0 1998 Martin Dunitz Ltd
International Journal of Psychiatry in Clinical Practice 1998 Volume 2 Pages 221 -224
221
Abnormal patterns of cerebral glucose metabolism in a pair of monozygotic twins with recent onset schizophrenia F ORTUNOl, J ARBIZU2 AND Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
s CERVERA~ Departments of ’Psychiatry and ’Nuclear Medicine, University Hospital, University of Navarra, Spain
Correspondence Address Dr F OrtuAo, Departamento de Psiquiatria, y Psicologia Mtdica, Clinica Universitaria, 31008 Pamplona, Spain Tel: +34 948 255400 Fax: i 3 4 948 172294 Received 27 October 1997; accepted for publication 27 April 1998
An F-WFDG-PET study of a pair of monozygotic twins with recent-onset schizophrenia revealed a higher index of metabolic asymmetry (JA)in the medial and posterior thalamus in both cases. Some questions regarding the influence of neuroleptic,treatment and handedness on metablic patterns and the role of the thalamus in schizophrenia are discussed in the light of recent studies. (Int J Psych Clin Pruct 1998; 2: 221 - 224)
Keywords schizophrenia thalamus physiopathology
deoxyglucose metabolism twins psychology
INTRODUCTION
MATERIAL AND METHOD
n this paper we report the results of a study of cerebral glucose metabolism (18-D-fluor-deoxyglucose, FDG) conducted using positron emission tomography (PET) in a pair of 18-year-old male monozygotic twins who had been suffering from schizophrenia for some months. One of the twins (twin A) had initially presented a marked delirious paranoid syndrome which had remitted partially at the time when the study was performed. The other (twin B) had less pronounced symptoms from the outset. Following the criteria of ICD-10, the diagnoses were paranoid schizophrenia (twin A) and undifferentiated schizophrenia (twin B). When we performed the PETFDG study, both patients had similar scores on the positive (P) and negative (N)scales of the PANSS; but different ones on the general psychopathology scale (GP). The profiles were predominantly slightly negative (inclusive PANS system).’.’ Both patients were left-handed (or not right-handed) (a hand preference questionnaire’ was used). When the study was performed, both twins were still under treatment: twin A had been takipg clozapine (75 mg/day) for 3 days (treatment with haloperidol had ceased 2 weeks previously); twin B was being treated with sulpiride (up to 150 rnglday).
The PET-FDG study was carried out in resting conditions. The standard uptake values (SUV) of 18 regions of interest in each hemisphere were determined. The index of asymmetry (IA) for each of the 18 regions of interest was then studied: this included the regions on the right and on the left (IA = (L - R) (L+R) x 1001, and both the absolute readings and the values which had been normalized with respect to the occipital were obtained.
I
RESULTS Table 2 shows the results of the SUV (standard uptake values) relative to the occipital of each of the regions of interest, as well as the index of asymmetry. They show a pattern of asymmetry L>R, common to both twins in all the cortical regions with the exception of the occipital. It is also noteworthy that the highest index of asymmetry in both patients was in the medial and posterior thalamus.
DISCUSSION The finding which stands out is the pattern of asymmetry, in which the left is greater than the right (L > R) in all the
222
F OrtuYlo et a1
cortical regions of interest, with the exception of the occipital cortex. This result is consistent with that of
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
Table 1 Patients’ characteristics
Table 2 Values of regions of interest, relative to occipital
IA:asymmetry gradient IA=(L - R)/(L+ R) x 100.
