- Email: [email protected]
Diffusion Tensor Imaging Study of the Anterior Limb of Internal Capsules in Neuroleptic-Naive Schizophrenia
Diffusion Tensor Imaging Study of the Anterior Limb of Internal Capsules in Neuroleptic-Naive Schizophrenia1 Li-qiu Zou, Hui-shu Yuan, Xin-long Pei, Wen-tian Dong, Peng-cheng Liu, Jing-xia Xie
Rationale and Objectives. Abnormalities in brain structure have been implicated in psychosis. Herein, we investigated the differences in fractional anisotropy (FA) and average diffusion coefficient (ADC) in the bilateral anterior limb of internal capsules between neuroleptic-naive schizophrenic patients and appropriately matched healthy controls. Materials and Methods. Magnetic resonance imaging was performed with a 1.5 T superconductive MR scanner, and diffusion tensor imaging was carried out in 21 neuroleptic-naive schizophrenic patients and 18 matched healthy controls. FA and ADC were measured by region of interest analysis. Results. Compared with healthy controls, the neuroleptic-naive schizophrenic patients showed significantly reduced FA in the bilateral anterior limb of the internal capsule. However, the difference in the ADC values between the patients and the controls was not significant. Conclusions. FA of the bilateral anterior limb of the internal capsule was reduced in neuroleptic-naive schizophrenic patients, indicating that the integrity of the white matter of the bilateral thalamus-frontal connection or the bilateral thalamus-anterior cingulate gyrus connection was destroyed. Key Words. Schizophrenia; diffusion tensor imaging; the anterior limb of internal capsule. ©
AUR, 2008
Schizophrenia is a common severe mental disorder mainly characterized by disordered thought, emotion, behavior, and will, and a disharmony between the self and environment. It has an estimated annual incidence of 0.11 in China (1). Schizophrenia is accompanied by a very high disability rate, and most patients are unable to engage in employment or educational pursuits, and are thus a burden to both the society and their families. Thus far, the
Acad Radiol 2008; 15:285–289 1
Department of Radiology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100083, P.R. China (L.-Q.Z., H.-S.Y., X.-L.P., J.-X.X.); Peking University Sixth Hospital, Beijing, P.R. China (W.-T.D.); Peking University Shenzhen Hospital, Beijing, P.R. China (P.-C.L). Received August 31, 2007; accepted September 26, 2007. Address correspondence to: H.S.Y. e-mail: [email protected]
© AUR, 2008 doi:10.1016/j.acra.2007.09.026
etiologic factors in schizophrenia have not been completely delineated. Thus exploring the etiologic factors and understanding the exact pathomechanism of schizophrenia are challenges for the clinicians and researchers of mental health departments. An increasing number of studies have suggested that the clinical symptoms of schizophrenia may not result from the impaired function of some part of the brain, but an abnormal connection between cerebral neurons. The presence of cerebral structural abnormalities in schizophrenia has been confirmed, and a large number of encephalic regions are affected, many of which are closely associated with cognitive function. Microstructural abnormalities in the white matter fiber bundle interconnecting these encephalic regions could also cause schizophrenia that is characterized by a widely distributed disconnection of cerebral circuits (2,3). Today, with the development of
285
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Academic Radiology, Vol 15, No 3, March 2008
Table 1 Parameters of the Consequence Scanning Sequence
T1WI SE
T2WI TSE
FLAIR
DTI EPI
Scanning position TR/TE (ms) TI (ms) FOV (mm) Slice thickness (mm) Slice spacing (mm) Scanning time (min)
Axial view 450/7.7 — 220 ⫻ 220 5 1 3.54
Axial view 4630/95 — 230 ⫻ 183 5 1 3.02
Axial view 9000/108 2500 220 ⫻ 220 5 1 3.38
Axial view 2000/40 — 220 ⫻ 220 3 1 3.18
SE, spin echo; TSE, turbo spin echo; FLAIR, fluid attenuated inversion recovery; DTI, diffusion tensor imaging; TR, repetition time; TE, echo time; FOV, field of view.
magnetic resonance imaging (MRI) technology, diffusion tensor imaging (DTI) has become the primary method for studying the microstructure of the white matter in schizophrenia. By using DTI, this study aims to quantitatively explore the difference between the fractional anisotropy (FA) value and the average diffusion coefficient (ADC) value of the microstructure of the anterior limb of the internal capsule (ALIC) interconnecting the frontal lobes and the anterior cingulate gyrus with the thalamus and to further investigate the pathomechanism of schizophrenia.
