Neuroscience Letters 585 (2015) 77–81
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Short communication
Aging of corticospinal tract fibers according to the cerebral origin in the human brain: A diffusion tensor imaging study Sung Ho Jang, Jeong Pyo Seo ∗ Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University 317-1, Daemyungdong, Namgu, Daegu 705-717, South Korea
h i g h l i g h t s • • • •
We investigated the differences of aging of CST fiber according to cerebral origin. The fiber number of CST from secondary motor cortex was decreased in 70s age group. Our results would be helpful for development of strategies with aging of the CST. The main function of the secondary motor cortex is motor planning and coordination.
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Article history: Received 17 July 2014 Received in revised form 1 November 2014 Accepted 18 November 2014 Available online 20 November 2014 Keywords: Corticospinal tract Motor function Aging Diffusion tensor imaging
a b s t r a c t The corticospinal tract (CST) is known to originate from multiple cerebral areas, including the primary motor cortex (M1). In this study, using diffusion tensor imaging (DTI), we attempted to investigate the differences of aging of CST fibers according to the cerebral origin in the human brain. Sixty healthy subjects aged from the 20s to the 70s were recruited, and 10 subjects were assigned to each age group. CST fibers were reconstructed from the M1 (Broadmann’s area [BA] 4), the secondary motor area (M2, BA 6), and the primary somatosensory cortex (S1, BA 1–3), respectively. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of CST fibers from each cerebral area were measured. Significant differences in the TV values of CST fibers from the M2 were observed between the 70s age group and the other age groups, except the 60s age group (p < 0.05). However, no significant difference in the values of FA and MD of CST fibers from the M2 were observed between age group (p > 0.05). No significant differences in the values of FA, MD, and TV of CST fibers from the S1 and M1 were observed between age groups (p > 0.05). We found that the fiber number of CST fibers from the M2 was decreased in the 70s age group compared with the 20s–50s age groups. Because the main function of the M2 is motor planning and coordination, our results would be helpful in development of strategies for coping with aging of the CST. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction Aging of the human brain is inevitable. Detailed knowledge about aging of the human brain would be helpful to understanding the aging process, and to develop of strategies for coping with aging in the elderly. Therefore, many studies have attempted to elucidate the aging of the human brain [7,30,32]. Motor function, along with cognitive function, is important in performance of the activities of daily living. Many studies have reported on the aging of
∗ Corresponding author. Tel.: +82 53 620 4098; fax: +82 53 620 4098. E-mail addresses: [email protected](S.H. Jang),[email protected] (J.P. Seo). http://dx.doi.org/10.1016/j.neulet.2014.11.030 0304-3940/© 2014 Published by Elsevier Ireland Ltd.
motor function in the human brain, however, the aging process of the neural tracts for motor function has not been clearly elucidated so far [11,15,27,30]. In the human brain, the descending motor pathways are classified according to the corticospinal tract (CST) and non-CST [8,33]. The CST, a major neural tract for motor function in the human brain, is mainly concerned with execution of movement of distal extremities, particularly motor function of the hand [8,12,33]. The CST is known to originate from multiple cerebral areas, including the primary motor cortex (M1), the secondary motor area (M2), and the somatosensory cortex [8,29,33]. The multiple cerebral origins of the CST are important because the function and characteristics of CST fibers are known to differ according to the origin of the cerebral cortex [16,18,22,26,28]. In addition, several studies have suggested
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Table 1 Demographic data for the patient and control groups.
Age (year) Sex (male/female) Handness, (right/left)
20s
30s
40s
50s
60s
70s
23.7 (±3.23) 5/5 10/0
33.7 (±2.21) 5/5 10/0
44.6 (±2.59) 5/5 10/0
53.3 (±1.89) 5/5 10/0
66.3 (±2.21) 5/5 10/0
73.6 (±2.07) 6/4 10/0
that vulnerability to aging could differ according to the brain area or structure: for example, white matter of the prefrontal region, frontal gray matter, or the genu of the corpus callosum have been reported as vulnerable areas with aging [10,17,24]. Recently introduced diffusion tensor imaging (DTI) has enabled evaluation of the integrity of white matter tracts by virtue of its ability to image water diffusion characteristics [2,20]. Diffusion tensor tractography, a three-dimensional visualized version of DTI, has enabled three-dimensional visualization of the architecture and integrity of neural tracts at the subcortical level [2,20]. A few studies have reported on aging-related changes of the CST [11,15,27]. However, these studies focused on the longitudinal changes with aging of the whole CST and no study on aging of the CST according to the cerebral origin has been reported. We hypothesized that aging of the CST might differ according to the cerebral origin because the function and characteristics of CST fibers differ according to the origin of the cerebral cortex [16,18,22,26,28]. Therefore, in the current study, using DTI, we attempted to investigate differences of aging of the CST according to the cerebral origin in the human brain. 