Neuroradiology DOI 10.1007/s00234-014-1419-y
DIAGNOSTIC NEURORADIOLOGY
Injury of the lower ascending reticular activating system in patients with hypoxic–ischemic brain injury: diffusion tensor imaging study Sung Ho Jang & Seong Ho Kim & Hyoung Won Lim & Sang Seok Yeo
Received: 9 June 2014 / Accepted: 30 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Many studies have reported on vulnerable areas and neural tracts of the brain after hypoxic–ischemic brain injury (HI-BI). However, little is known about injury of the ascending reticular activating system (ARAS). We attempted to investigate on injury of the lower portion of the ARAS in patients with HI-BI using diffusion tensor tractography (DTT). Methods Fourteen consecutive patients with HI-BI and 10 control subjects were recruited for this study. We classified the patients into two subgroups according to the preservation of arousal: subgroup A (eight patients)—intact arousal and subgroup B (six patients)—impaired arousal. The lower portion of the ARAS between the pontine reticular formation and the thalamus was reconstructed using the probabilistic tractography method. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) were measured. Results The FA value and TV were decreased in subgroup B compared with those of the control group, although no difference was observed in the MD value (p0.05).
S. H. Jang Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Gyeongsan, North Gyeongsang, Korea S. H. Kim Department of Neurosurgery, College of Medicine, Yeungnam University, Gyeongsan, North Gyeongsang, Korea H. W. Lim : S. S. Yeo (*) Department of Physical Therapy, College of Health Sciences, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 330-714, Republic of Korea e-mail: [email protected]
Conclusion Injury of the lower portion of the ARAS was found between the pontine reticular formation and the thalamus in patients with impaired arousal after HI-BI. We believe that analysis using DTT could be helpful in the evaluation of patients with impaired arousal after HI-BI. Keywords Diffusion tensor imaging . Hypoxic–ischemic brain injury . Ascending reticular activating system . Consciousness
Introduction Hypoxic–ischemic brain injury (HI-BI), a common cause of severe neurological disability, is characterized by reduction of oxygen supply to the brain, which is caused by various etiologies, including cardiac arrest, respiratory arrest, or poisoning [1, 2]. Various levels of arousal state can be seen during the recovery phase after HI-BI, and a significant portion of patients with HI-BI remain in an impaired state of arousal, such as a persistent vegetative state or a minimally conscious state [1, 3–7]. The persistent vegetative state is defined as a state of unconsciousness without awareness; in contrast, patients with minimally conscious state have partial preservation of conscious awareness and some level of attention [1, 3–7]. Many studies have reported on the vulnerable brain areas and neural tracts of HI-BI [7–13]. However, little is known about injury of the ascending reticular activating system (ARAS), which is responsible for arousal. Diffusion tensor imaging (DTI) is a technique that allows for evaluation of the integrity of white matter tracts by virtue of its ability to image water diffusion characteristics [14–16]. Diffusion tensor tractography (DTT), which is derived from DTI, has enabled three-dimensional reconstruction and estimation of neural tracts at the subcortical level [15, 17, 18]. Recent studies have reported on methods used for reconstruction of the
Neuroradiology
ARAS [19–21]. Although several studies using DTI or DTT have reported on neural injuries following HI-BI in patients with an adult brain, no study on injury of the ARAS in patients with HI-BI has been reported [11, 13, 22–25]. In the current study, using DTT, we attempted to investigate injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with HI-BI.