MATERIALS AND METHODS Clinical Materials Subjects: schizophrenia group.—This group comprised inpatients with schizophrenia between April 2005 and April 2006. The inclusion criteria were as follows: 1) ICD-10 and DSM-IV diagnostic criteria for schizophrenia paranoid type satisfied; 2) age ranging from 18 to 50 and course of disease not more than 5 years; 3) no previous use of antipsychotics or treatment with antipsychotics stopped for more than five half-lives before inclusion; 4) capable of undergoing the examination; and 5) right handedness. The exclusion criteria were as follows: 1) history of electric shock; 2) history of chronic nervous system diseases or serious physiologic diseases; 3) history of alcohol or illegal substances abuse; 4) psychoactive substance abuse or dependence; or 5) mental retardation, nervous system disease, or other diseases that may affect cerebral structure or function. Of the 29 inpatients, 7 did not complete the examination (2 because of head movement and 5 because of failure to cooperate) and 1 with cerebral disease was excluded; the remaining 21 patients (13 males and 8 females) had a mean age of 29 ⫾ 10 years.
286
Subjects: control group.—This group comprised 18 age- and sex-matched volunteers with right handedness (11 males and 7 females) with a mean age of 31 ⫾ 10 years. MRI Examination Equipment and Sequence MRI was performed with a 1.5 T superconductive MR scanner (Sonata Siemens, Germany), with a standard birdcage-style head coil. Subjects lay on their back and kept still during scanning. Their heads were fixed to decrease head movement; they wore ear plugs and earphones to decrease the interference due to the scanner noise. A head MRI scan was performed for the schizophrenia and control groups. For axial T1-weighted imaging, T2-weighted imaging, fluid attenuated inversion recovery sequence, and DTI, the scanning slices were parallel to the anteroposterior commissure line (AC-PC line) and the scanning range was set from the medulla oblongata to the roof of the skull. Two diffusion-weighted DTI sequence maps were generated with a voxel size of 1.6 ⫻ 1.6 ⫻ 3.0 mm and b values of 0 and 1000 s/mm2; 12 gradient magnetic fields sensitive to diffusion were applied in three-dimensional space. The consequence parameters are listed in Table 1. DTI Image Processing and Analysis The initial diffusion tensor data obtained was inputted in a PC, and the image was processed by the software Dtistudio (http://lbam.med.jhme.edu/DTIuser.asp version 2.4); the ADC map, FA map, and color map were rebuilt, which represent the characteristic vectors of water molecular diffusion (green represents the characteristic vector of the anteroposterior course; red, left-right; and blue, superoinferior), and nerve fibers with different courses were differently colored. This enabled easy identification of
Academic Radiology, Vol 15, No 3, March 2008
DTI OF THE ALIC IN NEUROLEPTIC-NAIVE SCHIZOPHRENIA
Figure 1. Color map, fractional anisotropy map, and average diffusion coefficient map of the anterior limb of the internal capsule of the control group (upper row) and schizophrenia group (lower row).
these fibers and was helpful in determining the exact location of the region of interest. The ALIC connects the thalamus and prefrontal lobe, walks in the anteroposterior course, and was colored green in Fig 1. Two main slices at the cross-section were chosen for measurements; the superior and inferior marginal slices were excluded to avoid the partial volume effect, and the anterior boundary was at the intersection between anterior limbs of the external and internal capsules, whereas the posterior boundary was at the level of the genu of the internal capsule. An region of interest with 2 ⫻ 2 pixels was used, and the mean FA and ADC values of 20 –24 pixels of each slice and each side were measured and recorded. The FA and ADC values of the bilateral ALIC were obtained from the schizophrenia and control groups, and eight groups of data were obtained in all. A group t-test (two-tail) and the statistical software SPSS 11.0 were used in statistical analysis. RESULT The FA and ADC values of the bilateral ALIC of the control group and schizophrenia group are listed in Table 2. 1. The mean FA values of the left and right ALIC of the 18 patients in the control group were 0.626 ⫾
Table 2 The FA and ADC Values of the Bilateral ALIC ALIC
Schizophrenia group (21) Left side Right side Control group (18) Left side Right side
FA Value
ADC Value (⫻10–4 mm2/s)
0.598 ⫾ 0.041 0.611 ⫾ 0.041
7.292 ⫾ 0.362 7.299 ⫾ 0.306
0.626 ⫾ 0.033 0.650 ⫾ 0.057
7.073 ⫾ 0.543 7.147 ⫾ 0.642
FA, fractional anisotropy; ADC, average diffusion coefficient; ALIC, anterior limb of the internal capsule.
