic" diagnoses , i.e. , atypical organic brain syndrome and organic personality syndrome. Valid WISC-R scores were available for 33 of the 37 children. In comparing scores between those with abnormal and normal MRIs, there was no significant difference between the two groups in full-scale IQ (X = 86 .4 ± 18.8 vs. X = 95.3 ± I1A , respectively; t =_1.65 ,df= 1,31 , NS [two-tailed)) or in performance IQ (X = 95 .6 ± 2 1.5 vs. X = 99.8 ± 14.9 , respectively; t = 0.64 , df = 1,31, NS [two-tailed)). However , children with abnormal MRIs obtained significantly lower _WISC-R verbal IQs than..Ehildren with normal MRIs (X = 80 .6 ± 14.1 vs . X = 92.2 ± 10.4 , respectively; t = 2.63 , df = 1,31 ,p < 0.02 [two-tailedj). To examine whether the verbalIQ differences may be more a product of location of abnormality, at-test was conducted to compare verbal IQ of those with the left ventricle larger than the right with those with equal size or the right ventricle greater than the left. (There were only 30 subjects for whom both WISC-R scores and asymmetry ratings were available.) There were no significant differences between asymmetry groups in verbal IQ (t = 1.64 , df = 1,28, NS). In fact , those with larger left ventricles had higher verbalIQs than those with~ymmetrical ventricles or right ventricles larger than left (X = 95 .1 ± 12.3 vs. X = 86.1 ± 13.7, respectively). Asymmetry and Diagnosis Table 3 shows the frequencies of ventricle asymmetry ratings for the schizophrenia spectrum diagnoses versus all other diagnoses. A greater proportion of children with schizophrenia spectrum diagnoses (50%) had larger left than right frontal horns of the lateral ventricles than children with other diagnoses (20%) (Fisher' s exact test, p = 0 .0356 [twotailed)). Although the small number of subjects carrying a pri?Iary major depressive disorder diagnosis precludes conducting a formal analysis, it is interesting to note that two of the three subjec ts who carried diagnoses of major depressive disorder had relative ventricular enlargement in the right ventricles.
Discussion From the exploratory analyses that were conducted in this pilot study, it appears that the MRI can provide useful information about the relative frequency of brain patholog y J. Am .A cad. Child Adolesc . Psy chiatry . 30 :3•May /991
MAGNETIC RESON ANC E IMAGI NG
associated with various severe childhood psychiatric disorders. The fact that children with abnormal MRls obtained significantly lower verbal IQs suggests that, regardle ss of location, structural brain abnormalities during childhood may affect the developing language system. Since children with larger left ventricles obtained verbal IQ scores as high as those with equal or larger right ventricles , it appears that the extent of verbal deficit cannot merely be explained by the location of the abnormality. Since there were no differences in performan ce IQ , language developm ent may be more vulnerable to influence from brain pathologies than the development of spatial abilities. This finding corroborates that of other research (Basser, 1962) and perhaps is because of the relatively slower localization of cerebral " language" structures (Rosen et al. , 1986). Additional larger scale research is needed to discriminate if there are indeed critical periods for language development. The MRI technique might also provide provocative data that addresses the etiology of schizophrenia. Numerou s studies have explored brain pathology in adult schizophrenics. Among abnormalities observed have been ventricular enlargement (Kelsoe et al. , 1988), change s in the corpus callosum (Mathew et al., 1985; Nasrallah et al., 1986), and decreased size of the frontal lobes (Andreasen, 1986) particularly on the left (Stratta, 1989). These studies can be compared , however, with those that find no differences in brain structure between schizophrenics and controls (Johnstone et aI. , 1986; Smith et aI., 1987). Only a few studies have examined cerebral abnormalities in schizophrenic children (Schultz et al. , 1983; Woody et al., 1987). The study of child psychiatric populations as a means to provide further insight into the etiology of schizophrenia presents various developmental obstacl es. First, episodes of schizophrenia usually do not occur until at least adolescence . Secondly , younger children do