previous studies, which detect a pattern of predominantly left metabolic imbalance in samples of schizophrenic
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
Cerebral glucose metabolism in schizophrenic twins
Figure 1 Axial (above) and coronal (below) PET-FDG slices of twin A (left) and twin B (right) There is less activity in the right posterior thalamic region than in the left in both cases, especially twin A (arrow)
patients, both in overall cerebral metabolic activity and in given cortical or sub-cortical regions of interest. Recent comparative PET-FDG studies performed on schizophrenic patients and healthy control subjects have shown that the pattern of asymmetry in the healthy control groups is R>L, while schizophrenic patients are distinguished by a significant reduction in the R/L quotient with respect to the norm, with inversion of the latter (L > R predominance) in the temporal cortex: frontal and temporal ~ o r t e xbasal ,~ ganglia,6 and thalamus.’ These results have been interpreted as supporting the hypothesis that dysfunction of cerebral symmetry occurs in schizophrenia.’ In the present study, inversion of asymmetry is present in both twins in all the cortical regions of interest, with the exception of the occipital. The study by Gur et al,4in which the metabolic activity in two groups of schizophrenic patients and one healthy control group is compared, a gradient of imbalance towards the left was only observed in the group of patients who, like our two cases, were undergoing their first episode of schizophrenia. We need to address the question as to whether the bias to the left in the metabolic pattern is due to the patient’s left-handedness. Most of the studies reporting anomalies in metabolic asymmetry include only right-handed patients. One exception is that by Siege1 et al,5 who performed a second analysis of the data excluding all left-handed patients, in order to rule out the possibility that they were affecting the final result, and found that, paradoxically enough, the anomalies found were actually heightened. The question as to whether abnormal asymmetry in PET-FDG studies and other functional tests on schizophrenic patients might be related to their handedness, their
223
disease, or both is still open to debate. This has been under discussion ever since the controversial findings by Blokage’ concerning the greater incidence of non-right-handedness among schizophrenic monozygotic twins, a finding which once again lends support to the hypothesis that the origin of schizophrenia is connected with an abnormal lateralization p r o c e s ~ . ~ ~ l ~ Secondly, we would like to emphasize that the highest index of asymmetry was found in the medial and posterior thalamus in both cases (Table 2 and Figure 1). On the one hand, the region where consistent asymmetry with R > L predominance is expected, at least in healthy patients, is in the temporal cortex,” but this is not the case with the thalamus. On the other, our result is in agreement with those of Buchsbaum et al,’ who found that patients had a pattern characterized by less activity in the right thalamic metabolism than in the left, at.the expense of less activity in the right posterior thalamic region. Values of IA>5% in both thalamic regions in twin A are particularly noteworthy. Although no set limit seems to exist at which an index of metabolic asymmetry is considered to become pathological, one PET-FDG study of cases of cortico-basal degeneration takes 5% as being the threshold IA value for disease.12 One complex question is that of the influence of neuroleptic treatment on the cerebral metabolism in general and, in particular, on asymmetries observed in the thalamus. Neuroleptic treatment tends to increase thalamic metabolism in schizophrenic patients.13 However, abnormal asymmetries like those observed in our two cases are not induced by atypical neuroleptic treatment with clozapine and sulpiride. Such asymmetries are also found in untreated schizophrenic patients, and the suggestion has been made that the action of clozapine is precisely that of reducing such asymmetries.6 On the basis of the results of two other studies, it can also be surmised that sulpiride has the same effect on metabolic asymmetries. One of these studies was of pairs of discordant monozygotic twins diagnosed as having schizophrenia, who were found to have an increase in the glucose metabolism, particularly in the left lenticular nucleus. This was observed to be greater in the affected twins than in their healthy ~ib1ings.l~ The other PET-FDG study compared the action of chlorpromazine with that of sulpiride on cerebral metabolism in schizophrenic patients,15 showing that the only effect of sulpiride was to increase metabolism in the right lenticular nucleus. On the basis of these two studies, we tentatively conclude that sulpiride compensates for heightened left metabolic activity (localized in the lenticular nucleus) by increasing that in the contralateral region. In short, like clozapine, this drug may have a corrective effect on the metabolic asymmetry present in the cerebral metabolism of schizophrenic patients. Regarding the differences in intensity between the asymmetries in the two cases, we need to ask what factors may have influenced these and, in particular, whether they are related to psychopathological differences, bearing in mind that, apart from the different neuroleptic treatment
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
224
F Orrutlo et a1
given, there were no differences in interindividual variables (age, sex or handedness) that could affect cerebral metabolic patterns. There are no notable differences in intensity of positive or negative symptoms between these two cases, as their scores on the P, N and PANSS scales are practically identical. On the other hand, their scores on the GP scale differ by 10 points. This suggests the need to look more closely at such cases to identify what other psychopathological variables might be specifically related to the function of the circuits involved in a region in which asymmetry has been detected (in our case, the posterior thalamus). In this study, the most interesting finding is the presence of abnormal asymmetries in this region, since this area plays a major part in theories suggesting the involvement of the striate-thalamic-cortical circuits in schizophrenic pathology. These theories stress the importance of the thalamus in the regulation of entry of sensory and cognitive information to the cortex, and are
backed up by studies indicating the presence of abnormalities in neurosensory selection or information-filtering mechanisms in schizophrenic patients.16
REFERENCES 1. Kay SR, Fizbein A, Opler LA (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bull 13: 261-76. 2. Peralta V, Cuesta M (1994) Validation of Positive and Negative Symptoms Scale (PANSS) in a sample of Spanish schizophrenic patients. Acta Luso Esp Neurol Psiquiatr Ciencias Afnes 22(4): 171-7. 3. Lezak MD (1995) In: Neuropsychological assessment 3rd edn, p. 307. Oxford University Press, Oxford. 4. Gur RE, Mozley D, Resnick SM et a1 (1995) Resting cerebral glucose metabolism in first episode and previously treated patients with schizophrenia relates to clinical features. Arch Gen Psychiatry 52: 657-67. 5. Siege1 BV, Buchsbaum MS, Bunney WE et a1 (1993) Corticalstriatal-thalamic circuits and brain glucose metabolic activity in 70 unrnedicated male schizophrenic patients. Am J Psychiatry 150: 1325- 36. 6. Potkin SG, Buchsbaum MS, Jin Y et a1 (1994) Clorapine effects on glucose metabolic rate in striatum and frontal cortex. Clin Psychiatry 55 (suppl B): 63-6. 7. Buchsbaum MS, Someya T, Teng CY et a1 (1996) PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 153: 191-9. 8. Blokage CE (1977) Schizophrenia, brain asymmetry development and twinning: Cellular relationship with etiological and possibly prognostic implications. Biol Psychiatry 12: 19-35.
9. Lewis SW, Chitkara B, Reveley AM (1989) Hand preference in psychotic twins.Bid Psychiatry 25: 215-21. 10. Torrey EF, Ragland JD, Gold JM et a1 (1993) Handedness in twins with schizophrenia: was Blokage correct? Schizophr Res 9: 83- 5. 11. Loessner A, Alavi A, Lewandrowski KU et a1 (1994) Regional cerebral function determined by FDG-PETin healthy volunteers: Normal patterns and changes with age. J Nucl Med 36: 1141-9. 12. Eidelberg D, Dhawan V, Moeller JR et a1 (1991) The metabolic landscape of cortico-basal ganglionic degeneration: regional asymmetries studied with positron emission tomography. J Neurol Neurosurg Psychiatry 54: 856-62. 13. Resnick SM, Gur RE, Alavi A et a1 (1988) Positron emission tomography and subcortical glucose metabolism in schizophrenia. Psychiatry Res 24: 1- 11. 14. Resnick SM, Gut RE, Torrey EF et a1 (1990) PET-FDG imaging in identical twins discordant for schizophrenia. J Nucl Med 31: 751. 15. Wik G, Wiesel FA, Sjdgren I et a1 (1989) Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography. Psychopharmacology 97: 309 - 18. 16. Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49: 206- 15.