0.033 and 0.650 ⫾ 0.057, respectively, and no significant statistical difference was observed with the t-test (t ⫽ 1.534, P ⬎ .05, bilateral 95% confidence interval). The mean left and right ADC values were (7.073 ⫾ 0.543) ⫻ 10⫺4 mm2/second and (7.147 ⫾ 0.642) ⫻ 10⫺4 mm2/second, respectively, and there is no significant statistical difference between them. 2. The mean FA values of the left and right ALIC of the 21 patients of the schizophrenia group were 0.598 ⫾ 0.041 and 0.611 ⫾ 0.041, respectively, and no significant statistical difference was observed with the t-test (t ⫽ 0.968, P ⬎ .05, bilateral 95%
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ZOU ET AL
confidence interval). The mean left and right ADC values were (7.292 ⫾ 0.363) ⫻ 10⫺4 mm2/second, and (7.299 ⫾ 0.305) ⫻ 10⫺4 mm2/second, respectively, and there is no significant statistical difference between them (t ⫽ ⫺0.064, P ⬎ .05, bilateral 95% confidence interval). The mean FA and ADC values of the left and right ALIC of the schizophrenia group and control group were compared. An independent group t-test was used with bilateral 95% confidence interval, and the left ALIC (t ⫽ ⫺2.292, P ⬍ .05) and right ALIC FA (t ⫽ ⫺2.183, P ⬍ .05) values were obtained. The FA values of the left and right ALIC of both groups were statistically significant, and the mean FA value of the schizophrenia group was lower than that of the control group; however, no significant statistical difference was observed in the ADC values of the left and right ALIC between the schizophrenia group and control group.
DISCUSSION Schizophrenia is considered to be a disease caused by an abnormality in the interconnection between neurons of different encephalic regions and is characterized by a widely distributed disconnection of cerebral circuits (2,3); thus, some clinical symptoms and cognitive defects of schizophrenia can be explained. The possibility of the existence of microscopic pathologic changes in the nerve fiber bundles of schizophrenia patients needs to be examined. The thalamus-cortical pathway walks in the ALIC is the final common pathway of the high-grade cognition feedback loop, and connects the frontal lobe, the anterior part of the cingulate gyrus, and thalamus. Damaged white matter fiber bundles in the ALIC cause functional disconnection in this feedback loop, resulting in abnormal symptoms related to behavior and intelligence observed in schizophrenia patients. The diffusion of water molecules in the white matter is affected by the macroscopic and ultramicroscopic structures of nerve fibers, such as the cell envelope and cytoskeleton. Changes in neuraxial density, water capacity, and myelinization degree also affect white matter anisotropy. DTI is a new technique in the field of nuclear magnetic resonance that has been developed in recent decades. Developed from diffusion imaging, DTI is a
288
Academic Radiology, Vol 15, No 3, March 2008
method of studying the diffusion movement of water molecules in living tissues; it can appraise the intactness of the living microstructure of the white matter without invasion, and provide a new approach for the study of white matter destruction in early schizophrenia. Since it was proposed by Basser in 1994, DTI has been widely used in animal experiments and clinical studies, such as the simulation of diffuse axonal injury in animal brain and studies on myelin sheath development in normal infants, leukodystrophy in children, multiple sclerosis, cerebral apoplexy, brain tumor, cerebral trauma, and mental diseases; it can not only reveal the pathologic changes that remain undetected by MRI, but can also generate a three-dimensional image of a nerve fiber’s course. As confirmed by a large number of studies, cognitive dysmetria in schizophrenia may result from disconnection among the neural circuits but not due to damage in a single region. The prefrontal lobe is the center of higher cognitive function and it is the central executive system of working memory; its dysfunction has been considered as the primary feature of schizophrenia, and structural abnormalities in the frontal lobe of schizophrenia patients have been confirmed by multiple neuroimaging and autopsy studies. The thalamus is the relay station mediating information from the cortex and limbic system as well as the gating filter of the sensory conductive pathway; it participates in the processing of attention and information. These functions derive from the thalamic ventral anterior nucleus and dorsomedial nucleus, prefrontal lobe, and thalamuscortex-thalamus circuit. The frontal thalamic peduncle and the fibrae corticothalamicae connecting the prefrontal lobe with the thalamus walk in the ALIC; the frontal thalamic peduncle connects the mediodorsal and the anterior thalamic nucleus with the frontal lobe. Cortical projections and the cingulate gyrus are also connected by the frontal thalamic peduncle; this further supports the hypothesis of an abnormal ALIC (connection between frontal lobe and thalamus) in schizophrenia. With regard to functional neuroanatomy, the ALIC includes two limbic circuits: the inner limbic circuit (consisting of the hippocampal formation, mamillary body, nuclei anteriores thalami, and cingulate gyrus) and the bottom-lateral limbic circuit (interconnected by the orbitofrontal cortex, nuclei thalami medialis, amygdala, and the anterior part of the temporal lobe). A structural defect in the ALIC may result in the disruption of these circuits and a functional disconnection between the temporal lobe and prefrontal lobe (these circuits are also required for a