not often meet the DSM-IlI-R criteria. Finally, many adult schizoph renics had normal childhoods. Tanguay and Cantor (1986) question whether childho od symptoms associated with a biological risk of schizophrenia may be different from the DSM-IlI-R characteristics associated with the adult onset of schizophrenia. If concepts of developmental psychop athology (Rutter, 1988) are applied , it may be hypothesized that schizophrenia may have different symptomatic manifestations at different ages. In line with this argument, the inclusion of children with schizotypal and borderline features within the " schizophrenia spectrum " appears justified as a line of research. Studies need to address, however , the issue of whether borderline features in child psychiatric populations appear phenomenologically distinct from those in adult psychiatric populations to the degree that justifies including this diagnosis within a childhood schizoph renia spectrum. The number of subjects in this study is too small to provide conclusions but does lend support for working hypotheses. Weinberger (1987) proposes a neurodevelopmen tal model of schizophrenia that involves the interaction of early developmental pathology and normal brain maturation events. He suggests that those at higher risk carry early predispositions that are not manifested until a critical point in neurodevelopment. The finding that the schizophrenia l .Am . Acad . Child Adolesc. Psychiatry, 30 :3, May 1991
spectrum group contains a significantly higher number of subjects whose left frontal horns of the lateral ventricles were larger than the right perhap s indicates that this group is at higher risk of exhibiting cerebral patholog y in the left frontal area. The notion that those at higher risk for schizophrenia may exhibit pathology in this area is congruent with Weinberger' s theory associating lesions of the left dorsolateral prefrontal area with schizophrenia. Perhaps such a lesion represents cerebal pathology central to schizophrenia that is present from early neurodevelopm ent and may be manifested through different psychiatric symptoms, dependent upon both age and environmental factors . Several concerns can be raised regarding this pilot study. First , the readings of abnormal structure and asymmetry were not evaluated by quantitative measures. Second , the concept of "schizophrenia spectrum" is not a standardized classification for use with children, despite the presence of numerous symptoms that resemble those utilized in the adult literature. Recent work suggests that premorbid psychopathology in children does not predict schizophrenia spectrum disorders (Parnas and Jorgensen , 1989). Further delineation and justi fication of what constitutes an extension of the schizophrenia spectrum disorde rs to children is needed in future studies . The authors are beginn ing a longitudinal study that will establish a data base for relatin g cerebral pathology , "soft neurolo gical signs ," psychiatric symptoms, and neuropsychological deficits apparent in childh ood to later development of schizophrenia. In addition , the authors hope to provide more quantit ative measures of cerebral abnormalities through the use of spectroscopy , particul arly through establishing normative developmental trends in metabolism in the left prefrontal area. References Andreasen, N., Nasrall ah, H . A ., Dunn, V. et al. (1986), Structural abnormalities in the front al system in schizo phrenia . Arch. Gen . Psychiatry, 43: 136-144. Baron, M., Gruen, R., Rainer, 1. D ., Kane, J., Asnis, L. & Lord , S. (1985), A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia. Am . J. Psychiatry, 142:447-455 . Basser, L. S. (1962), Hemiplegia of early onset and facult y of speech with specia l reference to the effect of hemispherectom y. Brain , 85:427-460 . Bauman , M. & Kemper, T . L. (1985), Histoanatomic obse rvatio ns of the brain in early infantile autism. Neurology , 35:866-8 74 . Bettes , B. A. & Walker, E. (1987), Positive and negative symptoms in psychotic and other psychia trically disturbed chi ldren. J . Child Psycho/. Psychiatry, 28:555-568 . Chapin, K., Wightman , L., Lycaki, H., Josef, N. & Rosenbaum , G . (1987), Difference in reaction time between subjects with schizotypa l and bo rderline person al ity disorders . Am . J. P sych iat ry . 144 :94 8-950.