2. Methods 2.1. Subjects Sixty right-handed healthy subjects (males: 30, females: 30, mean age: 49.2 years; range: 20–78 years) with no previous history of psychiatric, neurological, or physical illness, and no brain lesion on conventional MRI (T1-weighted, T2-weighted, fluid attenuated inversion recovery [FLAIR], and T2-weighted gradient recall echo [GRE] images), confirmed by a neuroradiologist, were enrolled in this study. Subjects were divided according to age intervals of 10 years. Ten subjects were recruited for each group. The Edinburg Handedness Inventory was used for evaluation of handedness (Table 1 [23]. All subjects provided written informed consent prior to the start of the study, and the study protocol was approved by the Institutional Review Board of a university hospital. 2.2. Data acquisition DTI data were acquired using a Synergy-L SENSE head coil on a 1.5T Gyroscan Intera system (Philips, Best, The Netherlands) equipped with single-shot echo-planar imaging. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissureposterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 128 × 128, field of view = 221 × 221 mm2 , TR = 10,726 ms, TE = 76 ms, parallel imaging reduction factor (SENSE factor) = 2, EPI factor = 49 and b = 1000 s/mm2 , NEX = 1, slice gap = 0 mm, and slice thickness = 2.3 mm. (acquired voxel size 1.73 × 1.73 × 2.3 mm3 ). 2.3. Fiber tracking The Oxford Center for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library was used for analysis of diffusion-weighted imaging data. Affine multi-scale twodimensional registration was used for correction of head motion effect and image distortion due to eddy current. A probabilistic
tractography method based on a multi-fiber model was used for fiber tracking, and applied in the current study utilizing tractography routines implemented in FMRIB Diffusion (0.5 mm step lengths, 5000 streamline samples, curvature thresholds = 0.2) [3,4,14,31]. The CSTs for Brodmann’s areas (BA) 1–4, and 6 were determined by selection of fibers passing through seed and target regions of interest (ROI). The seed ROI was located at the ponto-medullary junction on the color map (anterior blue portion) [28]. Target ROIs were placed as follows: (1) the primary somatosensory cortex (S1); BA 1, 2, and 3 (anterior boundary: central sulcus, posterior boundary: postcentral sulcus, medial boundary: the midline between the right and left hemispheres), (2) the M1; BA 4 (anterior boundary: precentral sulcus, posterior boundary: central sulcus, medial boundary: the midline between the right and left hemispheres), and (3) the M2; BA 6 (anterior boundary: vertical line to the anterior commissure, posterior boundary: anterior margin of the primary motor cortex, medial boundary: midline between the right and left hemispheres) (Fig. 1) [6]. Out of 5000 samples generated from each seed voxel, results for each contact were visualized threshold, and weightings of tract probability at a minimum of one streamline through each voxel for analysis. The values of fractional anisotropy, mean diffusivity, and tract volume of each CST were measured [29,31]. The value of fractional anisotropy indicates the degree of directionality of water diffusion, and represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axons, myelin, and microtubules, and the value of mean diffusivity indicates the magnitude of water diffusion [2,21]. The value of tract volume is determined by counting the number of voxels contained within a neural tract and, reflects the total number of fibers in a neural tract [25]. 2.4. Statistical analysis SPSS software (v.15.0; SPSS, Chicago, IL) was used for data analysis. Using multivariate analysis of variance (MANOVA) with LSD post-hoc test, we determined the differences in values for each DTI parameter (fractional anisotropy, mean diffusivity, and tract volume) between age groups. Spearman’s correlation analysis was performed for assessment of any significant correlations between DTI parameters (fractional anisotropy, mean diffusivity, and tract volume) of the CST and age. The independent t-test was used for determination of the difference in values of each DTI parameter from each CST between right and left hemispheres, and between male and female. The significance level for the p value was set at 0.05. 3. Results A summary of mean values of DTI parameters of the CST fibers from each cerebral cortex in each age group is shown in Table 2. Result of MANOVA showed significant difference in the tract volume from the M2 (p < 0.05). Significant differences in the value of tract volume of CST fibers from the M2 were observed between the 70s age group and the other age groups, except the 60s age group (p < 0.05). However, no significant difference in the values of fractional anisotropy and mean diffusivity of CST fibers from the M2 was observed between age groups (p > 0.05). No significant dif-
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Fig. 1. (A) The seed region of interest (ROI) was given on the lower pons. Target ROIs were placed on Brodmann’s areas (BA) 1–3 (red color) for the primary sensorimotor cortex (S1), BA 4 (blue color) for the primary motor cortex (M1), and BA 6 (green color): the secondary motor area (M2). (B) The corticospinal tract (CST) was reconstructed in both hemispheres (red – CST from BA 1–3, blue – CST from BA 4, green – CST from BA 6). (C) Diffusion tensor tractography of the CSTs from each seed ROI in each age group. (For interpretation of the reference to color in this figure legend, the reader is referred to the web version of this article).