Academic Radiology, Vol 15, No 3, March 2008
DTI OF THE ALIC IN NEUROLEPTIC-NAIVE SCHIZOPHRENIA
partial connection between the temporal lobe and prefrontal lobe) (4). Wang (5) discovered a decreased FA value in the anterior region of the cingulate fasciculus in schizophrenia by DTI. Zhou et al (6) have discovered a decrease in the volume of the bilateral ALIC in chronic schizophrenia. In addition, it has been confirmed that there is a structural and functional abnormality in the regions connected by the ALIC (7–9), and as reported by Lang (10), the volume of the bilateral ALIC in neuroleptic-naïve schizophrenia patients are decreased; this indicates that a volume abnormality in the ALIC already existed in the early period of the disease. The infusion status of the internal capsule has been measured by different methods; different results have been obtained. For example, Buchsbaum (11) et al discovered decreased anisotropy of diffusion in the internal capsule in schizophrenia patients, whereas no abnormality in internal capsule diffusion was observed by Agartz (12) and Foong (13) et al. However, most subjects were chronic schizophrenia patients who had undergone treatment and showed stable pathogenesis. In this study, schizophrenia patients who had never been medicated were selected; this eliminated the effects of drugs on water molecular diffusion in the ALIC. Schizophrenia patients who had not taken drugs in the past 5 years were selected as the subjects of the study. The small region of interest method was used to measure the FA values and ADC values of the ALIC in neuroleptic-naive schizophrenic patients and the matched healthy control group. The FA values of the bilateral ALIC in schizophrenic patients were significantly lower than those of the control group; this indicates that an abnormality in water infusion in the white matter exists in the bilateral ALIC even during the early period of pathologic changes. However, there is no significant difference in the ADC values of the bilateral ALIC between schizophrenia pa-
tients and control patients; this indicates that FA is more sensitive than ADC. The use of DTI to study the interconnection among cortical neurons (intactness of white matter) in schizophrenia is still in an initial stage; however, this technique can help us understand the clinical symptoms and the pathogenesis of mental diseases in further detail. REFERENCES 1. Shen YC, Chen CH, Zhang WX. The methodology and material analysis of the epidemiological investigation of chinese mental disorder in 12 areas. Chin J Neurol 1986; 19:65– 69. 2. Niznikiewicz M, Donnino R, McCarley RW, et al. Abnormal angular gyrus asymmetry in schizophrenia. Am J Psychiatry 2000; 157:428 – 437. 3. Nopoulos PC, Ceilley JW, Gailis EA, et al. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry 1999; 46:703–711. 4. Lawrie SM, Buechel C, Whalley HC, et al. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002; 51:1008 –1011. 5. Wang F, Sun Z, Cui L, et al. Anterior cingulum abnormalities in male patients with schizophrenia determined through diffusion tensor imaging. Am J Psychiatry 2004; 161:573–575. 6. Zhou SY, Suzuki M, Hagino H, et al. Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia. Biol Psychiatry 2003; 54:427– 436. 7. Buchanan RW, Vladar K, Barta PE, et al. Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 1998; 155:1049 – 1055. 8. Byne W, Buchsbaum MS, Kemether E, et al. Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 2001; 58:133–140. 9. Takahashi T, Suzuki M, Kawasaki Y, et al. Volumetric magnetic resonance imaging study of the anterior cingulate gyrus in schizotypal disorder. Eur Arch Psychiatry Clin Neurosci 2002; 252:268 –277. 10. Lang DJ, Kopala LC, Vandorpe RA, et al. Reduced basal ganglia volumes after switching to olanzapine in chronically treated patients with schizophrenia. Am J Psychiatry 2004; 161:1829 –1836. 11. Buchsbaum MS, Tang CY, Peled S, et al. MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998; 9:425– 430. 12. Agartz I, Andersson JL, Skare S. Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. Neuroreport 2001; 12:2251–2254. 13. Foong J, Symms MR, Barker GJ, et al. Investigating regional white matter in schizophrenia using diffusion tensor imaging. Neuroreport 2002; 13:333–336.