Subjects and methods Subjects Fourteen consecutive patients with HI-BI (six males, eight females; mean age 44.1; range 18 to 73) and 10 age- and sex-matched normal control subjects (four males, six females; mean age 44.1; range 20 to 74) with no history of neurologic or psychiatric disease were recruited for this study. Among patients with HI-BI who were admitted to the department of rehabilitation, 14 patients with HI-BI were recruited according to the following inclusion criteria: (1) an obvious history of HI-BI (cardiac arrest 11, respiratory arrest 2, toxic shock 1), (2) age range 18–75 years, (3) more than 2 months after HI-BI onset, and (4) no history of neurologic or psychiatric disorder. Using eye opening subscore of the Glasgow Coma Scale (GCS), we classified the patients into two subgroups according to the preservation of arousal: subgroup A—patients with intact arousal (eye opening subscore of GCS 4) and subgroup B—patients with impaired arousal (eye opening subscore of GCS 1–3) [1, 26]. GCS score was evaluated at the time of DTI scanning. The study protocol was approved by the institutional review board of a university hospital and the study was conducted retrospectively. Diffusion tensor image A six-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd., Best, The Netherlands) with single-shot echoplanar imaging was used for acquisition of DTI data. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure–posterior 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, b=1,000 s/mm2, NEX=1, and slice thickness of 2.3 mm (acquired voxel size 1.73×1.73×2.3 mm3). Probabilistic fiber tracking The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL;
www.fmrib.ox.ac.uk/fsl) was used for analysis of diffusionweighted imaging data. Affine multiscale two-dimensional registration was used for correction of head motion effect and image distortion due to eddy current. Fiber tracking was performed using a probabilistic tractography method based on a multifiber model and applied in the current study utilizing tractography routines implemented in FMRIB diffusion (5,000 streamline samples, 0.5-mm step lengths, curvature thresholds = 0.2) [27]. The pathway of the ARAS was determined by selection of fibers passing through single seed regions of interest (ROI) and the target (termination) ROI. A seed ROI was placed on the reticular formation of the pons on each hemisphere at the level of the trigeminal nerve entry zone [19, 28, 29]. The target ROI was given on the intralaminar nuclei of the thalamus at the level of the commissural plane [19, 28, 29]. Out of 5,000 samples generated from the seed voxel, results for contact were visualized at a threshold minimum of 1 streamlined through each voxel for analysis (Fig. 1). Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the lower portion of the ARAS between the pontine reticular formation and thalamus were measured. Statistical analysis SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA) was used for analysis of data. One-way ANOVA with LSD post hoc was used for determination of differences in each DTT parameter between the subgroups of patients and the control group. The level of statistical significance was set at p0.05). However, in subgroup B, the FA value and TV were significantly lower than those of the control group (p0.05). For MD, no significant difference was observed between all subgroups of patients and the control group (p>0.05) (Fig. 2).
Discussion In the current study, using DTT, we evaluated the lower portion of the ARAS between the pontine reticular formation
and the thalamus in patients with HI-BI and observed the following results: (1) the FA value and TV were decreased in subgroup B compared with those of the control group, although no difference was observed in the MD value, and (2) no difference in all DTT parameters in terms of the FA, MD, and TV was observed between subgroup A and the control group and between subgroups A and B. The FA value indicates the degree of directionality of water diffusion and has a range of 0 (completely isotropic diffusion) to 1 (completely anisotropic diffusion) [14–16, 33]. It represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures (e.g., axons, myelin, and microtubules), and the MD value indicates the magnitude of water diffusion, which can increase in some
Table 1 Demographic data for the patient and control groups Age (years) Sex, male/female Duration from onset (months) Etiology (cardiac arrest, respiratory arrest, toxic shock)
Subgroup A (n=8)
Subgroup B (n=6)
Control group (n=10)
49.4±17.4 4/4 9.7±9.4 7/0/1
37.0±14.6 2/4 6.6±7.3 4/2/0
48.1±15.1 7/8
Neuroradiology Table 2 Glasgow Coma Scale score for the patient groups Subgroup A
Subgroup B
Eye opening Best verbal response Best motor response Eye opening Best verbal response Best motor response Median (interquartile range) 4.0 5.0 (4.0–4.0) (5.0–5.0) Total 15.0 (15.0–15.0)
6.0 (6.0–6.0)
forms of pathology, particularly vasogenic edema or accumulation of cellular debris from axonal damage [14–16]. The TV 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 [33]. Therefore, decrement of the FA value and TV without change of the MD value may indicate injury of the neural tract [14–16, 33]. As a result, patients in subgroup B appeared to show injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus.