Consensus Conference: Magnetic Resonance Imaging. (1988), JAMA , 259:2132-2 138. Courchesne , E., Yeung-Courchesne , R. , Press, G . A., HesseJink , J . R. & Jernigan, T. L. (1988), Hypoplasia of cerebe llar vermal lobules VI and VII in autism. N . Eng /. J . Med ., 3 18:1349-1354 . Drayer, B. P. (1988), Imaging of the agi ng brain. Pari II. Pathologic conditions. Radiology. 166:797-806. Gaffney, G. R. , Tsai, L. Y., Kuperman, S. & Minchin, S. (1987), Cerebellar structure in autism . Am . J. Dis. Child.• 14 1:1330--1332. Gaffney, G . R. , Kuperman , S., Tsai, L. Y. & Minch in, S. (1989), Forebrain structure in infantile autism . J . Am. Acad. Child Ado/esc. Psychiatry, 28:534-537 .
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HENDREN ET AL. Garber, H. J. , Weilburg, J. B. , Buonanno, F. S. , Manschreck , T . C. & New, P. F. 1. (1988), Use of magnetic resonance imaging in psychiatry.
Am. J. Psychiatry, 145:164- 171. George , A. & Soloff, P. H . (1986), Schizotypal symptoms in patients with borderline personality disorders. Am . J . Psychiatry, 143:212-215. Gunderson , J. G. , Siever, L. 1. & Spaulding , E. (1983), The search for a schizotype: crossing the border again. Arch. Gen. Psychiatry, 40:1522 . Johnstone, E. C. , Crow , T . J. , MacMillan , J. F., Owens, D. G. C. , Bydder, G . M. & Steiner, R. E. ( 1986), A magnetic resonance study of early schizophrenia. J. Neural. Neurosurg. Psychiatry, 49 :136-1 39 . Kelsoe, J. R., Cadet , J. L., Pickar, D. & Weinberger , D. R. (1988) , Quantitative neuroanatomy in schizophrenia . Arch. Gen. Psychiatry, 45:533- 54 1. Kutcher, S ., Blackwood , D. H . R., St. Clair, D., Gaskell , D. & Muir, W. 1. (1987) , Auditor y P300 in borderline personality disorder and schizophrenia . Arch. Gen. Psychiatry, 44:645- 650. Lee, B. C., Lipper, E., Nass, R., Ehrlich , M. E., de Ciccio-Bloom, E. & Auld , P. A. M. (1986), MRI of the central nervous system in neonates and young children . AJNR, 7:605- 616 . Lorenger , A. , Oldham, 1. & Tul is, E. (1982), Familial transmis sion of DSM-/ll borderline personality disorder. Arch. Gen. Psychiatry, 39:795799. Mathew, R. J., Partain, C. L. , Prakash , R. , Kulkarni, M. V ., Logan, T . P. & Wilson , W. H. (1985), A study of the septum pellucidum and corpus callosum in schizophrenia with MR imaging . Acta Psychiatr.
Scand., 72:414-421. Nasrallah, H.A . , Andreasen, N. C ., Coffman , J. A ., Olson , S. C ., Dunn, V. D., Ehrha rdt, J. C . & Chapman , S. M. (1986), A controlled magnetic resonance imaging study of corp us callosum thickne ss in schizophrenia .
BioI. Psychiatry, 21:274-282. Parnas, J. & Jergensen, A . (1989), Pre-morbid psychopathol ogy in schizophrenia spectrum. Br. J. Psychiatry, 155:623- 627. Prior, M. R. , Tress, B. , Hoffman, W. L. & Boldt , D. (1984), Computed tomographic study of children with classic autism. Arch. Neurol., 41:482484. Rangel-Guerra, R. A . , Perez-P ayan , H . , M inkoff, L. & T odd, L. E. (1983) , Nuclear magn etic resona nce in bip olar affective disorders .