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Rationale and Objectives. Abnormalities in brain structure have been implicated in psychosis. Herein, we investigated the differences in fractional anisotropy (FA) and average diffusion coefficient (ADC) in the bilateral anterior limb of internal capsules between neuroleptic-naive schizophrenic patients and appropriately matched healthy controls. Materials and Methods. Magnetic resonance imaging was performed with a 1.5 T superconductive MR scanner, and diffusion tensor imaging was carried out in 21 neuroleptic-naive schizophrenic patients and 18 matched healthy controls. FA and ADC were measured by region of interest analysis. Results. Compared with healthy controls, the neuroleptic-naive schizophrenic patients showed significantly reduced FA in the bilateral anterior limb of the internal capsule. However, the difference in the ADC values between the patients and the controls was not significant. Conclusions. FA of the bilateral anterior limb of the internal capsule was reduced in neuroleptic-naive schizophrenic patients, indicating that the integrity of the white matter of the bilateral thalamus-frontal connection or the bilateral thalamus-anterior cingulate gyrus connection was destroyed. Key Words. Schizophrenia; diffusion tensor imaging; the anterior limb of internal capsule. ©
AUR, 2008
Schizophrenia is a common severe mental disorder mainly characterized by disordered thought, emotion, behavior, and will, and a disharmony between the self and environment. It has an estimated annual incidence of 0.11 in China (1). Schizophrenia is accompanied by a very high disability rate, and most patients are unable to engage in employment or educational pursuits, and are thus a burden to both the society and their families. Thus far, the
Acad Radiol 2008; 15:285–289 1
Department of Radiology, Peking University Third Hospital, 49 North Garden Road, Haidian District, Beijing 100083, P.R. China (L.-Q.Z., H.-S.Y., X.-L.P., J.-X.X.); Peking University Sixth Hospital, Beijing, P.R. China (W.-T.D.); Peking University Shenzhen Hospital, Beijing, P.R. China (P.-C.L). Received August 31, 2007; accepted September 26, 2007. Address correspondence to: H.S.Y. e-mail: [email protected]
© AUR, 2008 doi:10.1016/j.acra.2007.09.026
etiologic factors in schizophrenia have not been completely delineated. Thus exploring the etiologic factors and understanding the exact pathomechanism of schizophrenia are challenges for the clinicians and researchers of mental health departments. An increasing number of studies have suggested that the clinical symptoms of schizophrenia may not result from the impaired function of some part of the brain, but an abnormal connection between cerebral neurons. The presence of cerebral structural abnormalities in schizophrenia has been confirmed, and a large number of encephalic regions are affected, many of which are closely associated with cognitive function. Microstructural abnormalities in the white matter fiber bundle interconnecting these encephalic regions could also cause schizophrenia that is characterized by a widely distributed disconnection of cerebral circuits (2,3). Today, with the development of
285
ZOU ET AL
Academic Radiology, Vol 15, No 3, March 2008
Table 1 Parameters of the Consequence Scanning Sequence
T1WI SE
T2WI TSE
FLAIR
DTI EPI
Scanning position TR/TE (ms) TI (ms) FOV (mm) Slice thickness (mm) Slice spacing (mm) Scanning time (min)
Axial view 450/7.7 — 220 ⫻ 220 5 1 3.54
Axial view 4630/95 — 230 ⫻ 183 5 1 3.02
Axial view 9000/108 2500 220 ⫻ 220 5 1 3.38
Axial view 2000/40 — 220 ⫻ 220 3 1 3.18
SE, spin echo; TSE, turbo spin echo; FLAIR, fluid attenuated inversion recovery; DTI, diffusion tensor imaging; TR, repetition time; TE, echo time; FOV, field of view.
magnetic resonance imaging (MRI) technology, diffusion tensor imaging (DTI) has become the primary method for studying the microstructure of the white matter in schizophrenia. By using DTI, this study aims to quantitatively explore the difference between the fractional anisotropy (FA) value and the average diffusion coefficient (ADC) value of the microstructure of the anterior limb of the internal capsule (ALIC) interconnecting the frontal lobes and the anterior cingulate gyrus with the thalamus and to further investigate the pathomechanism of schizophrenia.
MATERIALS AND METHODS Clinical Materials Subjects: schizophrenia group.—This group comprised inpatients with schizophrenia between April 2005 and April 2006. The inclusion criteria were as follows: 1) ICD-10 and DSM-IV diagnostic criteria for schizophrenia paranoid type satisfied; 2) age ranging from 18 to 50 and course of disease not more than 5 years; 3) no previous use of antipsychotics or treatment with antipsychotics stopped for more than five half-lives before inclusion; 4) capable of undergoing the examination; and 5) right handedness. The exclusion criteria were as follows: 1) history of electric shock; 2) history of chronic nervous system diseases or serious physiologic diseases; 3) history of alcohol or illegal substances abuse; 4) psychoactive substance abuse or dependence; or 5) mental retardation, nervous system disease, or other diseases that may affect cerebral structure or function. Of the 29 inpatients, 7 did not complete the examination (2 because of head movement and 5 because of failure to cooperate) and 1 with cerebral disease was excluded; the remaining 21 patients (13 males and 8 females) had a mean age of 29 ⫾ 10 years.