Table 2 Mean values of each corticospinal tract according to the cerebral origin and age group. S1: BA 1,2,3
20s 30s 40s 50s 60s 70s
M1: BA 4
M2: BA 6
FA
MD
TV
FA
MD
TV
FA
MD
TV
0.413 (±0.028) 0.411 (±0.025) 0.410 (±0.040) 0.411 (±0.030) 0.413 (±0.038) 0.409 (±0.032)
0.881 (±0.050) 0.884 (±0.058) 0.913 (±0.080) 0.922 (±0.099) 0.891 (±0.112) 0.916 (±0.133)
2055.2 (±431.9) 1986.8 (±536.6) 1926.2 (±515.2) 1995.7 (±467.4) 1905.5 (±544.3) 1851.2 (±509.6)
0.414 (±0.029) 0.407 (±0.013) 0.407 (±0.032) 0.404 (±0.025) 0.402 (±0.031) 0.397 (±0.034)
0.884 (±0.056) 0.907 (±0.061) 0.902 (±0.055) 0.932 (±0.098) 0.914 (±0.107) 0.943 (±0.144)
2456.9 (±494.9) 2566.3 (±476.1) 2403.2 (±515.2) 2412.6 (±583.6) 2438.7 (±708.9) 2424.1 (±480.6)
0.455 (±0.049) 0.454 (±0.052) 0.456 (±0.045) 0.452 (±0.044) 0.456 (±0.052) 0.434 (±0.037)
0.837 (±0.058) 0.862 (±0.078) 0.844 (±0.067) 0.868 (±0.091) 0.832 (±0.127) 0.873 (±0.116)
1608.6 (±356.9) 1617.6 (±250.4) 1612.5 (±354.8) 1606.7 (±259.8) 1476.9 (±313.7) 1377.5a (±144.4)
S1: The primary somatosensory cortex, BA: Brodmann’s area, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation). a Significant differences were observed with other age groups, except for the 60s age group (p < 0.05).
ferences in the values of fractional anisotropy, mean diffusivity, and tract volume of CST fibers from the S1 and M1 were observed between age groups (p > 0.05) (Fig. 2). In addition, age did not show correlation with any of the DTI parameters (fractional anisotropy, mean diffusivity, and tract volume) of CST fibers from each cerebral area (p > 0.05). In comparison of the DTI parameters between
hemispheres, the values of fractional anisotropy of CST fibers from the S1 and M1 in the left hemisphere were significantly higher than those of the right hemisphere (p < 0.05) (Table 3). However, the values of mean diffusivity of CST fibers from the S1 and M1 in the right hemisphere were significantly higher than those of the left hemisphere (p < 0.05). By contrast, no significant difference in the values
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Fig. 2. Mean values of diffusion tensor imaging parameters. The tract volume of corticospinal tract (CST) fibers from the secondary motor area (M2) is decreased in the 70s age group compared with those of the 20s–50s age groups. The values of fractional anisotropy and mean diffusivity of CST fibers from the primary somatosensory cortex (S1) and the primary motor cortex (M1) in the right hemisphere are lower and higher than those in the left hemisphere, respectively; TV: tract volume (voxels), FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)). *p < 0.05.
Table 3 Mean values of each corticospinal tract according to hemispheres. Rt. hemisphere
FA MD TV
FA MD TV
S1
M1
M2
0.403 (±0.028) 0.931 (±0.096) 1922.9 (±460.3) Lt. hemisphere
0.397 (±0.029) 0.930 (±0.100) 2470.0 (±538.6)
0.449 (±0.028) 0.851 (±0.090) 1560.3 (±284.1)
S1
M1
M2
0.419 (±0.034) 0.872 (±0.081) 1983.9 (±531.3)
0.413 (±0.025) 0.897 (±0.083) 2435.5 (±508.8)
0.454 (±0.050) 0.854 (±0.095) 1539.6 (±313.1)
S1: The primary somatosensory cortex, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation). Table 4 Mean values of each corticospinal tract according to gender. Male
FA MD TV
S1
M1
M2
0.409 (±0.025) 0.909 (±0.084) 1990.8 (±377.9)
0.406 (±0.025) 0.917 (±0.081) 2440.7 (±452.1)
0.452 (±0.044) 0.859 (±0.085) 1504.3 (±281.4)
S1
M1
M2
0.413 (±0.038) 0.883 (±0.089) 1913.4 (±597.9)
0.405 (±0.031) 0.894 (±0.091) 2465.7 (±591.4)
0.450 (±0.050) 0.846 (±0.100) 1598.8 (±309.5)
Female
FA MD TV
S1: The primary somatosensory cortex, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation).
