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Handedness in twins with schizophrenia: was Boklage correct?
Schizophrenia Research. 9 (1993) 83-85 $J 1993 Elsevier Science Publishers B.V. All rights reserved
SCHRES
83 0920-9964/93/$06.00
00282
Short
Communication
Handedness in twins with schizophrenia: was Boklage correct? E. Fuller Torrey”, J. Daniel Raglandb, James M. Gold”, Terry E. Goldberg”, Llewellyn B. Bigelow” and Irving I. Gottesmanc
Ann E. Bowlera,
“NIMH Neuropsychiatric Research Center, St. Eli-_abelh’s Hospital, Washington. DC 20032, USA, hDepartment of Psychiatry, University of Penns.ylvania, Philadelphia, PA, USA and ‘Department of Ps.vchology. University qf Virginia, Charlottesville. VA, USA (Received
3 August
1992; revision
received 29 September
1992; accepted
4 October
1992)
Boklage’s report of increased non-right handedness among monozygotic twins with schizophrenia has been cited as evidence to support an association of abnormal brain lateralization with the development of schizophrenia. The present study found no such association. Two previous attempts to replicate Boklage’s findings (Luchins et al. 1980; Lewis et al. 1989) also reported do not appear to support an association of brain lateralization I&x words: Handedness;
Laterality;
little support. Studies and schizophrenia.
of twin handedness
Twins; (Schizophrenia)
The literature on handedness in individuals with schizophrenia is one of the most confusing and contradictory areas in schizophrenia research. There are reports that the disease is associated with more left handedness (Cur, 1977) more right handedness (Taylor et al., 1980) more ambiguous handedness (Green et al., 1989), or that there is no difference from control populations (Kameyama et al., 1983). The picture becomes even more confused when footedness and eyedness are also measured for they do not always conform to handedness (Plato, 1985). Because handedness is thought to reflect one aspect of brain lateralization, it can be used to probe the issue of whether brain lateralization is related to the etiology or pathophysiology of schizophrenia. One of the most controversial studies of handedness in schizophrenia was Boklage’s (1977) study of 28 monozygotic (MZ) and 33 dizygotic (DZ) twins with schizophrenia including 13 MZ discordant pairs. Boklage did not examine the twins personally but utilized data which had been collected by Slater, Gottesman and Shields. Dividing Correspondence to: E. Fuller Torrey, NIMH Neuroscience Center, St. Elizabeths ton, DC 20032, USA.
Twin Study Unit. Hospital, Washing-
the twins into right handed (RH) and non-right handed (NRH), Boklage reported that: (1) nonright handedness occurs more frequently in MZ than in DZ twins; (2) non-right handedness occurs more frequently in twins in which one (discordant) or both (concordant) have been diagnosed with schizophrenia than in normal control twins and is especially frequent in the discordant pairs; (3) in twin pairs discordant for schizophrenia in which one is NRH, that twin is more likely to be the one with schizophrenia; (4) twinships in which at least one twin was NRH had less severe clinical types of schizophrenia than those in which both were RH. Boklage’s findings have been cited as support for the theory that abnormal brain lateralization is related to the etiology of schizophrenia (Crow, 1987). Two research groups have attempted to replicate Boklage’s findings. Luchins et al. (1980) reexamined handedness from the Pollin et al. study of 14 MZ twins discordant for schizophrenia. Since no DZ twins were included they could not address Boklage’s first finding. They reported no support for his second finding, qualified support for his third and fourth findings, and an additional trend within MZ discordant pairs for the NRH twin with schizophrenia to be heavier at birth. Lewis
84