Fig. 2 Comparison of diffusion tensor imaging parameters of the ascending reticular activating system between the patient and control groups
2.5 2.5 (2.0–3.0) (2.0–3.0) 6.0 (5.3–6.8)
1.0 (1.0–1.0)
Previous studies have reported on vulnerable neural areas following HI-BI in the adult human brain [8, 12]. A higher metabolic rate, demand for oxygen and nutrients of the neurons in these locations, or their location in vascular border zones is related to vulnerability to HI-BI [34, 35]. These areas comprise the basal ganglia, hippocampus, cerebellum, thalamic nuclei, subthalamic nuclei, hypothalamus, and amygdala [7–10, 12]. Since the introduction of DTI, several studies have reported on DTI findings of HI-BI in patients with an adult brain [11, 13, 22–25]. Most of these studies
Neuroradiology
demonstrated neural injuries that were not directly related to the ARAS [11, 13, 22, 24, 25]. By contrast, in 2010, Newcombe et al. reported on differences observed on DTI findings of the brain stem in patients with a vegetative state following traumatic brain injury or HI-BI [36]. They found that DTI abnormalities in the brain stem were observed only in patients with TBI, although DTI abnormalities in the supratentorial gray and white matter were found in both patient groups [36]. However, they measured the whole midbrain, pons, and thalamus not specific to the ARAS. By contrast, in our study, the lower portion of the ARAS was reconstructed three-dimensionally, and DTT parameters were measured in patients with HIBI. Therefore, this is the first study to demonstrate injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with HI-BI. However, limitations of DTI and insufficient clinical data to determine the severity of impaired arousal should be considered in the interpretation of the results [37, 38]. First, the fiber tracking technique is operator dependent. Second, although DTI is a powerful anatomic imaging tool which can demonstrate the gross fiber architecture, DTI may underestimate the fiber tracts due to regions of fiber complexity and crossing can prevent full reflection of the underlying fiber architecture by DTI. Another limitation of this study was that we used only GCS score to determine the impaired arousal because the GCS score cannot represent the injury of attention which is an important component of arousal. In conclusion, we found injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with impaired arousal after HI-BI. We believe that DTT analysis for the ARAS could be helpful in the evaluation of patients with impaired consciousness after HIBI. In particular, early detection of injury of the ARAS would be helpful for early intervention for patients with impaired consciousness [39]. Therefore, conduct of further studies on the early stage of HI-BI and detailed classification of impaired arousal using other evaluation tools such as Coma Recovery Scale—Revised should be encouraged.
Ethical standards and patient consent We declare that all human and animal studies have been approved by the Institutional Review Board at Yeungnam University Medical Center and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Acknowledgments This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01001873). Conflict of interest We declare that we have no conflict of interest.
References 1. Lu-Emerson C, Khot S (2010) Neurological sequelae of hypoxicischemic brain injury. NeuroRehabilitation 26:35–45 2. Howard RS, Holmes PA, Siddiqui A et al (2012) Hypoxic-ischaemic brain injury: imaging and neurophysiology abnormalities related to outcome. QJM 105:551–561 3. Anderson CA, Arciniegas DB (2010) Cognitive sequelae of hypoxicischemic brain injury: a review. NeuroRehabilitation 26:47–63 4. Khot S, Tirschwell DL (2006) Long-term neurological complications after hypoxic-ischemic encephalopathy. Semin Neurol 26: 422–431 5. Dougherty JH Jr, Rawlinson DG, Levy DE et al (1981) Hypoxicischemic brain injury and the vegetative state: clinical and neuropathologic correlation. Neurology 31:991–997 6. Hoesch RE, Koenig MA, Geocadin RG (2008) Coma after global ischemic brain injury: pathophysiology and emerging therapies. Crit Care Clin 24:44–25, vii-viii 7. Mills VM, Cassidy JW, Katz DI (1997) Neurologic rehabilitation: a guide to diagnosis, prognosis, and treatment planning. Blackwell Science, Malden, MA 8. Chalela JA, Wolf RL, Maldjian JA et al (2001) MRI identification of early white matter injury in