of fractional anisotropy, mean diffusivity, and tract volume of each CST fibers in the S1, M1, and M2 were observed between male and female (p > 0.05) (Table 4). 4. Discussion It is well-known that vulnerability to aging could differ according to the brain area and the characteristics of CST fibers differ according to the cerebral origin [1,10,16,17,18,22,24,26,28]. In the current study, we hypothesized that aging of the CST might differ according to the cerebral origin and investigated differences
of aging of CST fibers according to the cerebral origin (M1, M2, and S1) in normal subjects ranging in age from the 20s to the 70s [16,18,22,26,28]. According to our findings, the tract volume of CST fibers from M2 was decreased in the 70s age group compared with those of the 20s–50s age groups, however, no difference in the values of fractional anisotropy and mean diffusivity of CST fibers was observed according to the cerebral origin. Fractional anisotropy represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axon, myelin, and microtubule, and mean diffusivity value indicates the magnitude of water diffusion [2,21]. Tract volume is determined by counting the number of voxels contained within a neural tract, and thus, reflects the total number of fibers in a neural tract [19]. Specifically, the decline in the value of tract volume of CST fibers from the M2 in the 70s age group suggests a decline in the total number of CST fibers from the M2 in this age group. In addition, our results for the values of fractional anisotropy and tract volume appear to indicate that CST fibers in the left hemisphere have the characteristics of higher anisotropy, and lower diffusivity than CST fibers in the right hemisphere. Previous studies have reported on the functional difference of the CST according to the cerebral origin, as follows: M1 – execution of movements, M2 – planning and coordination of movement, and S1 – descending control of somatosensory afferent inputs to movement [16,18,22,26]. These different functions appear to have an association with different neurological manifestations following injury of each CST fiber, such as weakness (M1), apraxia (M2), and impaired somatosensory motor coordination (S1) [9,22]. Therefore, we think that the decline in the fiber number of CST fibers from the M2 might accompany problem of planning and coordination of movement [16,18,22,26]. Our results appear to coincide with those of previous neurobehavioral studies reporting that the deterioration of fine motor coordination ability was greater than the grip strength in elderly subjects: in detail, Kim et al. [1994] reported that the fine motor activity of the hand was more decreased than the grip strength with aging, and Bowden and McNulty [2013] reported that fine motor activity of the hand was the best predictor of age-related declines in motor performance [5,13]. Several studies have reported on aging of the CST using DTI, and all of these studies investigated the longitudinal changes with aging of the whole CST [11,15,27]. In 2011, Jang et al. measured DTI parameters of tractography for the CST in 60 normal subjects (from the 20s to the 70s) [11]. It was found that tract number and fractional anisotropy value decreased, and mean diffusivity value increased according to increment of age with a near-linear pattern. In addition, significant changes were found in all three
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parameters in the 50s–70s age groups compared with the DTI parameters of subjects in the 20s age group. Consequently, they concluded that the CST in normal subjects showed continuous degeneration from the 20s to the 70s, and degeneration of the CST begins to manifest significantly in the 50s [11]. In 2012, in a study investigating microstructural changes of the CST with aging in 84 healthy subjects (13–70 years), Sala et al. found linear relationships between age and mean diffusivity increase, and fractional anisotropy decrease using a quadratic model [27]. In a recent study, Lebel et al. [2012] investigated DTI changes of the CST over the lifespan in 403 healthy subjects (5–83 years) [15]. They reported that the value of fractional anisotropy increased during childhood and adolescence, reached a peak at 35 years, and then decreased; in contrast, the value of mean diffusivity showed an opposite trend, decreasing first, reaching a minimum at 33.8 years, and then increasing later in life. Therefore, to the best of our knowledge, this is the first study to demonstrate differences of aging of the CST according to the cerebral origin. In conclusion, we investigated differences of aging of CST fibers according to the cerebral origin and found that the fiber number of CST fibers from the M2 was decreased in the 70s age group compared with the 20s–50s age groups. Because the main function of the M2 is motor planning and coordination, our results would be helpful in development of strategies for coping with aging of the CST. This study is limited in that there are no neurobehavioral data for CST fibers from each cerebral origin (M1, M2, and S1). Another limitation is that we did not have data for older people in the over 70s age group. Therefore, conduct of further complementary studies with neurobehavioral data for CST fibers according to the cerebral origin and data including older subjects over 80 years is warranted. Acknowledgement This work was supported by the DGIST R&D Program of the Ministry of Education, Science and Technology of Korea (14-BD-0401). References [1] J.S. Allen, J. Bruss, C.K. Brown, H. Damasio, Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal region, Neurobiol. Aging 26 (2005) 1245–1260, discussion 1279–1282. [2] Y. Assaf, O. Pasternak, Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review, J. Mol. Neurosci. 34 (2008) 51–61. [3] T.E. Behrens, H.J. Berg, S. Jbabdi, M.F. Rushworth, M.W. Woolrich, Probabilistic diffusion tractography with multiple fibre orientations: what can we gain? NeuroImage 34 (2007) 144–155. [4] T.E. Behrens, H. Johansen-Berg, M.W. Woolrich, S.M. Smith, C.A. Wheeler-Kingshott, P.A. Boulby, G.J. Barker, E.L. Sillery, K. Sheehan, O. Ciccarelli, A.J. Thompson, J.M. Brady, P.M. Matthews, Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging, Nat. Neurosci. 6 (2003) 750–757. [5] J.L. Bowden, P.A. McNulty, The magnitude and rate of reduction in strength, dexterity and sensation in the human hand vary with ageing, Exp. Gerontol. 48 (2013) 756–765. [6] K. Brodmann, L.J. Gary, Brodmann’s Localisation in the Cerebral Cortex: The Principles of Comparative Localisation in the Cerebral Cortex Based on the Cytoarchitectonics, Springer Limited, London, 2006. [7] E. Carmeli, H. Patish, R. Coleman, The aging hand, J. Gerontol. Ser. A: Biol. Sci. Med. Sci. 58 (2003) 146–152. [8] R.A. Davidoff, The pyramidal tract, Neurology 40 (1990) 332–339. [9] J.H. Hong, J. Lee, Y.W. Cho, W.M. Byun, H.K. Cho, S.M. Son, S.H. Jang, Limb apraxia in a patient with cerebral infarct: diffusion tensor tractography study, Neurorehabilitation 30 (2012) 255–259.