et al. (1989) reported data from 3 1 MZ and 34 DZ twins including 13 MZ pairs discordant for schizophrenia. They found essentially no support for his first three findings and did not test the fourth. The following study is another attempt to replicate Boklage’s findings. Handedness was determined for 27 monozygotic (MZ) twins discordant for DSM-IITR schizophrenia or schizoaffective disorder, 13 MZ twins concordant for these diseases, and 8 MZ normal control twins as part of a larger study of MZ twins with schizophrenia, schizoaffective disorder, and bipolar disorder (Suddath et al., 1990). The affected twins in the discordant pairs included 16 males and 11 females, had a mean age at the time of testing of 30.7 years (range 17-44) and have now been discordant for a mean of 12.1 years (range 4-25). Diagnosis was determined using a structured clinical interview (Spitzer et al. 1987) with DSM-IITR criteria. Hand preference was determined using the Edinburgh Inventory (Oldfield, 1971) for all except 5 twin pairs (4 discordant, 1 normal control); in these 5 pairs hand preference was determined by observation of writing and by history from the mother. Because DZ twins were not included in this study, Boklage’s first finding could not be tested. No support was found for his second finding as 6 of the 27 twin pairs discordant for schizophrenia and schizoaffective disorder (22.2 percent), 4 of the 13 pairs concordant for these diseases (30.8 percent), and 2 of the 8 normal control twin pairs (25 percent) included a NRH twin; these findings are consistent with other studies of normal MZ twins in which approximately 25 percent of twin pairs include a NRH twin (Segal, 1989). No support was found for Boklage’s third or fourth findings. Among our 6 discordant pairs in which one was NRH, the affected twin was NRH in three pairs, the well twin was NRH in two pairs, and in the other pair both were NRH. When the 6 pairs with a NRH member were compared with the 21 pairs in which both were RH on measures of disease severity for the affected twin, no differences were found for either Axis V at time of testing (p= 0.51) or total years of hospitalization (p=O.O7) (r-test of means), although the results were in the same direction reported by Boklage. Given the finding by Luchins et al. (1980) that 3 NRH affected twins in MZ discordant twin pairs
were significantly heavier at birth than 7 RH affected twins, we compared the birth weights of the 4 NRH affected twins with those of the 22 RH affected twins in our study. The results were the opposite of those of Luchins et al; the mean birth weight for the 4 NRH affected twins was 1903 g and the mean birth weight for the 22 RH affected twins was 2590 g (f-test of the means, p < 0.002). Although poorly understood, handedness in singletons is thought to be influenced by a combination of genetic factors, prenatal and perinatal birth injuries, and by learning (e.g. imitating the mother or NRH being forced to become RH in school (Michel, 1992). In MZ twins there is an additional factor of mirror imaging, thought to be caused when some zygotes split slightly later in development after asymmetry has become fixed (Newman, 1928). Mirror imaging produces twin pairs in which one is RH and the other NRH and may also (but not necessarily) produce ectodermal mirroring of hair crowns or minor physical anomalies. The existence of mirror imaging as well as the increased incidence of perinatal injuries among twins presumably accounts for the increased incidence of NRH individuals among MZ twins compared with nontwin populations. The results of handedness assessment of the 40 MZ twins with schizophrenia or schizoaffective disorder in our series, combined with the findings of Luchins et al. (1980) (14 MZ pairs) and Lewis et al. (1989) (3 1 MZ pairs), fail to replicate Boklage’s findings on his 28 MZ pairs. As such the results do not support hypotheses linking the development of schizophrenia to this particular index of brain lateralization. The existence of structural (e.g. hippocampus), functional (e.g. dichotic listening), and neurochemical (e.g. neurotransmitter) cerebral asymmetries in schizophrenia will continue to be studied, and such studies may show that schizophrenia is related to the process of lateralization. However, handedness does not appear to be a useful measure for studying lateralization in this disease. REFERENCES Boklage, C.E. (1977) Schizophrenia, brain asymmetry development and twinning: cellular relationship with etiological and possibly prognostic implications. Biol. Psychiatry 12, 19-35.