International Journal of Psychiatry in Clinical Practice 1998 Volume 2 Pages 221 -224
221
Abnormal patterns of cerebral glucose metabolism in a pair of monozygotic twins with recent onset schizophrenia F ORTUNOl, J ARBIZU2 AND Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
s CERVERA~ Departments of ’Psychiatry and ’Nuclear Medicine, University Hospital, University of Navarra, Spain
Correspondence Address Dr F OrtuAo, Departamento de Psiquiatria, y Psicologia Mtdica, Clinica Universitaria, 31008 Pamplona, Spain Tel: +34 948 255400 Fax: i 3 4 948 172294 Received 27 October 1997; accepted for publication 27 April 1998
An F-WFDG-PET study of a pair of monozygotic twins with recent-onset schizophrenia revealed a higher index of metabolic asymmetry (JA)in the medial and posterior thalamus in both cases. Some questions regarding the influence of neuroleptic,treatment and handedness on metablic patterns and the role of the thalamus in schizophrenia are discussed in the light of recent studies. (Int J Psych Clin Pruct 1998; 2: 221 - 224)
Keywords schizophrenia thalamus physiopathology
deoxyglucose metabolism twins psychology
INTRODUCTION
MATERIAL AND METHOD
n this paper we report the results of a study of cerebral glucose metabolism (18-D-fluor-deoxyglucose, FDG) conducted using positron emission tomography (PET) in a pair of 18-year-old male monozygotic twins who had been suffering from schizophrenia for some months. One of the twins (twin A) had initially presented a marked delirious paranoid syndrome which had remitted partially at the time when the study was performed. The other (twin B) had less pronounced symptoms from the outset. Following the criteria of ICD-10, the diagnoses were paranoid schizophrenia (twin A) and undifferentiated schizophrenia (twin B). When we performed the PETFDG study, both patients had similar scores on the positive (P) and negative (N)scales of the PANSS; but different ones on the general psychopathology scale (GP). The profiles were predominantly slightly negative (inclusive PANS system).’.’ Both patients were left-handed (or not right-handed) (a hand preference questionnaire’ was used). When the study was performed, both twins were still under treatment: twin A had been takipg clozapine (75 mg/day) for 3 days (treatment with haloperidol had ceased 2 weeks previously); twin B was being treated with sulpiride (up to 150 rnglday).
The PET-FDG study was carried out in resting conditions. The standard uptake values (SUV) of 18 regions of interest in each hemisphere were determined. The index of asymmetry (IA) for each of the 18 regions of interest was then studied: this included the regions on the right and on the left (IA = (L - R) (L+R) x 1001, and both the absolute readings and the values which had been normalized with respect to the occipital were obtained.
I
RESULTS Table 2 shows the results of the SUV (standard uptake values) relative to the occipital of each of the regions of interest, as well as the index of asymmetry. They show a pattern of asymmetry L>R, common to both twins in all the cortical regions with the exception of the occipital. It is also noteworthy that the highest index of asymmetry in both patients was in the medial and posterior thalamus.
DISCUSSION The finding which stands out is the pattern of asymmetry, in which the left is greater than the right (L > R) in all the
222
F OrtuYlo et a1
cortical regions of interest, with the exception of the occipital cortex. This result is consistent with that of
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
Table 1 Patients’ characteristics
Table 2 Values of regions of interest, relative to occipital
IA:asymmetry gradient IA=(L - R)/(L+ R) x 100.