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Short communication
Aging of corticospinal tract fibers according to the cerebral origin in the human brain: A diffusion tensor imaging study Sung Ho Jang, Jeong Pyo Seo ∗ Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University 317-1, Daemyungdong, Namgu, Daegu 705-717, South Korea
h i g h l i g h t s • • • •
We investigated the differences of aging of CST fiber according to cerebral origin. The fiber number of CST from secondary motor cortex was decreased in 70s age group. Our results would be helpful for development of strategies with aging of the CST. The main function of the secondary motor cortex is motor planning and coordination.
a r t i c l e
i n f o
Article history: Received 17 July 2014 Received in revised form 1 November 2014 Accepted 18 November 2014 Available online 20 November 2014 Keywords: Corticospinal tract Motor function Aging Diffusion tensor imaging
a b s t r a c t The corticospinal tract (CST) is known to originate from multiple cerebral areas, including the primary motor cortex (M1). In this study, using diffusion tensor imaging (DTI), we attempted to investigate the differences of aging of CST fibers according to the cerebral origin in the human brain. Sixty healthy subjects aged from the 20s to the 70s were recruited, and 10 subjects were assigned to each age group. CST fibers were reconstructed from the M1 (Broadmann’s area [BA] 4), the secondary motor area (M2, BA 6), and the primary somatosensory cortex (S1, BA 1–3), respectively. Values of fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of CST fibers from each cerebral area were measured. Significant differences in the TV values of CST fibers from the M2 were observed between the 70s age group and the other age groups, except the 60s age group (p < 0.05). However, no significant difference in the values of FA and MD of CST fibers from the M2 were observed between age group (p > 0.05). No significant differences in the values of FA, MD, and TV of CST fibers from the S1 and M1 were observed between age groups (p > 0.05). We found that the fiber number of CST fibers from the M2 was decreased in the 70s age group compared with the 20s–50s age groups. Because the main function of the M2 is motor planning and coordination, our results would be helpful in development of strategies for coping with aging of the CST. © 2014 Published by Elsevier Ireland Ltd.
1. Introduction Aging of the human brain is inevitable. Detailed knowledge about aging of the human brain would be helpful to understanding the aging process, and to develop of strategies for coping with aging in the elderly. Therefore, many studies have attempted to elucidate the aging of the human brain [7,30,32]. Motor function, along with cognitive function, is important in performance of the activities of daily living. Many studies have reported on the aging of
∗ Corresponding author. Tel.: +82 53 620 4098; fax: +82 53 620 4098. E-mail addresses: [email protected](S.H. Jang),[email protected] (J.P. Seo). http://dx.doi.org/10.1016/j.neulet.2014.11.030 0304-3940/© 2014 Published by Elsevier Ireland Ltd.
motor function in the human brain, however, the aging process of the neural tracts for motor function has not been clearly elucidated so far [11,15,27,30]. In the human brain, the descending motor pathways are classified according to the corticospinal tract (CST) and non-CST [8,33]. The CST, a major neural tract for motor function in the human brain, is mainly concerned with execution of movement of distal extremities, particularly motor function of the hand [8,12,33]. The CST is known to originate from multiple cerebral areas, including the primary motor cortex (M1), the secondary motor area (M2), and the somatosensory cortex [8,29,33]. The multiple cerebral origins of the CST are important because the function and characteristics of CST fibers are known to differ according to the origin of the cerebral cortex [16,18,22,26,28]. In addition, several studies have suggested
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Table 1 Demographic data for the patient and control groups.
Age (year) Sex (male/female) Handness, (right/left)
20s
30s
40s
50s
60s
70s
23.7 (±3.23) 5/5 10/0
33.7 (±2.21) 5/5 10/0
44.6 (±2.59) 5/5 10/0
53.3 (±1.89) 5/5 10/0
66.3 (±2.21) 5/5 10/0
73.6 (±2.07) 6/4 10/0
that vulnerability to aging could differ according to the brain area or structure: for example, white matter of the prefrontal region, frontal gray matter, or the genu of the corpus callosum have been reported as vulnerable areas with aging [10,17,24]. Recently introduced diffusion tensor imaging (DTI) has enabled evaluation of the integrity of white matter tracts by virtue of its ability to image water diffusion characteristics [2,20]. Diffusion tensor tractography, a three-dimensional visualized version of DTI, has enabled three-dimensional visualization of the architecture and integrity of neural tracts at the subcortical level [2,20]. A few studies have reported on aging-related changes of the CST [11,15,27]. However, these studies focused on the longitudinal changes with aging of the whole CST and no study on aging of the CST according to the cerebral origin has been reported. We hypothesized that aging of the CST might differ according to the cerebral origin because the function and characteristics of CST fibers differ according to the origin of the cerebral cortex [16,18,22,26,28]. Therefore, in the current study, using DTI, we attempted to investigate differences of aging of the CST according to the cerebral origin in the human brain. 