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AJNR, 4:229-231. Rei ss , D . , Feinste in , C . , Weinberger , D . R., Kin g , R. , W yatt , R . J . & Brallier, D . (198 3), Ventricular enlargeme nt in child psychi atr y patient s: a contro lled study with planimetric measurements . Am. J ,
Psychiat ry, 140:453-456 . Rosen , G. D. , She rman, G. F. & Gal abu rda , A . M . (1986), Biological interac tions in dysle xia . In: Child Ne uropsychology. Volume 1: Theory and Research , ed J . E. Obrzut & G. W . Hynd . Orlando , Academic Press. Rutt er , M . (19 88) , Ep idem iological appro aches to de vel opmental psychopa thology. Arch . Gen . Psychiatry, 45 :486-495. Schulz, S . C ., Koller, M. M . , Kishore, P. R . , Hanmer, R . M ., Gehl , J. 1. & Fr iedel , R . O . (1983), Ventricular enlargement in teen age patients with sc hizophrenia spec tru m disorder. Am. J , Psychiatry , 140: 1592-1595 . Siever, L. J. (1985) , Biolog ical markers in schizotypal personality disorder. Schizophr . Bull ., 11:564-575 . Smith , R . c., Baumgartner , R . , & Calderon, M. (1987) , M agnetic res onance imaging studies of the brains of schizophrenic patient s.
Psychiatry Res., 20:33-46. Spit zer , R. , Endicott, J. & Gibbon , M . (1 979) , Crossing the bord er into borderline per son ality and bord erline schizophrenia: the developm ent of criteria. Arch. Gen . Psych iatry, 36:17-24. Stratta, P . , Ros si , A. , Gallucci , M . , Armicarelli, I. , Pa ssariello , R . & Casacchia, M. (1989) , Hemispheric as ym metries and schizophreni a: a preliminary magnet ic resona nce ima ging study . Bioi .
Psychiatry, 25:275-284 . T anguay , P . E. & Cant or , S . L. (1986) , Sc hizo phrenia in children: introduc tion . J , Am . Acad. Child Adolesc . Psych iatry , 25:59 1-594 . Tatum , W .O., Co ker, S . B . , Ghobrial, M. & Abd-Allah , S . (1989), Th e open opercular sig n: diagn osis and signific ance. Ann . Ne ural .. 25: 196---1 99. Wei nbe rger, D . R. (1987 ), Implications of normal brain development for the patho genesis of schizophrenia. Arch. Gen. Psychiatry , 44:660669 . Woody, R . C. , Bolyard, K . , Eisenh auer , G . & Altsc huler, L. ( 1987) , CT sca n and MRI find ings in a child with sc hizo phre nia . J , Child Neurol., 2: 105-110.
l.Am.Acad. Child A dolesc . Psychiatry , 30:3, Ma y 1991
466
ciated w ith structural deficits . In addition, the results could serve as a baseline for follow-up studies. Finally, the find ings could.be.used to.determine the degree to which cerebral pathology apparent in childhood predicts later development of psychiatric disorders. This study represents an initial investigation of the relationship between brain pathology and types of ps ychiatric disturbance in children.
Method Subjects Thirty-seven children (26 boys and 11 girls) who were inpatients at a university children's psychiatric hospital were referred for MRIs. Subjects were hospitalized during a period ranging from 1986 to 1988; their ages ranged from 5 to 14 years. This subject sample includes all children for whom an MRI was ind icated as part of a complete medical and neurological work-up based on the seriousness of their developmental, emotional, cognitive, and behavioral disturbance, and it included approximately one-third of the total number of children hospitalized during this period. DSMIII-R diagnoses were assigned by the treating clinician who worked closely with the children and were blind to the MRI .findings. Diagnoses were reviewed by the research team who were also blind to the :MRI findings for specific ch ildren to establish the primary diagnosis for each child and to assure compliance with criteria. (Children hospitalized before the use of DSM-III-R may have received a primary DSM-III Axis I diagnoses of pervasive developmental disorder (PDD) or schizoid disorder of childhood.)