286
Subjects: control group.—This group comprised 18 age- and sex-matched volunteers with right handedness (11 males and 7 females) with a mean age of 31 ⫾ 10 years. MRI Examination Equipment and Sequence MRI was performed with a 1.5 T superconductive MR scanner (Sonata Siemens, Germany), with a standard birdcage-style head coil. Subjects lay on their back and kept still during scanning. Their heads were fixed to decrease head movement; they wore ear plugs and earphones to decrease the interference due to the scanner noise. A head MRI scan was performed for the schizophrenia and control groups. For axial T1-weighted imaging, T2-weighted imaging, fluid attenuated inversion recovery sequence, and DTI, the scanning slices were parallel to the anteroposterior commissure line (AC-PC line) and the scanning range was set from the medulla oblongata to the roof of the skull. Two diffusion-weighted DTI sequence maps were generated with a voxel size of 1.6 ⫻ 1.6 ⫻ 3.0 mm and b values of 0 and 1000 s/mm2; 12 gradient magnetic fields sensitive to diffusion were applied in three-dimensional space. The consequence parameters are listed in Table 1. DTI Image Processing and Analysis The initial diffusion tensor data obtained was inputted in a PC, and the image was processed by the software Dtistudio (http://lbam.med.jhme.edu/DTIuser.asp version 2.4); the ADC map, FA map, and color map were rebuilt, which represent the characteristic vectors of water molecular diffusion (green represents the characteristic vector of the anteroposterior course; red, left-right; and blue, superoinferior), and nerve fibers with different courses were differently colored. This enabled easy identification of
Academic Radiology, Vol 15, No 3, March 2008
DTI OF THE ALIC IN NEUROLEPTIC-NAIVE SCHIZOPHRENIA
Figure 1. Color map, fractional anisotropy map, and average diffusion coefficient map of the anterior limb of the internal capsule of the control group (upper row) and schizophrenia group (lower row).
these fibers and was helpful in determining the exact location of the region of interest. The ALIC connects the thalamus and prefrontal lobe, walks in the anteroposterior course, and was colored green in Fig 1. Two main slices at the cross-section were chosen for measurements; the superior and inferior marginal slices were excluded to avoid the partial volume effect, and the anterior boundary was at the intersection between anterior limbs of the external and internal capsules, whereas the posterior boundary was at the level of the genu of the internal capsule. An region of interest with 2 ⫻ 2 pixels was used, and the mean FA and ADC values of 20 –24 pixels of each slice and each side were measured and recorded. The FA and ADC values of the bilateral ALIC were obtained from the schizophrenia and control groups, and eight groups of data were obtained in all. A group t-test (two-tail) and the statistical software SPSS 11.0 were used in statistical analysis. RESULT The FA and ADC values of the bilateral ALIC of the control group and schizophrenia group are listed in Table 2. 1. The mean FA values of the left and right ALIC of the 18 patients in the control group were 0.626 ⫾
Table 2 The FA and ADC Values of the Bilateral ALIC ALIC
Schizophrenia group (21) Left side Right side Control group (18) Left side Right side
FA Value
ADC Value (⫻10–4 mm2/s)
0.598 ⫾ 0.041 0.611 ⫾ 0.041
7.292 ⫾ 0.362 7.299 ⫾ 0.306
0.626 ⫾ 0.033 0.650 ⫾ 0.057
7.073 ⫾ 0.543 7.147 ⫾ 0.642
FA, fractional anisotropy; ADC, average diffusion coefficient; ALIC, anterior limb of the internal capsule.
