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Brain structure changes across the lifespan of schizophrenia: Excessive gray matter changes in schizophrenia
X19. Neurodevelopmental
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Brain structure changes across the lifespan of schizophrenia: Excessive gray matter changes in schizophrenia
H.E. Hulshoff Pol, R.S. Kahn. Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, The Netherlands Schizophrenia is a chronic psychiatric disorder affecting approximately 1% of populations around the world. Its symptoms include hallucinations, delusions, disorganized speech, disorganized behavior, abnormal or stereotyped movements, flattened affect, anhedonia, and cognitive impairments. In the majority of patients, schizophrenia is characterized by a progressive decline in emotional and social functioning. Although its cause is unknown, numerous Iindings from imaging studies strongly support the view that schizophrenia is a brain disease particularly involving decrements in gray matter. Global gray matter volume decreases of approximately 2% have been reported in schizophrenia. However, results from a recent meta-analysis of volumetric magnetic resonance imaging studies in schizophrenia also suggest that changes may be more prominent in some brain areas than others (Wright et al, 2000). Indeed, relative to the cerebral volume differences, volume decreases up to 6% have been reported in the amygdala and hippocampal complex. Findings from studies using statistical analysis of images on a voxel-by-voxel basis predominantly suggest involvement of the thalamus and prefrontal-thalamic-cerebellar circuitry, and structural changes in the temporal pole, insula, amygdala and dorsolateral prefrontal cortex in schizophrenia. However, diffuse gray (and white) matter abnormalities have also been suggested. Recent evidence suggests that the decreases in gray matter volume may be progressive over the course of the illness in schizophrenia (Mathalon et al, 2001). We completed a crosssectional magnetic resonance imaging study in 159 patients with schizophrenia and 158 healthy subjects and found that the older patients with schizophrenia had proportionally more gray matter volume decrease as compared to the younger patients. However. it is not known whether the excessive gray matter loss in schizophrenia affects the gray matter globally or whether some areas show more progressive decrease than other areas. Therefore, we analyzed focal gray matter density across the 55-year time-span in these same subjects, using a voxel-based method. Its aim was to determine whether changes in gray matter density become more prominent with age in schizophrenia. A linear regression analysis was performed through all brains for each voxel separately, covarying for sex, and handedness. The critical threshold t-value for a 2-tailed alpha significance level of p <: 0.05 after correcting for multiple comparisons according to random field theory was kl > 5.0. Its main Iinding was that distinct focal areas in the brains of patients with schizophrenia display decreased gray matter density, including the left amygdala and left hippocampus, and the thalamus, (orbito) frontal, temporal, precuneus, cingulate, and insular gyri bilaterally. Moreover, left amygdala density was more pronounced in the older than in the younger schizophrenic patients. Other areas that displayed more prominent age-related decreases in gray matter density in schizophrenia - albeit not significant - were found in the hippocampus, thalamus, lateral orbit0 and inferior frontal, subcallosal, and superior temporal gyri on the left, and in the right medial temporal and inferior
issues in schizophrenia
s151
parietal gyri. These findings could not be explained by age at onset, outcome, neuroleptic medication at the time of the scan, changes in gray matter density variation with age, or by time of measurement effects. Significant changes in gray matter density were found in brain regions that were previously reported to be altered in volume in schizophrenia. The primarily leftsided involvement of the medial temporal area is in agreement with earlier Endings suggesting decreased hemispheric dominance with predominantly leftsided brain involvement in schizophrenia. The more prominent decrease in left amygdala density in older as compared to younger schizophrenic patients suggests a loss of gray matter in this limbic brain region over the course of the illness. In healthy subjects no changes with age were found in the amygdala - which is consistent with earlier findings suggesting that the volume of the amygdala starts to decrease only after the age of 60. Since the amygdala has particularly widespread