Procedure All subjects received the Wechsler Intelligence Scale for Children-Revised (WISC-R) and cranial MRIs . Both were performed in conjunction with treatment, and consent was obtained from the parent(s) or legal guardian . The MRI scans were performed on a 1.5 Tesla superconducting magnet. Tj-weighted images were obtained with spin-echo techniques using a repetition time (fR) of 600 ms and an echo time (TE) of 20 ms. Proton den sity and T 2 -weighted images were performed using spin-echo pulse sequences with a TR of 2,000 or 2 ,500 ms and TE of 30 and 80 ms. Images were I.Am.Acad. Child Adolesc , Psychiatry. 30 :3. May 1991
MAGNETIC RESONANCE IMAGING TABLE 1. Characteristics of Subjects with Abnormal MRls Age (Yrs-Mos) Sex
Handedness
14-11
M
Rt
8-7
F
Both
13-7
M
10-6
Schizotypal? WISC-R SCORES Borderlin e? VIQ PIQ FSIQ
Primary Diagnosi s Schizophrenia
No
82
98
Atypic al organi c brain syndrome
No
68
54
Lt
Major depression
No
97
129
M
Rt
Organic personality syndrome
No
92
114
10-6
F
Rt
Post-traumatic stress disorder
No
77
104
12-5
M
Rt
Pervasive development al disorder
No
72
72
13-6
F
Rt
Atypical psychosis
No
81
78
9-1
M
Rt
Pervas ive developmental disorder
No
66
101
12-3
M
Rt
Majo r depress ion
No
94
108
8-0
F
Rt
Pervasive developmental disorder
Yes
50
65
12-4
M
Rt
Conduct disorder
No
113
126
12-3
F
Rt
Pervasive developmental disorder
Yes
78
86
14-11
M
Rt
Schizophrenia
No
81
98
Note: VIQ
=
Verbal IQ; PIQ
= Performance IQ; FSIQ
Top normal size pituitary; decreased signal intensity on It 58 Enlarged fourth ventricle; atrophy inferior cerebellar vermi s; enlarged posterior fossa 112 Asymmetrical lateral ventricle, rt>lt with mass shift 102 Enlarged fourth ventricle; hypoplasia inferior cerebellar vermis ; enlarged cisterna magna 88 Focal cortical encephalomalacia , anterior It temporal lobe 70 Sing le, nonspecific area of abnormal signal intensity, It semi-ovaIe region 88 Abnormal focal area of increased signal intensity in It peri ventricular white matter 81 Diffuse delayed maturation of white matter in basa l gang lia bilaterally 100 Small area of abnormal signal inten sity in area of It anterior basal gangli a or medial temporal lobe 53 Loss of large portion of brain parenchyma, rt temporal lobe 121 Tonsillar posi tion suggests Chiari I malformation 80 Mild to modera te hydrocephalus-probably comm unica ting type 88 Nonspecific focal areas of abnormal white matter
= Full-scale IQ.
obtained in 5 mm slice thicknesses in sagittal, axial, and coronal planes . Neuroradiologists, who were blind to the subjects' diagnoses, categorized the images as either "normal" or " abnormal" for each child (Table I). A variety of indicators classified images as "abnormal," including focal variable signal intensities, encephalomalacia, ventricular enlargement, atrophy, and abnormal white matter signal. In addition, the neuroradiologists, who were blind to the subjects' psychiatric diagnoses, rated scans according to apparent asymmetry between the left and right frontal horns of the lateral ventricles. The coronal slice from the head of the caudate nucleus was used for this rating. Each scan was rated as either displaying: (1) the left ventricle larger than the right, (2) equal size or minimal asymmetry, or (3) the right ventricle larger than the left, using a qualitative scale from 0 (symmetry) to 3 (extreme asymmetry). Two neuroradiologists agreed upon the asymmetry rating for each subject. Asymmetry ratings were available for 34 of the 37 subjects. Analyses of the scans proceeded in a two-step process . First, subjects were grouped according to their primary Axis I diagnoses (Table 2). DSM-llI and DSM-llI-R diagnostic groupings were used as a basis for delineating categories of diagnoses. PDD (N = 8) and schizophrenia -related disorders (N = 6) were distinguished as separate diagnostic I. Am .Aca d. Child Adolesc . Psychiatry , 30:3 , Ma y 199 1
MR I Finding
89