anoxic-ischemic encephalopathy. Neurology 56:481–485 9. Cummings JL, Tomiyasu U, Read S et al (1984) Amnesia with hippocampal lesions after cardiopulmonary arrest. Neurology 34: 679–681 10. Hawker K, Lang AE (1990) Hypoxic-ischemic damage of the basal ganglia. Case reports and a review of the literature. Mov Disord 5: 219–224 11. Hong JH, Jang SH (2010) Diffusion tensor imaging of neural tract injury in a patient with hypoxic-ischemic brain injury. Neural Regen Res 5:1825–1828 12. Huang BY, Castillo M (2008) Hypoxic-ischemic brain injury: imaging findings from birth to adulthood. Radiographics 28:417–439, quiz 617 13. Lee AY, Shin DG, Park JS et al (2012) Neural tracts injuries in patients with hypoxic ischemic brain injury: diffusion tensor imaging study. Neurosci Lett 528:16–21 14. Basser PJ, Pierpaoli C (1996) Microstructural and physiological features of tissues elucidated by quantitative-diffusion-tensor MRI. J Magn Reson B 111:209–219 15. Mori S, Crain BJ, Chacko VP et al (1999) Three-dimensional tracking of axonal projections in the brain by magnetic resonance imaging. Ann Neurol 45:265–269 16. Assaf Y, Pasternak O (2008) Diffusion tensor imaging (DTI)-based white matter mapping in brain research: a review. J Mol Neurosci 34: 51–61 17. Puig J, Pedraza S, Blasco G et al (2011) Acute damage to the posterior limb of the internal capsule on diffusion tensor tractography as an early imaging predictor of motor outcome after stroke. AJNR Am J Neuroradiol 32:857–863 18. Jang SH, Chang CH, Lee J et al (2013) Functional role of the corticoreticular pathway in chronic stroke patients. Stroke 44: 1099–1104 19. Yeo SS, Chang PH, Jang SH (2013) The ascending reticular activating system from pontine reticular formation to the thalamus in the human brain. Front Hum Neurosci 7:416 20. Edlow BL, Takahashi E, Wu O et al (2012) Neuroanatomic connectivity of the human ascending arousal system critical to consciousness and its disorders. J Neuropathol Exp Neurol 71: 531–546 21. Edlow BL, Haynes RL, Takahashi E et al (2013) Disconnection of the ascending arousal system in traumatic coma. J Neuropathol Exp Neurol 72:505–523
Neuroradiology 22. Kremer S, Renard F, Noblet V et al (2010) Diffusion tensor imaging in human global cerebral anoxia: correlation with histology in a case with autopsy. J Neuroradiol 37:301–303 23. Luyt CE, Galanaud D, Perlbarg V et al (2012) Diffusion tensor imaging to predict long-term outcome after cardiac arrest: a bicentric pilot study. Anesthesiology 117:1311–1321 24. Neil JJ (2008) Diffusion imaging concepts for clinicians. J Magn Reson Imaging 27:1–7 25. Scheurer E, Lovblad KO, Kreis R et al (2011) Forensic application of postmortem diffusion-weighted and diffusion tensor MR imaging of the human brain in situ. AJNR Am J Neuroradiol 32: 1518–1524 26. Cavanna AE, Shah S, Eddy CM et al (2011) Consciousness: a neurological perspective. Behav Neurol 24:107–116 27. Smith SM, Jenkinson M, Woolrich MW et al (2004) Advances in functional and structural MR image analysis and implementation as FSL. Neuroimage 23(Suppl 1):S208–S219 28. Afifi AK, Bergman RA (2005) Functional neuroanatomy: text and atlas, 2nd edn. Lange Medical Books/McGraw-Hill, New York 29. Daube JR (1986) Medical neurosciences: an approach to anatomy, pathology, and physiology by systems and levels, 2nd edn. Little, Brown and Co, Boston 30. Folstein MF, Folstein SE, McHugh PR (1975) Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 12:189–198
31. Teasdale G, Jennett B (1974) Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81–84 32. Giacino JT, Ashwal S, Childs N et al (2002) The minimally conscious state: definition and diagnostic criteria. Neurology 58:349–353 33. Seo JP, Jang SH (2013) Different characteristics of the corticospinal tract according to the cerebral origin: DTI study. AJNR Am J Neuroradiol 34:1359–1363 34. Cervos-Navarro J, Diemer NH (1991) Selective vulnerability in brain hypoxia. Crit Rev Neurobiol 6:149–182 35. Howard R, Trend P, Russell RW (1987) Clinical features of ischemia in cerebral arterial border zones after periods of reduced cerebral blood flow. Arch Neurol 44:934–940 36. Newcombe VF, Williams GB, Scoffings D et al (2010) Aetiological differences in neuroanatomy of the vegetative state: insights from diffusion tensor imaging and functional implications. J Neurol Neurosurg Psychiatry 81:552–561 37. Lee SK, Kim DI, Kim J et al (2005) Diffusion-tensor MR imaging and fiber tractography: a new method of describing aberrant fiber connections in developmental CNS anomalies. Radiographics 25: 53–65, discussion 66–58 38. Yamada K, Sakai K, Akazawa K et al (2009) MR tractography: a review of its clinical applications. Magn Reson Med Sci 8:165–174 39. Georgiopoulos M, Katsakiori P, Kefalopoulou Z et al (2010) Vegetative state and minimally conscious state: a review of the therapeutic interventions. Stereotact Funct Neurosurg 88:199–207