previous studies, which detect a pattern of predominantly left metabolic imbalance in samples of schizophrenic
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
Cerebral glucose metabolism in schizophrenic twins
Figure 1 Axial (above) and coronal (below) PET-FDG slices of twin A (left) and twin B (right) There is less activity in the right posterior thalamic region than in the left in both cases, especially twin A (arrow)
patients, both in overall cerebral metabolic activity and in given cortical or sub-cortical regions of interest. Recent comparative PET-FDG studies performed on schizophrenic patients and healthy control subjects have shown that the pattern of asymmetry in the healthy control groups is R>L, while schizophrenic patients are distinguished by a significant reduction in the R/L quotient with respect to the norm, with inversion of the latter (L > R predominance) in the temporal cortex: frontal and temporal ~ o r t e xbasal ,~ ganglia,6 and thalamus.’ These results have been interpreted as supporting the hypothesis that dysfunction of cerebral symmetry occurs in schizophrenia.’ In the present study, inversion of asymmetry is present in both twins in all the cortical regions of interest, with the exception of the occipital. The study by Gur et al,4in which the metabolic activity in two groups of schizophrenic patients and one healthy control group is compared, a gradient of imbalance towards the left was only observed in the group of patients who, like our two cases, were undergoing their first episode of schizophrenia. We need to address the question as to whether the bias to the left in the metabolic pattern is due to the patient’s left-handedness. Most of the studies reporting anomalies in metabolic asymmetry include only right-handed patients. One exception is that by Siege1 et al,5 who performed a second analysis of the data excluding all left-handed patients, in order to rule out the possibility that they were affecting the final result, and found that, paradoxically enough, the anomalies found were actually heightened. The question as to whether abnormal asymmetry in PET-FDG studies and other functional tests on schizophrenic patients might be related to their handedness, their
223
disease, or both is still open to debate. This has been under discussion ever since the controversial findings by Blokage’ concerning the greater incidence of non-right-handedness among schizophrenic monozygotic twins, a finding which once again lends support to the hypothesis that the origin of schizophrenia is connected with an abnormal lateralization p r o c e s ~ . ~ ~ l ~ Secondly, we would like to emphasize that the highest index of asymmetry was found in the medial and posterior thalamus in both cases (Table 2 and Figure 1). On the one hand, the region where consistent asymmetry with R > L predominance is expected, at least in healthy patients, is in the temporal cortex,” but this is not the case with the thalamus. On the other, our result is in agreement with those of Buchsbaum et al,’ who found that patients had a pattern characterized by less activity in the right thalamic metabolism than in the left, at.the expense of less activity in the right posterior thalamic region. Values of IA>5% in both thalamic regions in twin A are particularly noteworthy. Although no set limit seems to exist at which an index of metabolic asymmetry is considered to become pathological, one PET-FDG study of cases of cortico-basal degeneration takes 5% as being the threshold IA value for disease.12 One complex question is that of the influence of neuroleptic treatment on the cerebral metabolism in general and, in particular, on asymmetries observed in the thalamus. Neuroleptic treatment tends to increase thalamic metabolism in schizophrenic patients.13 However, abnormal asymmetries like those observed in our two cases are not induced by atypical neuroleptic treatment with clozapine and sulpiride. Such asymmetries are also found in untreated schizophrenic patients, and the suggestion has been made that the action of clozapine is precisely that of reducing such asymmetries.6 On the basis of the results of two other studies, it can also be surmised that sulpiride has the same effect on metabolic asymmetries. One of these studies was of pairs of discordant monozygotic twins diagnosed as having schizophrenia, who were found to have an increase in the glucose metabolism, particularly in the left lenticular nucleus. This was observed to be greater in the affected twins than in their healthy ~ib1ings.l~ The other PET-FDG study compared the action of chlorpromazine with that of sulpiride on cerebral metabolism in schizophrenic patients,15 showing that the only effect of sulpiride was to increase metabolism in the right lenticular nucleus. On the basis of these two studies, we tentatively conclude that sulpiride compensates for heightened left metabolic activity (localized in the lenticular nucleus) by increasing that in the contralateral region. In short, like clozapine, this drug may have a corrective effect on the metabolic asymmetry present in the cerebral metabolism of schizophrenic patients. Regarding the differences in intensity between the asymmetries in the two cases, we need to ask what factors may have influenced these and, in particular, whether they are related to psychopathological differences, bearing in mind that, apart from the different neuroleptic treatment
Int J Psych Clin Pract Downloaded from informahealthcare.com by University of California Irvine on 10/30/14 For personal use only.