categories , since neither could be combined with other diagnostic groups . The disruptive behavior disorder category (N = 15) consisted of subjects with a primary diagnosis of either conduct disorder (N = 14) or oppositional defiant disorder (N = 1). Subjects diagnosed with either dysthymia or major depression were grouped under a mood disorder category (N = 3). The "other" category (N = 5) grouped together subjects with the remaining diagnoses (identity disorder , post-traumatic stress disorder, atypical brain syndrome, organic personality disorder, separation anxiety disorder), whose frequencies did not merit separate categories. The frequencies of abnormal MRls occurring between diagnostic categories were compared . In addition, WISC-R verbal, performa nce, and full-scale IQs of subjects with abnormal MRls were compared with those with normal MRls . The second step in the analyses was to determine if particular differences in the asymmetry ratings among particular types of disorde rs provided any indication of specific brain regions of pathology . For this purpose, the diagnoses were recategorized into two groups. The first group was comprised of the schizophrenia-related disorders (schizophrenia, schizoid disorder of childhood, schizophreniform disorder, or atypical psychosis) plus schizotypal and borderline personality disorders. In this recategorization, an
467
HENDR EN ET A L. T AB L E 2. Incidence of Normal and Abnormal MRIs and Primary Axis I Diagnosis for 37 Severely Disturbed Children
3. Comparison" of the Lateral Ventricle Asymmetry Ratings of Schizophrenia Spectrum Diagnoses versus All Other Diagnoses
T ABLE
MRI Finding
Asymmetry Rating
Diagnosi s
Norm al
Abnor mal
Diagnosis
Left > Right
Equal or Right > Left
Pervasive developmen tal disorde r Schizophrenia-related disorder' Disruptive behavior disorder Mood disorder Other
4 3
4
Schizophren ia spectrum Other diagnoses
8 4
6 16
14
3 I
I
2
2
3
"Includes schizophrenia, schizop hreniform, schizo id disorder of childhood, and other psychosis .
Axis II diagnosis of schizotypal or borderline personalit y disorder preempted any other diagnosis on Axis I that was not schizophrenia related . The second group was comprised of all other diagnoses combined. This comparison was chosen because research on schizophrenia has produced more specific hypotheses concerning the focus of dysfunction . "Schizophrenia spectrum " disorder, therefore, reflects inclusion of subjects who displayed DSM-III -R schizotypal and borderline features , since research suggests that schizotypal (Baron et aI., 1985; Siever, 1985) and borderline (Kutcher et al., 1987) personality disorders may be related etiologically to schizophrenia, and the full range of schizophrenic symptom atology is less likely to be exhibited in children (Bettes and Walker, 1987). Although there is also research suggesting that borderline personality disorder, as seen in adults, is not linked genetically to schizophrenia (Lorenger et al., 1982; Chapin et aI. , 1987), a decis ion was made to include children with suspected borderline personality disorder , as (1) a sufficient number of studies have suggested that the DSM -Il/ diagnosis of borderline personality disorder is often concomitant with one of schizotypal personality disorder in adult psychiatric populations (Spitzer et aI., 1979; Gunderson et aI. , 1983; George and Soloff, 1986), suggesting the lack of differentiation between the two diagnoses; and (2) it is felt that differentiation between schizotypal and borderline personality disorder diagnoses is even more tenuous within child psychiatric population s. Those subjects who had definit e or suspected diagnoses of schizotypal or borderline personalit y disorder were included in this category, regardles s of additional Axis I diagnoses from other categories . Ventricular asymmetry ratings for subjects with schizophrenia spectrum disorder were compared against all other diagnostic categories combined. The frequency of those with the left ventricle larger than the right was compared to the frequency of those with equal size or the right ventricle larger than the left.