DIAGNOSTIC NEURORADIOLOGY
Injury of the lower ascending reticular activating system in patients with hypoxic–ischemic brain injury: diffusion tensor imaging study Sung Ho Jang & Seong Ho Kim & Hyoung Won Lim & Sang Seok Yeo
Received: 9 June 2014 / Accepted: 30 July 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract Introduction Many studies have reported on vulnerable areas and neural tracts of the brain after hypoxic–ischemic brain injury (HI-BI). However, little is known about injury of the ascending reticular activating system (ARAS). We attempted to investigate on injury of the lower portion of the ARAS in patients with HI-BI using diffusion tensor tractography (DTT). Methods Fourteen consecutive patients with HI-BI and 10 control subjects were recruited for this study. We classified the patients into two subgroups according to the preservation of arousal: subgroup A (eight patients)—intact arousal and subgroup B (six patients)—impaired arousal. The lower portion of the ARAS between the pontine reticular formation and the thalamus was reconstructed using the probabilistic tractography method. Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) were measured. Results The FA value and TV were decreased in subgroup B compared with those of the control group, although no difference was observed in the MD value (p0.05).
S. H. Jang Department of Physical Medicine and Rehabilitation, College of Medicine, Yeungnam University, Gyeongsan, North Gyeongsang, Korea S. H. Kim Department of Neurosurgery, College of Medicine, Yeungnam University, Gyeongsan, North Gyeongsang, Korea H. W. Lim : S. S. Yeo (*) Department of Physical Therapy, College of Health Sciences, Dankook University, 119, Dandae-ro, Dongnam-gu, Cheonan-si, Chungnam 330-714, Republic of Korea e-mail: [email protected]
Conclusion Injury of the lower portion of the ARAS was found between the pontine reticular formation and the thalamus in patients with impaired arousal after HI-BI. We believe that analysis using DTT could be helpful in the evaluation of patients with impaired arousal after HI-BI. Keywords Diffusion tensor imaging . Hypoxic–ischemic brain injury . Ascending reticular activating system . Consciousness
Introduction Hypoxic–ischemic brain injury (HI-BI), a common cause of severe neurological disability, is characterized by reduction of oxygen supply to the brain, which is caused by various etiologies, including cardiac arrest, respiratory arrest, or poisoning [1, 2]. Various levels of arousal state can be seen during the recovery phase after HI-BI, and a significant portion of patients with HI-BI remain in an impaired state of arousal, such as a persistent vegetative state or a minimally conscious state [1, 3–7]. The persistent vegetative state is defined as a state of unconsciousness without awareness; in contrast, patients with minimally conscious state have partial preservation of conscious awareness and some level of attention [1, 3–7]. Many studies have reported on the vulnerable brain areas and neural tracts of HI-BI [7–13]. However, little is known about injury of the ascending reticular activating system (ARAS), which is responsible for arousal. Diffusion tensor imaging (DTI) is a technique that allows for evaluation of the integrity of white matter tracts by virtue of its ability to image water diffusion characteristics [14–16]. Diffusion tensor tractography (DTT), which is derived from DTI, has enabled three-dimensional reconstruction and estimation of neural tracts at the subcortical level [15, 17, 18]. Recent studies have reported on methods used for reconstruction of the
Neuroradiology
ARAS [19–21]. Although several studies using DTI or DTT have reported on neural injuries following HI-BI in patients with an adult brain, no study on injury of the ARAS in patients with HI-BI has been reported [11, 13, 22–25]. In the current study, using DTT, we attempted to investigate injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with HI-BI.