85 Crow, T.J. (1987) The scope for nongenetic factors in etiology: the retrovirus/transposon hypothesis. In: H. Helmchen and F.A. Henn (Eds.), Biological perspectives of schizophrenia. Wiley, New York, pp. 855105. Green, M.F., Satz, P., Smith, C. and Nelson, L. (1989) Is there atypical handedness in schizophrenia? J. Abn. Psychol. 98, 57-61. Gur. R. (1977) Motoric laterality imbalance in schizophrenia. Arch. Gen. Psychiatry 34, 33-57. Kameyama, T., Niwa. S., Hiramatsu, K. and Saitoh, 0. (1983) Hand preference and eye dominance patterns in Japanese schizophrenics. In: P. Flor-Henry and J. Gruzelier (Eds.), Laterality and Psychopathology. Elsevier, Amsterdam, pp. 1633180. Lewis, SW., Chitkara, B. and Reveley, A.M. (1989) Hand preference in psychotic twins. Biol. Psychiatry 25, 2155221. Luchins, D., Pollin, W. and Wyatt, R.J. (1980) Laterality in monozygotic schizophrenic twins: an alternative hypothesis. Biol. Psychiatry 15, 87-93. Michel, G.F. (1992) Maternal influences on infant handedness during play with toys. Behav. Genet. 22, 163-175. Newman, H.H. (1928) Studies of human twins: asymmetry
reversal of mirror imaging in identical twins. Biol. Bull. 55, 298-315. Oldfield, R.C. (1971) The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9,977 I 13. Plato, C.C., Fox, K.M. and Garruto, R.M. (1985) Measures of lateral functional dominance: foot preference, eye preference, digital interlocking, arm folding and foot overlapping. Hum. Biol. 57, 327-334. Segal, N.L. (1989) Origins and implications of handedness and relative birth weight for IQ in monozygotic pairs. Neuropsychology 27, 5499561. Spitzer, R.L.. Williams, J.B.W. and Gibbon, M. (1987) Structured clinical interview for DSM-IIIR (SCID 4/l/87). Biometrics Research Department, New York State Psychiatric Institute, New York. Suddath, R.L., Christison, G.W., Torrey, E.F., Casanova, M.F., and Weinberger, D.L. (1990) Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N. Engl. J. Med. 322, 7899794. Taylor, P.J., Dalton, R. and Fleminger. J.J. (1980) Handedness in schizophrenia. Br. J. Psychiatry 136, 3755383.
SCHRES
83 0920-9964/93/$06.00
00282
Short
Communication
Handedness in twins with schizophrenia: was Boklage correct? E. Fuller Torrey”, J. Daniel Raglandb, James M. Gold”, Terry E. Goldberg”, Llewellyn B. Bigelow” and Irving I. Gottesmanc
Ann E. Bowlera,
“NIMH Neuropsychiatric Research Center, St. Eli-_abelh’s Hospital, Washington. DC 20032, USA, hDepartment of Psychiatry, University of Penns.ylvania, Philadelphia, PA, USA and ‘Department of Ps.vchology. University qf Virginia, Charlottesville. VA, USA (Received
3 August
1992; revision
received 29 September
1992; accepted
4 October
1992)
Boklage’s report of increased non-right handedness among monozygotic twins with schizophrenia has been cited as evidence to support an association of abnormal brain lateralization with the development of schizophrenia. The present study found no such association. Two previous attempts to replicate Boklage’s findings (Luchins et al. 1980; Lewis et al. 1989) also reported do not appear to support an association of brain lateralization I&x words: Handedness;
Laterality;
little support. Studies and schizophrenia.
of twin handedness
Twins; (Schizophrenia)
The literature on handedness in individuals with schizophrenia is one of the most confusing and contradictory areas in schizophrenia research. There are reports that the disease is associated with more left handedness (Cur, 1977) more right handedness (Taylor et al., 1980) more ambiguous handedness (Green et al., 1989), or that there is no difference from control populations (Kameyama et al., 1983). The picture becomes even more confused when footedness and eyedness are also measured for they do not always conform to handedness (Plato, 1985). Because handedness is thought to reflect one aspect of brain lateralization, it can be used to probe the issue of whether brain lateralization is related to the etiology or pathophysiology of schizophrenia. One of the most controversial studies of handedness in schizophrenia was Boklage’s (1977) study of 28 monozygotic (MZ) and 33 dizygotic (DZ) twins with schizophrenia including 13 MZ discordant pairs. Boklage did not examine the twins personally but utilized data which had been collected by Slater, Gottesman and Shields. Dividing Correspondence to: E. Fuller Torrey, NIMH Neuroscience Center, St. Elizabeths ton, DC 20032, USA.