Results Characteristics of Abnormal versus Normal Scans Of the 37 series of images, 13 were categorized as abnormal (Table 1). Table 2 shows the frequency of abnormal MRls within each diagnostic category. Four of eight children with primary diagnoses of PDD had abnormal images. Three out of the six children diagnosed with schizophrenia, schizoid disorder of childhood , schizophreniform, or other
468
"Fisher's exact p = 0.0356 (two-tailed).
psychosis had abnormal images. In contrast , only one out of the 15 children with a primary disruptive behavior disorder diagnosis had an abnormal MRI. Althou gh three of the five children with "other" diagnoses obtained abnormal scans, two of these three children with abnormal scans had "organic" diagnoses , i.e. , atypical organic brain syndrome and organic personality syndrome. Valid WISC-R scores were available for 33 of the 37 children. In comparing scores between those with abnormal and normal MRIs, there was no significant difference between the two groups in full-scale IQ (X = 86 .4 ± 18.8 vs. X = 95.3 ± I1A , respectively; t =_1.65 ,df= 1,31 , NS [two-tailed)) or in performance IQ (X = 95 .6 ± 2 1.5 vs. X = 99.8 ± 14.9 , respectively; t = 0.64 , df = 1,31, NS [two-tailed)). However , children with abnormal MRIs obtained significantly lower _WISC-R verbal IQs than..Ehildren with normal MRIs (X = 80 .6 ± 14.1 vs . X = 92.2 ± 10.4 , respectively; t = 2.63 , df = 1,31 ,p < 0.02 [two-tailedj). To examine whether the verbalIQ differences may be more a product of location of abnormality, at-test was conducted to compare verbal IQ of those with the left ventricle larger than the right with those with equal size or the right ventricle greater than the left. (There were only 30 subjects for whom both WISC-R scores and asymmetry ratings were available.) There were no significant differences between asymmetry groups in verbal IQ (t = 1.64 , df = 1,28, NS). In fact , those with larger left ventricles had higher verbalIQs than those with~ymmetrical ventricles or right ventricles larger than left (X = 95 .1 ± 12.3 vs. X = 86.1 ± 13.7, respectively). Asymmetry and Diagnosis Table 3 shows the frequencies of ventricle asymmetry ratings for the schizophrenia spectrum diagnoses versus all other diagnoses. A greater proportion of children with schizophrenia spectrum diagnoses (50%) had larger left than right frontal horns of the lateral ventricles than children with other diagnoses (20%) (Fisher' s exact test, p = 0 .0356 [twotailed)). Although the small number of subjects carrying a pri?Iary major depressive disorder diagnosis precludes conducting a formal analysis, it is interesting to note that two of the three subjec ts who carried diagnoses of major depressive disorder had relative ventricular enlargement in the right ventricles.
Discussion From the exploratory analyses that were conducted in this pilot study, it appears that the MRI can provide useful information about the relative frequency of brain patholog y J. Am .A cad. Child Adolesc . Psy chiatry . 30 :3•May /991
MAGNETIC RESON ANC E IMAGI NG
associated with various severe childhood psychiatric disorders. The fact that children with abnormal MRls obtained significantly lower verbal IQs suggests that, regardle ss of location, structural brain abnormalities during childhood may affect the developing language system. Since children with larger left ventricles obtained verbal IQ scores as high as those with equal or larger right ventricles , it appears that the extent of verbal deficit cannot merely be explained by the location of the abnormality. Since there were no differences in performan ce IQ , language developm ent may be more vulnerable to influence from brain pathologies than the development of spatial abilities. This finding corroborates that of other research (Basser, 1962) and perhaps is because of the relatively slower localization of cerebral " language" structures (Rosen et al. , 1986). Additional larger scale research is needed to discriminate if there are indeed critical periods for language development. The MRI technique might also provide provocative data that addresses the etiology of schizophrenia. Numerou s studies have explored brain pathology in adult schizophrenics. Among abnormalities observed have been ventricular enlargement (Kelsoe et al. , 1988), change s in the corpus callosum (Mathew et al., 1985; Nasrallah et al., 1986), and decreased size of the frontal lobes (Andreasen, 1986) particularly on the left (Stratta, 1989). These studies can be compared , however, with those that find no differences in brain structure between schizophrenics and controls (Johnstone et aI. , 1986; Smith et aI., 1987). Only a few studies have examined cerebral abnormalities in schizophrenic children (Schultz