anatomical projections to the lateral orbitofrontal gyri and hippocampus as well as to the medial orbitofrontal gyri, insula, temporal pole, and medial dorsal nucleus of the thalamus - while receiving extensive sensory input from the neocortex, our findings may suggest that a circuit involving the amygdala and its projection areas show (progressive) changes in schizophrenia. Involvement of the amygdala in schizophrenia would be consistent with its central role in emotional and social behavior, both of which are disturbed in schizophrenia. The amygdala represents an important route by which external stimuli can influence and activate emotions. It has been suggested that the amygdala enables the formation of stimulus-reward associations, and that these associations help to establish the emotional significance of external events, including social actions. Whether the excessive age-related decreases in the amygdala and connected brain structures are related to the genetic risk to develop schizophrenia or are related to (neurodegenerative) processes that are non-genetic in origin remains to be established in future studies. Smaller intracranial volumes in monozygotic patients and their cotwins suggested that increased genetic risk to develop schizophrenia is related to reduced brain growth early in life. Additional whole-brain volume loss was found in the patients, irrespective of zygosity, suggesting involvement of non-genetic processes (Baare et al, 2001). Indeed, stunted brain development secondary to factors that affect brain growth during the tirst trimester of gestation may also be a potential risk factor for developing schizophrenia (Hulshoff Pol et al, 2000). Since gray matter volumes increase during childhood and then decrease before adulthood, with different areas changing at different rates per year (for review see Durston et al, 2001), involvement of developmental processes occuring during childhood may also be of influence on the (focal) changes in gray matter volume in schizophrenia.
References
PI Baare WFC, van Oel CJ, Hulshoff Pol BE, et al, 2001. Arch Gen Psychiatry
5, 3340.
121 Durston S, Hulshoff Pol HE, Casey BJ, et al, 2001. Am J Child Adolescent Psychiatry, in press.
I31 Hulshoff Pol HE, Hoek HW, Susser E, et al, 2000. Am 3 Psychiatry 157, 1170-l 172.
[41 Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A, 2001. Arch Gen Psychiatry 58, 148-57.
[51 Wright IC, Rabe-Hesketh S, Woodruff PW, et al, 2000. Am J Psychiatry 157, 16-25.
-1
Brain structure changes across the lifespan of schizophrenia: Excessive gray matter changes in schizophrenia
H.E. Hulshoff Pol, R.S. Kahn. Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, The Netherlands Schizophrenia is a chronic psychiatric disorder affecting approximately 1% of populations around the world. Its symptoms include hallucinations, delusions, disorganized speech, disorganized behavior, abnormal or stereotyped movements, flattened affect, anhedonia, and cognitive impairments. In the majority of patients, schizophrenia is characterized by a progressive decline in emotional and social functioning. Although its cause is unknown, numerous Iindings from imaging studies strongly support the view that schizophrenia is a brain disease particularly involving decrements in gray matter. Global gray matter volume decreases of approximately 2% have been reported in schizophrenia. However, results from a recent meta-analysis of volumetric magnetic resonance imaging studies in schizophrenia also suggest that changes may be more prominent in some brain areas than others (Wright et al, 2000). Indeed, relative to the cerebral volume differences, volume decreases up to 6% have been reported in the amygdala and hippocampal complex. Findings from studies using statistical analysis of images on a voxel-by-voxel basis predominantly suggest involvement of the thalamus and prefrontal-thalamic-cerebellar circuitry, and structural changes in the temporal pole, insula, amygdala and dorsolateral prefrontal cortex in schizophrenia. However, diffuse gray (and white) matter abnormalities have also been suggested. Recent evidence suggests that the decreases in gray matter volume may be progressive over the course of the illness in schizophrenia (Mathalon et al, 2001). We completed a crosssectional magnetic resonance imaging study in 159 patients with schizophrenia and 158 healthy subjects and found that the older patients with schizophrenia had proportionally more gray matter volume decrease as compared to the younger patients. However. it is not known whether the excessive gray matter loss in schizophrenia affects the gray matter globally or whether some areas show more progressive decrease than other areas. Therefore, we