Twin Study Unit. Hospital, Washing-
the twins into right handed (RH) and non-right handed (NRH), Boklage reported that: (1) nonright handedness occurs more frequently in MZ than in DZ twins; (2) non-right handedness occurs more frequently in twins in which one (discordant) or both (concordant) have been diagnosed with schizophrenia than in normal control twins and is especially frequent in the discordant pairs; (3) in twin pairs discordant for schizophrenia in which one is NRH, that twin is more likely to be the one with schizophrenia; (4) twinships in which at least one twin was NRH had less severe clinical types of schizophrenia than those in which both were RH. Boklage’s findings have been cited as support for the theory that abnormal brain lateralization is related to the etiology of schizophrenia (Crow, 1987). Two research groups have attempted to replicate Boklage’s findings. Luchins et al. (1980) reexamined handedness from the Pollin et al. study of 14 MZ twins discordant for schizophrenia. Since no DZ twins were included they could not address Boklage’s first finding. They reported no support for his second finding, qualified support for his third and fourth findings, and an additional trend within MZ discordant pairs for the NRH twin with schizophrenia to be heavier at birth. Lewis
84
et al. (1989) reported data from 3 1 MZ and 34 DZ twins including 13 MZ pairs discordant for schizophrenia. They found essentially no support for his first three findings and did not test the fourth. The following study is another attempt to replicate Boklage’s findings. Handedness was determined for 27 monozygotic (MZ) twins discordant for DSM-IITR schizophrenia or schizoaffective disorder, 13 MZ twins concordant for these diseases, and 8 MZ normal control twins as part of a larger study of MZ twins with schizophrenia, schizoaffective disorder, and bipolar disorder (Suddath et al., 1990). The affected twins in the discordant pairs included 16 males and 11 females, had a mean age at the time of testing of 30.7 years (range 17-44) and have now been discordant for a mean of 12.1 years (range 4-25). Diagnosis was determined using a structured clinical interview (Spitzer et al. 1987) with DSM-IITR criteria. Hand preference was determined using the Edinburgh Inventory (Oldfield, 1971) for all except 5 twin pairs (4 discordant, 1 normal control); in these 5 pairs hand preference was determined by observation of writing and by history from the mother. Because DZ twins were not included in this study, Boklage’s first finding could not be tested. No support was found for his second finding as 6 of the 27 twin pairs discordant for schizophrenia and schizoaffective disorder (22.2 percent), 4 of the 13 pairs concordant for these diseases (30.8 percent), and 2 of the 8 normal control twin pairs (25 percent) included a NRH twin; these findings are consistent with other studies of normal MZ twins in which approximately 25 percent of twin pairs include a NRH twin (Segal, 1989). No support was found for Boklage’s third or fourth findings. Among our 6 discordant pairs in which one was NRH, the affected twin was NRH in three pairs, the well twin was NRH in two pairs, and in the other pair both were NRH. When the 6 pairs with a NRH member were compared with the 21 pairs in which both were RH on measures of disease severity for the affected twin, no differences were found for either Axis V at time of testing (p= 0.51) or total years of hospitalization (p=O.O7) (r-test of means), although the results were in the same direction reported by Boklage. Given the finding by Luchins et al. (1980) that 3 NRH affected twins in MZ discordant twin pairs