Subjects and methods Subjects Fourteen consecutive patients with HI-BI (six males, eight females; mean age 44.1; range 18 to 73) and 10 age- and sex-matched normal control subjects (four males, six females; mean age 44.1; range 20 to 74) with no history of neurologic or psychiatric disease were recruited for this study. Among patients with HI-BI who were admitted to the department of rehabilitation, 14 patients with HI-BI were recruited according to the following inclusion criteria: (1) an obvious history of HI-BI (cardiac arrest 11, respiratory arrest 2, toxic shock 1), (2) age range 18–75 years, (3) more than 2 months after HI-BI onset, and (4) no history of neurologic or psychiatric disorder. Using eye opening subscore of the Glasgow Coma Scale (GCS), we classified the patients into two subgroups according to the preservation of arousal: subgroup A—patients with intact arousal (eye opening subscore of GCS 4) and subgroup B—patients with impaired arousal (eye opening subscore of GCS 1–3) [1, 26]. GCS score was evaluated at the time of DTI scanning. The study protocol was approved by the institutional review board of a university hospital and the study was conducted retrospectively. Diffusion tensor image A six-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Ltd., Best, The Netherlands) with single-shot echoplanar imaging was used for acquisition of DTI data. For each of the 32 non-collinear diffusion sensitizing gradients, we acquired 67 contiguous slices parallel to the anterior commissure–posterior 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, b=1,000 s/mm2, NEX=1, and slice thickness of 2.3 mm (acquired voxel size 1.73×1.73×2.3 mm3). Probabilistic fiber tracking The Oxford Centre for Functional Magnetic Resonance Imaging of the Brain (FMRIB) Software Library (FSL;
www.fmrib.ox.ac.uk/fsl) was used for analysis of diffusionweighted imaging data. Affine multiscale two-dimensional registration was used for correction of head motion effect and image distortion due to eddy current. Fiber tracking was performed using a probabilistic tractography method based on a multifiber model and applied in the current study utilizing tractography routines implemented in FMRIB diffusion (5,000 streamline samples, 0.5-mm step lengths, curvature thresholds = 0.2) [27]. The pathway of the ARAS was determined by selection of fibers passing through single seed regions of interest (ROI) and the target (termination) ROI. A seed ROI was placed on the reticular formation of the pons on each hemisphere at the level of the trigeminal nerve entry zone [19, 28, 29]. The target ROI was given on the intralaminar nuclei of the thalamus at the level of the commissural plane [19, 28, 29]. Out of 5,000 samples generated from the seed voxel, results for contact were visualized at a threshold minimum of 1 streamlined through each voxel for analysis (Fig. 1). Fractional anisotropy (FA), mean diffusivity (MD), and tract volume (TV) of the lower portion of the ARAS between the pontine reticular formation and thalamus were measured. Statistical analysis SPSS software (version 20.0, SPSS Inc., Chicago, IL, USA) was used for analysis of data. One-way ANOVA with LSD post hoc was used for determination of differences in each DTT parameter between the subgroups of patients and the control group. The level of statistical significance was set at p0.05). However, in subgroup B, the FA value and TV were significantly lower than those of the control group (p0.05). For MD, no significant difference was observed between all subgroups of patients and the control group (p>0.05) (Fig. 2).