2. Methods 2.1. Subjects Sixty right-handed healthy subjects (males: 30, females: 30, mean age: 49.2 years; range: 20–78 years) with no previous history of psychiatric, neurological, or physical illness, and no brain lesion on conventional MRI (T1-weighted, T2-weighted, fluid attenuated inversion recovery [FLAIR], and T2-weighted gradient recall echo [GRE] images), confirmed by a neuroradiologist, were enrolled in this study. Subjects were divided according to age intervals of 10 years. Ten subjects were recruited for each group. The Edinburg Handedness Inventory was used for evaluation of handedness (Table 1 [23]. All subjects provided written informed consent prior to the start of the study, and the study protocol was approved by the Institutional Review Board of a university hospital. 2.2. Data acquisition DTI data were acquired using a Synergy-L SENSE head coil on a 1.5T Gyroscan Intera system (Philips, Best, The Netherlands) equipped with single-shot echo-planar imaging. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissureposterior commissure line. Imaging parameters were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 128 × 128, field of view = 221 × 221 mm2 , TR = 10,726 ms, TE = 76 ms, parallel imaging reduction factor (SENSE factor) = 2, EPI factor = 49 and b = 1000 s/mm2 , NEX = 1, slice gap = 0 mm, and slice thickness = 2.3 mm. (acquired voxel size 1.73 × 1.73 × 2.3 mm3 ). 2.3. Fiber tracking The Oxford Center for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library was used for analysis of diffusion-weighted imaging data. Affine multi-scale twodimensional registration was used for correction of head motion effect and image distortion due to eddy current. A probabilistic
tractography method based on a multi-fiber model was used for fiber tracking, and applied in the current study utilizing tractography routines implemented in FMRIB Diffusion (0.5 mm step lengths, 5000 streamline samples, curvature thresholds = 0.2) [3,4,14,31]. The CSTs for Brodmann’s areas (BA) 1–4, and 6 were determined by selection of fibers passing through seed and target regions of interest (ROI). The seed ROI was located at the ponto-medullary junction on the color map (anterior blue portion) [28]. Target ROIs were placed as follows: (1) the primary somatosensory cortex (S1); BA 1, 2, and 3 (anterior boundary: central sulcus, posterior boundary: postcentral sulcus, medial boundary: the midline between the right and left hemispheres), (2) the M1; BA 4 (anterior boundary: precentral sulcus, posterior boundary: central sulcus, medial boundary: the midline between the right and left hemispheres), and (3) the M2; BA 6 (anterior boundary: vertical line to the anterior commissure, posterior boundary: anterior margin of the primary motor cortex, medial boundary: midline between the right and left hemispheres) (Fig. 1) [6]. Out of 5000 samples generated from each seed voxel, results for each contact were visualized threshold, and weightings of tract probability at a minimum of one streamline through each voxel for analysis. The values of fractional anisotropy, mean diffusivity, and tract volume of each CST were measured [29,31]. The value of fractional anisotropy indicates the degree of directionality of water diffusion, and represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axons, myelin, and microtubules, and the value of mean diffusivity indicates the magnitude of water diffusion [2,21]. The value of tract volume is determined by counting the number of voxels contained within a neural tract and, reflects the total number of fibers in a neural tract [25]. 2.4. Statistical analysis SPSS software (v.15.0; SPSS, Chicago, IL) was used for data analysis. Using multivariate analysis of variance (MANOVA) with LSD post-hoc test, we determined the differences in values for each DTI parameter (fractional anisotropy, mean diffusivity, and tract volume) between age groups. Spearman’s correlation analysis was performed for assessment of any significant correlations between DTI parameters (fractional anisotropy, mean diffusivity, and tract volume) of the CST and age. The independent t-test was used for determination of the difference in values of each DTI parameter from each CST between right and left hemispheres, and between male and female. The significance level for the p value was set at 0.05. 3. Results A summary of mean values of DTI parameters of the CST fibers from each cerebral cortex in each age group is shown in Table 2. Result of MANOVA showed significant difference in the tract volume from the M2 (p < 0.05). Significant differences in the value of tract volume of CST fibers from the M2 were observed between the 70s age group and the other age groups, except the 60s age group (p < 0.05). However, no significant difference in the values of fractional anisotropy and mean diffusivity of CST fibers from the M2 was observed between age groups (p > 0.05). No significant dif-
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Fig. 1. (A) The seed region of interest (ROI) was given on the lower pons. Target ROIs were placed on Brodmann’s areas (BA) 1–3 (red color) for the primary sensorimotor cortex (S1), BA 4 (blue color) for the primary motor cortex (M1), and BA 6 (green color): the secondary motor area (M2). (B) The corticospinal tract (CST) was reconstructed in both hemispheres (red – CST from BA 1–3, blue – CST from BA 4, green – CST from BA 6). (C) Diffusion tensor tractography of the CSTs from each seed ROI in each age group. (For interpretation of the reference to color in this figure legend, the reader is referred to the web version of this article).