were significantly heavier at birth than 7 RH affected twins, we compared the birth weights of the 4 NRH affected twins with those of the 22 RH affected twins in our study. The results were the opposite of those of Luchins et al; the mean birth weight for the 4 NRH affected twins was 1903 g and the mean birth weight for the 22 RH affected twins was 2590 g (f-test of the means, p < 0.002). Although poorly understood, handedness in singletons is thought to be influenced by a combination of genetic factors, prenatal and perinatal birth injuries, and by learning (e.g. imitating the mother or NRH being forced to become RH in school (Michel, 1992). In MZ twins there is an additional factor of mirror imaging, thought to be caused when some zygotes split slightly later in development after asymmetry has become fixed (Newman, 1928). Mirror imaging produces twin pairs in which one is RH and the other NRH and may also (but not necessarily) produce ectodermal mirroring of hair crowns or minor physical anomalies. The existence of mirror imaging as well as the increased incidence of perinatal injuries among twins presumably accounts for the increased incidence of NRH individuals among MZ twins compared with nontwin populations. The results of handedness assessment of the 40 MZ twins with schizophrenia or schizoaffective disorder in our series, combined with the findings of Luchins et al. (1980) (14 MZ pairs) and Lewis et al. (1989) (3 1 MZ pairs), fail to replicate Boklage’s findings on his 28 MZ pairs. As such the results do not support hypotheses linking the development of schizophrenia to this particular index of brain lateralization. The existence of structural (e.g. hippocampus), functional (e.g. dichotic listening), and neurochemical (e.g. neurotransmitter) cerebral asymmetries in schizophrenia will continue to be studied, and such studies may show that schizophrenia is related to the process of lateralization. However, handedness does not appear to be a useful measure for studying lateralization in this disease. REFERENCES Boklage, C.E. (1977) Schizophrenia, brain asymmetry development and twinning: cellular relationship with etiological and possibly prognostic implications. Biol. Psychiatry 12, 19-35.
85 Crow, T.J. (1987) The scope for nongenetic factors in etiology: the retrovirus/transposon hypothesis. In: H. Helmchen and F.A. Henn (Eds.), Biological perspectives of schizophrenia. Wiley, New York, pp. 855105. Green, M.F., Satz, P., Smith, C. and Nelson, L. (1989) Is there atypical handedness in schizophrenia? J. Abn. Psychol. 98, 57-61. Gur. R. (1977) Motoric laterality imbalance in schizophrenia. Arch. Gen. Psychiatry 34, 33-57. Kameyama, T., Niwa. S., Hiramatsu, K. and Saitoh, 0. (1983) Hand preference and eye dominance patterns in Japanese schizophrenics. In: P. Flor-Henry and J. Gruzelier (Eds.), Laterality and Psychopathology. Elsevier, Amsterdam, pp. 1633180. Lewis, SW., Chitkara, B. and Reveley, A.M. (1989) Hand preference in psychotic twins. Biol. Psychiatry 25, 2155221. Luchins, D., Pollin, W. and Wyatt, R.J. (1980) Laterality in monozygotic schizophrenic twins: an alternative hypothesis. Biol. Psychiatry 15, 87-93. Michel, G.F. (1992) Maternal influences on infant handedness during play with toys. Behav. Genet. 22, 163-175. Newman, H.H. (1928) Studies of human twins: asymmetry
reversal of mirror imaging in identical twins. Biol. Bull. 55, 298-315. Oldfield, R.C. (1971) The assessment and analysis of handedness: The Edinburgh Inventory. Neuropsychologia 9,977 I 13. Plato, C.C., Fox, K.M. and Garruto, R.M. (1985) Measures of lateral functional dominance: foot preference, eye preference, digital interlocking, arm folding and foot overlapping. Hum. Biol. 57, 327-334. Segal, N.L. (1989) Origins and implications of handedness and relative birth weight for IQ in monozygotic pairs. Neuropsychology 27, 5499561. Spitzer, R.L.. Williams, J.B.W. and Gibbon, M. (1987) Structured clinical interview for DSM-IIIR (SCID 4/l/87). Biometrics Research Department, New York State Psychiatric Institute, New York. Suddath, R.L., Christison, G.W., Torrey, E.F., Casanova, M.F., and Weinberger, D.L. (1990) Anatomical abnormalities in the brains of monozygotic twins discordant for schizophrenia. N. Engl. J. Med. 322, 7899794. Taylor, P.J., Dalton, R. and Fleminger. J.J. (1980) Handedness in schizophrenia. Br. J. Psychiatry 136, 3755383.