0.033 and 0.650 ⫾ 0.057, respectively, and no significant statistical difference was observed with the t-test (t ⫽ 1.534, P ⬎ .05, bilateral 95% confidence interval). The mean left and right ADC values were (7.073 ⫾ 0.543) ⫻ 10⫺4 mm2/second and (7.147 ⫾ 0.642) ⫻ 10⫺4 mm2/second, respectively, and there is no significant statistical difference between them. 2. The mean FA values of the left and right ALIC of the 21 patients of the schizophrenia group were 0.598 ⫾ 0.041 and 0.611 ⫾ 0.041, respectively, and no significant statistical difference was observed with the t-test (t ⫽ 0.968, P ⬎ .05, bilateral 95%
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confidence interval). The mean left and right ADC values were (7.292 ⫾ 0.363) ⫻ 10⫺4 mm2/second, and (7.299 ⫾ 0.305) ⫻ 10⫺4 mm2/second, respectively, and there is no significant statistical difference between them (t ⫽ ⫺0.064, P ⬎ .05, bilateral 95% confidence interval). The mean FA and ADC values of the left and right ALIC of the schizophrenia group and control group were compared. An independent group t-test was used with bilateral 95% confidence interval, and the left ALIC (t ⫽ ⫺2.292, P ⬍ .05) and right ALIC FA (t ⫽ ⫺2.183, P ⬍ .05) values were obtained. The FA values of the left and right ALIC of both groups were statistically significant, and the mean FA value of the schizophrenia group was lower than that of the control group; however, no significant statistical difference was observed in the ADC values of the left and right ALIC between the schizophrenia group and control group.
DISCUSSION Schizophrenia is considered to be a disease caused by an abnormality in the interconnection between neurons of different encephalic regions and is characterized by a widely distributed disconnection of cerebral circuits (2,3); thus, some clinical symptoms and cognitive defects of schizophrenia can be explained. The possibility of the existence of microscopic pathologic changes in the nerve fiber bundles of schizophrenia patients needs to be examined. The thalamus-cortical pathway walks in the ALIC is the final common pathway of the high-grade cognition feedback loop, and connects the frontal lobe, the anterior part of the cingulate gyrus, and thalamus. Damaged white matter fiber bundles in the ALIC cause functional disconnection in this feedback loop, resulting in abnormal symptoms related to behavior and intelligence observed in schizophrenia patients. The diffusion of water molecules in the white matter is affected by the macroscopic and ultramicroscopic structures of nerve fibers, such as the cell envelope and cytoskeleton. Changes in neuraxial density, water capacity, and myelinization degree also affect white matter anisotropy. DTI is a new technique in the field of nuclear magnetic resonance that has been developed in recent decades. Developed from diffusion imaging, DTI is a
288
Academic Radiology, Vol 15, No 3, March 2008
method of studying the diffusion movement of water molecules in living tissues; it can appraise the intactness of the living microstructure of the white matter without invasion, and provide a new approach for the study of white matter destruction in early schizophrenia. Since it was proposed by Basser in 1994, DTI has been widely used in animal experiments and clinical studies, such as the simulation of diffuse axonal injury in animal brain and studies on myelin sheath development in normal infants, leukodystrophy in children, multiple sclerosis, cerebral apoplexy, brain tumor, cerebral trauma, and mental diseases; it can not only reveal the pathologic changes that remain undetected by MRI, but can also generate a three-dimensional image of a nerve fiber’s course. As confirmed by a large number of studies, cognitive dysmetria in schizophrenia may result from disconnection among the neural circuits but not due to damage in a single region. The prefrontal lobe is the center of higher cognitive function and it is the central executive system of working memory; its dysfunction has been considered as the primary feature of schizophrenia, and structural abnormalities in the frontal lobe of schizophrenia patients have been confirmed by multiple neuroimaging and autopsy studies. The thalamus is the relay station mediating information from the cortex and limbic system as well as the gating filter of the sensory conductive pathway; it participates in the processing of attention and information. These functions derive from the thalamic ventral anterior nucleus and dorsomedial nucleus, prefrontal lobe, and thalamuscortex-thalamus circuit. The frontal thalamic peduncle and the fibrae corticothalamicae connecting the prefrontal lobe with the thalamus walk in the ALIC; the frontal thalamic peduncle connects the mediodorsal and the anterior thalamic nucleus with the frontal lobe. Cortical projections and the cingulate gyrus are also connected by the frontal thalamic peduncle; this further supports the hypothesis of an abnormal ALIC (connection between frontal lobe and thalamus) in schizophrenia. With regard to functional neuroanatomy, the ALIC includes two limbic circuits: the inner limbic circuit (consisting of the hippocampal formation, mamillary body, nuclei anteriores thalami, and cingulate gyrus) and the bottom-lateral limbic circuit (interconnected by the orbitofrontal cortex, nuclei thalami medialis, amygdala, and the anterior part of the temporal lobe). A structural defect in the ALIC may result in the disruption of these circuits and a functional disconnection between the temporal lobe and prefrontal lobe (these circuits are also required for a