analyzed focal gray matter density across the 55-year time-span in these same subjects, using a voxel-based method. Its aim was to determine whether changes in gray matter density become more prominent with age in schizophrenia. A linear regression analysis was performed through all brains for each voxel separately, covarying for sex, and handedness. The critical threshold t-value for a 2-tailed alpha significance level of p <: 0.05 after correcting for multiple comparisons according to random field theory was kl > 5.0. Its main Iinding was that distinct focal areas in the brains of patients with schizophrenia display decreased gray matter density, including the left amygdala and left hippocampus, and the thalamus, (orbito) frontal, temporal, precuneus, cingulate, and insular gyri bilaterally. Moreover, left amygdala density was more pronounced in the older than in the younger schizophrenic patients. Other areas that displayed more prominent age-related decreases in gray matter density in schizophrenia - albeit not significant - were found in the hippocampus, thalamus, lateral orbit0 and inferior frontal, subcallosal, and superior temporal gyri on the left, and in the right medial temporal and inferior
issues in schizophrenia
s151
parietal gyri. These findings could not be explained by age at onset, outcome, neuroleptic medication at the time of the scan, changes in gray matter density variation with age, or by time of measurement effects. Significant changes in gray matter density were found in brain regions that were previously reported to be altered in volume in schizophrenia. The primarily leftsided involvement of the medial temporal area is in agreement with earlier Endings suggesting decreased hemispheric dominance with predominantly leftsided brain involvement in schizophrenia. The more prominent decrease in left amygdala density in older as compared to younger schizophrenic patients suggests a loss of gray matter in this limbic brain region over the course of the illness. In healthy subjects no changes with age were found in the amygdala - which is consistent with earlier findings suggesting that the volume of the amygdala starts to decrease only after the age of 60. Since the amygdala has particularly widespread anatomical projections to the lateral orbitofrontal gyri and hippocampus as well as to the medial orbitofrontal gyri, insula, temporal pole, and medial dorsal nucleus of the thalamus - while receiving extensive sensory input from the neocortex, our findings may suggest that a circuit involving the amygdala and its projection areas show (progressive) changes in schizophrenia. Involvement of the amygdala in schizophrenia would be consistent with its central role in emotional and social behavior, both of which are disturbed in schizophrenia. The amygdala represents an important route by which external stimuli can influence and activate emotions. It has been suggested that the amygdala enables the formation of stimulus-reward associations, and that these associations help to establish the emotional significance of external events, including social actions. Whether the excessive age-related decreases in the amygdala and connected brain structures are related to the genetic risk to develop schizophrenia or are related to (neurodegenerative) processes that are non-genetic in origin remains to be established in future studies. Smaller intracranial volumes in monozygotic patients and their cotwins suggested that increased genetic risk to develop schizophrenia is related to reduced brain growth early in life. Additional whole-brain volume loss was found in the patients, irrespective of zygosity, suggesting involvement of non-genetic processes (Baare et al, 2001). Indeed, stunted brain development secondary to factors that affect brain growth during the tirst trimester of gestation may also be a potential risk factor for developing schizophrenia (Hulshoff Pol et al, 2000). Since gray matter volumes increase during childhood and then decrease before adulthood, with different areas changing at different rates per year (for review see Durston et al, 2001), involvement of developmental processes occuring during childhood may also be of influence on the (focal) changes in gray matter volume in schizophrenia.
References
PI Baare WFC, van Oel CJ, Hulshoff Pol BE, et al, 2001. Arch Gen Psychiatry
5, 3340.
121 Durston S, Hulshoff Pol HE, Casey BJ, et al, 2001. Am J Child Adolescent Psychiatry, in press.
I31 Hulshoff Pol HE, Hoek HW, Susser E, et al, 2000. Am 3 Psychiatry 157, 1170-l 172.
[41 Mathalon DH, Sullivan EV, Lim KO, Pfefferbaum A, 2001. Arch Gen Psychiatry 58, 148-57.
[51 Wright IC, Rabe-Hesketh S, Woodruff PW, et al, 2000. Am J Psychiatry 157, 16-25.