Table 2 Mean values of each corticospinal tract according to the cerebral origin and age group. S1: BA 1,2,3
20s 30s 40s 50s 60s 70s
M1: BA 4
M2: BA 6
FA
MD
TV
FA
MD
TV
FA
MD
TV
0.413 (±0.028) 0.411 (±0.025) 0.410 (±0.040) 0.411 (±0.030) 0.413 (±0.038) 0.409 (±0.032)
0.881 (±0.050) 0.884 (±0.058) 0.913 (±0.080) 0.922 (±0.099) 0.891 (±0.112) 0.916 (±0.133)
2055.2 (±431.9) 1986.8 (±536.6) 1926.2 (±515.2) 1995.7 (±467.4) 1905.5 (±544.3) 1851.2 (±509.6)
0.414 (±0.029) 0.407 (±0.013) 0.407 (±0.032) 0.404 (±0.025) 0.402 (±0.031) 0.397 (±0.034)
0.884 (±0.056) 0.907 (±0.061) 0.902 (±0.055) 0.932 (±0.098) 0.914 (±0.107) 0.943 (±0.144)
2456.9 (±494.9) 2566.3 (±476.1) 2403.2 (±515.2) 2412.6 (±583.6) 2438.7 (±708.9) 2424.1 (±480.6)
0.455 (±0.049) 0.454 (±0.052) 0.456 (±0.045) 0.452 (±0.044) 0.456 (±0.052) 0.434 (±0.037)
0.837 (±0.058) 0.862 (±0.078) 0.844 (±0.067) 0.868 (±0.091) 0.832 (±0.127) 0.873 (±0.116)
1608.6 (±356.9) 1617.6 (±250.4) 1612.5 (±354.8) 1606.7 (±259.8) 1476.9 (±313.7) 1377.5a (±144.4)
S1: The primary somatosensory cortex, BA: Brodmann’s area, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation). a Significant differences were observed with other age groups, except for the 60s age group (p < 0.05).
ferences in the values of fractional anisotropy, mean diffusivity, and tract volume of CST fibers from the S1 and M1 were observed between age groups (p > 0.05) (Fig. 2). In addition, age did not show correlation with any of the DTI parameters (fractional anisotropy, mean diffusivity, and tract volume) of CST fibers from each cerebral area (p > 0.05). In comparison of the DTI parameters between
hemispheres, the values of fractional anisotropy of CST fibers from the S1 and M1 in the left hemisphere were significantly higher than those of the right hemisphere (p < 0.05) (Table 3). However, the values of mean diffusivity of CST fibers from the S1 and M1 in the right hemisphere were significantly higher than those of the left hemisphere (p < 0.05). By contrast, no significant difference in the values
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Fig. 2. Mean values of diffusion tensor imaging parameters. The tract volume of corticospinal tract (CST) fibers from the secondary motor area (M2) is decreased in the 70s age group compared with those of the 20s–50s age groups. The values of fractional anisotropy and mean diffusivity of CST fibers from the primary somatosensory cortex (S1) and the primary motor cortex (M1) in the right hemisphere are lower and higher than those in the left hemisphere, respectively; TV: tract volume (voxels), FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)). *p < 0.05.
Table 3 Mean values of each corticospinal tract according to hemispheres. Rt. hemisphere
FA MD TV
FA MD TV
S1
M1
M2
0.403 (±0.028) 0.931 (±0.096) 1922.9 (±460.3) Lt. hemisphere
0.397 (±0.029) 0.930 (±0.100) 2470.0 (±538.6)
0.449 (±0.028) 0.851 (±0.090) 1560.3 (±284.1)
S1
M1
M2
0.419 (±0.034) 0.872 (±0.081) 1983.9 (±531.3)
0.413 (±0.025) 0.897 (±0.083) 2435.5 (±508.8)
0.454 (±0.050) 0.854 (±0.095) 1539.6 (±313.1)
S1: The primary somatosensory cortex, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation). Table 4 Mean values of each corticospinal tract according to gender. Male
FA MD TV
S1
M1
M2
0.409 (±0.025) 0.909 (±0.084) 1990.8 (±377.9)
0.406 (±0.025) 0.917 (±0.081) 2440.7 (±452.1)
0.452 (±0.044) 0.859 (±0.085) 1504.3 (±281.4)
S1
M1
M2
0.413 (±0.038) 0.883 (±0.089) 1913.4 (±597.9)
0.405 (±0.031) 0.894 (±0.091) 2465.7 (±591.4)
0.450 (±0.050) 0.846 (±0.100) 1598.8 (±309.5)
Female
FA MD TV
S1: The primary somatosensory cortex, M1: the primary motor cortex, M2: the secondary motor area, FA: fractional anisotropy, MD: mean diffusivity (MD × 10−3 (mm2 /s)), TV: tract volume (voxels). Values indicate mean (±standard deviation).