et al. , 1983; Woody et al., 1987). The study of child psychiatric populations as a means to provide further insight into the etiology of schizophrenia presents various developmental obstacl es. First, episodes of schizophrenia usually do not occur until at least adolescence . Secondly , younger children do not often meet the DSM-IlI-R criteria. Finally, many adult schizoph renics had normal childhoods. Tanguay and Cantor (1986) question whether childho od symptoms associated with a biological risk of schizophrenia may be different from the DSM-IlI-R characteristics associated with the adult onset of schizophrenia. If concepts of developmental psychop athology (Rutter, 1988) are applied , it may be hypothesized that schizophrenia may have different symptomatic manifestations at different ages. In line with this argument, the inclusion of children with schizotypal and borderline features within the " schizophrenia spectrum " appears justified as a line of research. Studies need to address, however , the issue of whether borderline features in child psychiatric populations appear phenomenologically distinct from those in adult psychiatric populations to the degree that justifies including this diagnosis within a childhood schizoph renia spectrum. The number of subjects in this study is too small to provide conclusions but does lend support for working hypotheses. Weinberger (1987) proposes a neurodevelopmen tal model of schizophrenia that involves the interaction of early developmental pathology and normal brain maturation events. He suggests that those at higher risk carry early predispositions that are not manifested until a critical point in neurodevelopment. The finding that the schizophrenia l .Am . Acad . Child Adolesc. Psychiatry, 30 :3, May 1991
spectrum group contains a significantly higher number of subjects whose left frontal horns of the lateral ventricles were larger than the right perhap s indicates that this group is at higher risk of exhibiting cerebral patholog y in the left frontal area. The notion that those at higher risk for schizophrenia may exhibit pathology in this area is congruent with Weinberger' s theory associating lesions of the left dorsolateral prefrontal area with schizophrenia. Perhaps such a lesion represents cerebal pathology central to schizophrenia that is present from early neurodevelopm ent and may be manifested through different psychiatric symptoms, dependent upon both age and environmental factors . Several concerns can be raised regarding this pilot study. First , the readings of abnormal structure and asymmetry were not evaluated by quantitative measures. Second , the concept of "schizophrenia spectrum" is not a standardized classification for use with children, despite the presence of numerous symptoms that resemble those utilized in the adult literature. Recent work suggests that premorbid psychopathology in children does not predict schizophrenia spectrum disorders (Parnas and Jorgensen , 1989). Further delineation and justi fication of what constitutes an extension of the schizophrenia spectrum disorde rs to children is needed in future studies . The authors are beginn ing a longitudinal study that will establish a data base for relatin g cerebral pathology , "soft neurolo gical signs ," psychiatric symptoms, and neuropsychological deficits apparent in childh ood to later development of schizophrenia. In addition , the authors hope to provide more quantit ative measures of cerebral abnormalities through the use of spectroscopy , particul arly through establishing normative developmental trends in metabolism in the left prefrontal area. References Andreasen, N., Nasrall ah, H . A ., Dunn, V. et al. (1986), Structural abnormalities in the front al system in schizo phrenia . Arch. Gen . Psychiatry, 43: 136-144. Baron, M., Gruen, R., Rainer, 1. D ., Kane, J., Asnis, L. & Lord , S. (1985), A family study of schizophrenic and normal control probands: implications for the spectrum concept of schizophrenia. Am . J. Psychiatry, 142:447-455 . Basser, L. S. (1962), Hemiplegia of early onset and facult y of speech with specia l reference to the effect of hemispherectom y. Brain , 85:427-460 . Bauman , M. & Kemper, T . L. (1985), Histoanatomic obse rvatio ns of the brain in early infantile autism. Neurology , 35:866-8 74 . Bettes , B. A. & Walker, E. (1987), Positive and negative symptoms in psychotic and other psychia trically disturbed chi ldren. J . Child Psycho/. Psychiatry, 28:555-568 . Chapin, K., Wightman , L., Lycaki, H., Josef, N. & Rosenbaum , G . (1987), Difference in reaction time between subjects with schizotypa l and bo rderline person al ity disorders . Am . J. P sych iat ry . 144 :94 8-950.
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