224
F Orrutlo et a1
given, there were no differences in interindividual variables (age, sex or handedness) that could affect cerebral metabolic patterns. There are no notable differences in intensity of positive or negative symptoms between these two cases, as their scores on the P, N and PANSS scales are practically identical. On the other hand, their scores on the GP scale differ by 10 points. This suggests the need to look more closely at such cases to identify what other psychopathological variables might be specifically related to the function of the circuits involved in a region in which asymmetry has been detected (in our case, the posterior thalamus). In this study, the most interesting finding is the presence of abnormal asymmetries in this region, since this area plays a major part in theories suggesting the involvement of the striate-thalamic-cortical circuits in schizophrenic pathology. These theories stress the importance of the thalamus in the regulation of entry of sensory and cognitive information to the cortex, and are
backed up by studies indicating the presence of abnormalities in neurosensory selection or information-filtering mechanisms in schizophrenic patients.16
REFERENCES 1. Kay SR, Fizbein A, Opler LA (1987) The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bull 13: 261-76. 2. Peralta V, Cuesta M (1994) Validation of Positive and Negative Symptoms Scale (PANSS) in a sample of Spanish schizophrenic patients. Acta Luso Esp Neurol Psiquiatr Ciencias Afnes 22(4): 171-7. 3. Lezak MD (1995) In: Neuropsychological assessment 3rd edn, p. 307. Oxford University Press, Oxford. 4. Gur RE, Mozley D, Resnick SM et a1 (1995) Resting cerebral glucose metabolism in first episode and previously treated patients with schizophrenia relates to clinical features. Arch Gen Psychiatry 52: 657-67. 5. Siege1 BV, Buchsbaum MS, Bunney WE et a1 (1993) Corticalstriatal-thalamic circuits and brain glucose metabolic activity in 70 unrnedicated male schizophrenic patients. Am J Psychiatry 150: 1325- 36. 6. Potkin SG, Buchsbaum MS, Jin Y et a1 (1994) Clorapine effects on glucose metabolic rate in striatum and frontal cortex. Clin Psychiatry 55 (suppl B): 63-6. 7. Buchsbaum MS, Someya T, Teng CY et a1 (1996) PET and MRI of the thalamus in never-medicated patients with schizophrenia. Am J Psychiatry 153: 191-9. 8. Blokage CE (1977) Schizophrenia, brain asymmetry development and twinning: Cellular relationship with etiological and possibly prognostic implications. Biol Psychiatry 12: 19-35.
9. Lewis SW, Chitkara B, Reveley AM (1989) Hand preference in psychotic twins.Bid Psychiatry 25: 215-21. 10. Torrey EF, Ragland JD, Gold JM et a1 (1993) Handedness in twins with schizophrenia: was Blokage correct? Schizophr Res 9: 83- 5. 11. Loessner A, Alavi A, Lewandrowski KU et a1 (1994) Regional cerebral function determined by FDG-PETin healthy volunteers: Normal patterns and changes with age. J Nucl Med 36: 1141-9. 12. Eidelberg D, Dhawan V, Moeller JR et a1 (1991) The metabolic landscape of cortico-basal ganglionic degeneration: regional asymmetries studied with positron emission tomography. J Neurol Neurosurg Psychiatry 54: 856-62. 13. Resnick SM, Gur RE, Alavi A et a1 (1988) Positron emission tomography and subcortical glucose metabolism in schizophrenia. Psychiatry Res 24: 1- 11. 14. Resnick SM, Gut RE, Torrey EF et a1 (1990) PET-FDG imaging in identical twins discordant for schizophrenia. J Nucl Med 31: 751. 15. Wik G, Wiesel FA, Sjdgren I et a1 (1989) Effects of sulpiride and chlorpromazine on regional cerebral glucose metabolism in schizophrenic patients as determined by positron emission tomography. Psychopharmacology 97: 309 - 18. 16. Braff DL, Grillon C, Geyer MA (1992) Gating and habituation of the startle reflex in schizophrenic patients. Arch Gen Psychiatry 49: 206- 15.