of fractional anisotropy, mean diffusivity, and tract volume of each CST fibers in the S1, M1, and M2 were observed between male and female (p > 0.05) (Table 4). 4. Discussion It is well-known that vulnerability to aging could differ according to the brain area and the characteristics of CST fibers differ according to the cerebral origin [1,10,16,17,18,22,24,26,28]. In the current study, we hypothesized that aging of the CST might differ according to the cerebral origin and investigated differences
of aging of CST fibers according to the cerebral origin (M1, M2, and S1) in normal subjects ranging in age from the 20s to the 70s [16,18,22,26,28]. According to our findings, the tract volume of CST fibers from M2 was decreased in the 70s age group compared with those of the 20s–50s age groups, however, no difference in the values of fractional anisotropy and mean diffusivity of CST fibers was observed according to the cerebral origin. Fractional anisotropy represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures such as axon, myelin, and microtubule, and mean diffusivity value indicates the magnitude of water diffusion [2,21]. Tract volume is determined by counting the number of voxels contained within a neural tract, and thus, reflects the total number of fibers in a neural tract [19]. Specifically, the decline in the value of tract volume of CST fibers from the M2 in the 70s age group suggests a decline in the total number of CST fibers from the M2 in this age group. In addition, our results for the values of fractional anisotropy and tract volume appear to indicate that CST fibers in the left hemisphere have the characteristics of higher anisotropy, and lower diffusivity than CST fibers in the right hemisphere. Previous studies have reported on the functional difference of the CST according to the cerebral origin, as follows: M1 – execution of movements, M2 – planning and coordination of movement, and S1 – descending control of somatosensory afferent inputs to movement [16,18,22,26]. These different functions appear to have an association with different neurological manifestations following injury of each CST fiber, such as weakness (M1), apraxia (M2), and impaired somatosensory motor coordination (S1) [9,22]. Therefore, we think that the decline in the fiber number of CST fibers from the M2 might accompany problem of planning and coordination of movement [16,18,22,26]. Our results appear to coincide with those of previous neurobehavioral studies reporting that the deterioration of fine motor coordination ability was greater than the grip strength in elderly subjects: in detail, Kim et al. [1994] reported that the fine motor activity of the hand was more decreased than the grip strength with aging, and Bowden and McNulty [2013] reported that fine motor activity of the hand was the best predictor of age-related declines in motor performance [5,13]. Several studies have reported on aging of the CST using DTI, and all of these studies investigated the longitudinal changes with aging of the whole CST [11,15,27]. In 2011, Jang et al. measured DTI parameters of tractography for the CST in 60 normal subjects (from the 20s to the 70s) [11]. It was found that tract number and fractional anisotropy value decreased, and mean diffusivity value increased according to increment of age with a near-linear pattern. In addition, significant changes were found in all three
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parameters in the 50s–70s age groups compared with the DTI parameters of subjects in the 20s age group. Consequently, they concluded that the CST in normal subjects showed continuous degeneration from the 20s to the 70s, and degeneration of the CST begins to manifest significantly in the 50s [11]. In 2012, in a study investigating microstructural changes of the CST with aging in 84 healthy subjects (13–70 years), Sala et al. found linear relationships between age and mean diffusivity increase, and fractional anisotropy decrease using a quadratic model [27]. In a recent study, Lebel et al. [2012] investigated DTI changes of the CST over the lifespan in 403 healthy subjects (5–83 years) [15]. They reported that the value of fractional anisotropy increased during childhood and adolescence, reached a peak at 35 years, and then decreased; in contrast, the value of mean diffusivity showed an opposite trend, decreasing first, reaching a minimum at 33.8 years, and then increasing later in life. Therefore, to the best of our knowledge, this is the first study to demonstrate differences of aging of the CST according to the cerebral origin. In conclusion, we investigated differences of aging of CST fibers according to the cerebral origin and found that the fiber number of CST fibers from the M2 was decreased in the 70s age group compared with the 20s–50s age groups. Because the main function of the M2 is motor planning and coordination, our results would be helpful in development of strategies for coping with aging of the CST. This study is limited in that there are no neurobehavioral data for CST fibers from each cerebral origin (M1, M2, and S1). Another limitation is that we did not have data for older people in the over 70s age group. Therefore, conduct of further complementary studies with neurobehavioral data for CST fibers according to the cerebral origin and data including older subjects over 80 years is warranted. Acknowledgement This work was supported by the DGIST R&D Program of the Ministry of Education, Science and Technology of Korea (14-BD-0401). References [1] J.S. Allen, J. Bruss, C.K. Brown, H. Damasio, Normal neuroanatomical variation due to age: the major lobes and a parcellation of the temporal region, Neurobiol. Aging 26 (2005) 1245–1260, discussion 1279–1282. [2] Y. Assaf, O. Pasternak, Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review, J. Mol. Neurosci. 34 (2008) 51–61. [3] T.E. Behrens, H.J. Berg, S. Jbabdi, M.F. Rushworth, M.W. Woolrich, Probabilistic diffusion tractography with multiple fibre orientations: what can we gain? NeuroImage 34 (2007) 144–155. [4] T.E. Behrens, H. Johansen-Berg, M.W. Woolrich, S.M. Smith, C.A. Wheeler-Kingshott, P.A. Boulby, G.J. Barker, E.L. Sillery, K. Sheehan, O. Ciccarelli, A.J. Thompson, J.M. Brady, P.M. Matthews, Non-invasive mapping of connections between human thalamus and cortex using diffusion imaging, Nat. Neurosci. 6 (2003) 750–757. [5] J.L. Bowden, P.A. McNulty, The magnitude and rate of reduction in strength, dexterity and sensation in the human hand vary with ageing, Exp. Gerontol. 48 (2013) 756–765. [6] K. Brodmann, L.J. Gary, Brodmann’s Localisation in the Cerebral Cortex: The Principles of Comparative Localisation in the Cerebral Cortex Based on the Cytoarchitectonics, Springer Limited, London, 2006. [7] E. Carmeli, H. Patish, R. Coleman, The aging hand, J. Gerontol. Ser. A: Biol. Sci. Med. Sci. 58 (2003) 146–152. [8] R.A. Davidoff, The pyramidal tract, Neurology 40 (1990) 332–339. [9] J.H. Hong, J. Lee, Y.W. Cho, W.M. Byun, H.K. Cho, S.M. Son, S.H. Jang, Limb apraxia in a patient with cerebral infarct: diffusion tensor tractography study, Neurorehabilitation 30 (2012) 255–259.
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