Academic Radiology, Vol 15, No 3, March 2008
DTI OF THE ALIC IN NEUROLEPTIC-NAIVE SCHIZOPHRENIA
partial connection between the temporal lobe and prefrontal lobe) (4). Wang (5) discovered a decreased FA value in the anterior region of the cingulate fasciculus in schizophrenia by DTI. Zhou et al (6) have discovered a decrease in the volume of the bilateral ALIC in chronic schizophrenia. In addition, it has been confirmed that there is a structural and functional abnormality in the regions connected by the ALIC (7–9), and as reported by Lang (10), the volume of the bilateral ALIC in neuroleptic-naïve schizophrenia patients are decreased; this indicates that a volume abnormality in the ALIC already existed in the early period of the disease. The infusion status of the internal capsule has been measured by different methods; different results have been obtained. For example, Buchsbaum (11) et al discovered decreased anisotropy of diffusion in the internal capsule in schizophrenia patients, whereas no abnormality in internal capsule diffusion was observed by Agartz (12) and Foong (13) et al. However, most subjects were chronic schizophrenia patients who had undergone treatment and showed stable pathogenesis. In this study, schizophrenia patients who had never been medicated were selected; this eliminated the effects of drugs on water molecular diffusion in the ALIC. Schizophrenia patients who had not taken drugs in the past 5 years were selected as the subjects of the study. The small region of interest method was used to measure the FA values and ADC values of the ALIC in neuroleptic-naive schizophrenic patients and the matched healthy control group. The FA values of the bilateral ALIC in schizophrenic patients were significantly lower than those of the control group; this indicates that an abnormality in water infusion in the white matter exists in the bilateral ALIC even during the early period of pathologic changes. However, there is no significant difference in the ADC values of the bilateral ALIC between schizophrenia pa-
tients and control patients; this indicates that FA is more sensitive than ADC. The use of DTI to study the interconnection among cortical neurons (intactness of white matter) in schizophrenia is still in an initial stage; however, this technique can help us understand the clinical symptoms and the pathogenesis of mental diseases in further detail. REFERENCES 1. Shen YC, Chen CH, Zhang WX. The methodology and material analysis of the epidemiological investigation of chinese mental disorder in 12 areas. Chin J Neurol 1986; 19:65– 69. 2. Niznikiewicz M, Donnino R, McCarley RW, et al. Abnormal angular gyrus asymmetry in schizophrenia. Am J Psychiatry 2000; 157:428 – 437. 3. Nopoulos PC, Ceilley JW, Gailis EA, et al. An MRI study of cerebellar vermis morphology in patients with schizophrenia: evidence in support of the cognitive dysmetria concept. Biol Psychiatry 1999; 46:703–711. 4. Lawrie SM, Buechel C, Whalley HC, et al. Reduced frontotemporal functional connectivity in schizophrenia associated with auditory hallucinations. Biol Psychiatry 2002; 51:1008 –1011. 5. Wang F, Sun Z, Cui L, et al. Anterior cingulum abnormalities in male patients with schizophrenia determined through diffusion tensor imaging. Am J Psychiatry 2004; 161:573–575. 6. Zhou SY, Suzuki M, Hagino H, et al. Decreased volume and increased asymmetry of the anterior limb of the internal capsule in patients with schizophrenia. Biol Psychiatry 2003; 54:427– 436. 7. Buchanan RW, Vladar K, Barta PE, et al. Structural evaluation of the prefrontal cortex in schizophrenia. Am J Psychiatry 1998; 155:1049 – 1055. 8. Byne W, Buchsbaum MS, Kemether E, et al. Magnetic resonance imaging of the thalamic mediodorsal nucleus and pulvinar in schizophrenia and schizotypal personality disorder. Arch Gen Psychiatry 2001; 58:133–140. 9. Takahashi T, Suzuki M, Kawasaki Y, et al. Volumetric magnetic resonance imaging study of the anterior cingulate gyrus in schizotypal disorder. Eur Arch Psychiatry Clin Neurosci 2002; 252:268 –277. 10. Lang DJ, Kopala LC, Vandorpe RA, et al. Reduced basal ganglia volumes after switching to olanzapine in chronically treated patients with schizophrenia. Am J Psychiatry 2004; 161:1829 –1836. 11. Buchsbaum MS, Tang CY, Peled S, et al. MRI white matter diffusion anisotropy and PET metabolic rate in schizophrenia. Neuroreport 1998; 9:425– 430. 12. Agartz I, Andersson JL, Skare S. Abnormal brain white matter in schizophrenia: a diffusion tensor imaging study. Neuroreport 2001; 12:2251–2254. 13. Foong J, Symms MR, Barker GJ, et al. Investigating regional white matter in schizophrenia using diffusion tensor imaging. Neuroreport 2002; 13:333–336.
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