Discussion In the current study, using DTT, we evaluated the lower portion of the ARAS between the pontine reticular formation
and the thalamus in patients with HI-BI and observed the following results: (1) the FA value and TV were decreased in subgroup B compared with those of the control group, although no difference was observed in the MD value, and (2) no difference in all DTT parameters in terms of the FA, MD, and TV was observed between subgroup A and the control group and between subgroups A and B. The FA value indicates the degree of directionality of water diffusion and has a range of 0 (completely isotropic diffusion) to 1 (completely anisotropic diffusion) [14–16, 33]. It represents the white matter organization: in detail, the degree of directionality and integrity of white matter microstructures (e.g., axons, myelin, and microtubules), and the MD value indicates the magnitude of water diffusion, which can increase in some
Table 1 Demographic data for the patient and control groups Age (years) Sex, male/female Duration from onset (months) Etiology (cardiac arrest, respiratory arrest, toxic shock)
Subgroup A (n=8)
Subgroup B (n=6)
Control group (n=10)
49.4±17.4 4/4 9.7±9.4 7/0/1
37.0±14.6 2/4 6.6±7.3 4/2/0
48.1±15.1 7/8
Neuroradiology Table 2 Glasgow Coma Scale score for the patient groups Subgroup A
Subgroup B
Eye opening Best verbal response Best motor response Eye opening Best verbal response Best motor response Median (interquartile range) 4.0 5.0 (4.0–4.0) (5.0–5.0) Total 15.0 (15.0–15.0)
6.0 (6.0–6.0)
forms of pathology, particularly vasogenic edema or accumulation of cellular debris from axonal damage [14–16]. The TV 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 [33]. Therefore, decrement of the FA value and TV without change of the MD value may indicate injury of the neural tract [14–16, 33]. As a result, patients in subgroup B appeared to show injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus.
Fig. 2 Comparison of diffusion tensor imaging parameters of the ascending reticular activating system between the patient and control groups
2.5 2.5 (2.0–3.0) (2.0–3.0) 6.0 (5.3–6.8)
1.0 (1.0–1.0)
Previous studies have reported on vulnerable neural areas following HI-BI in the adult human brain [8, 12]. A higher metabolic rate, demand for oxygen and nutrients of the neurons in these locations, or their location in vascular border zones is related to vulnerability to HI-BI [34, 35]. These areas comprise the basal ganglia, hippocampus, cerebellum, thalamic nuclei, subthalamic nuclei, hypothalamus, and amygdala [7–10, 12]. Since the introduction of DTI, several studies have reported on DTI findings of HI-BI in patients with an adult brain [11, 13, 22–25]. Most of these studies
Neuroradiology
demonstrated neural injuries that were not directly related to the ARAS [11, 13, 22, 24, 25]. By contrast, in 2010, Newcombe et al. reported on differences observed on DTI findings of the brain stem in patients with a vegetative state following traumatic brain injury or HI-BI [36]. They found that DTI abnormalities in the brain stem were observed only in patients with TBI, although DTI abnormalities in the supratentorial gray and white matter were found in both patient groups [36]. However, they measured the whole midbrain, pons, and thalamus not specific to the ARAS. By contrast, in our study, the lower portion of the ARAS was reconstructed three-dimensionally, and DTT parameters were measured in patients with HIBI. Therefore, this is the first study to demonstrate injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with HI-BI. However, limitations of DTI and insufficient clinical data to determine the severity of impaired arousal should be considered in the interpretation of the results [37, 38]. First, the fiber tracking technique is operator dependent. Second, although DTI is a powerful anatomic imaging tool which can demonstrate the gross fiber architecture, DTI may underestimate the fiber tracts due to regions of fiber complexity and crossing can prevent full reflection of the underlying fiber architecture by DTI. Another limitation of this study was that we used only GCS score to determine the impaired arousal because the GCS score cannot represent the injury of attention which is an important component of arousal. In conclusion, we found injury of the lower portion of the ARAS between the pontine reticular formation and the thalamus in patients with impaired arousal after HI-BI. We believe that DTT analysis for the ARAS could be helpful in the evaluation of patients with impaired consciousness after HIBI. In particular, early detection of injury of the ARAS would be helpful for early intervention for patients with impaired consciousness [39]. Therefore, conduct of further studies on the early stage of HI-BI and detailed classification of impaired arousal using other evaluation tools such as Coma Recovery Scale—Revised should be encouraged.
Ethical standards and patient consent We declare that all human and animal studies have been approved by the Institutional Review Board at Yeungnam University Medical Center and have therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We declare that all patients gave informed consent prior to inclusion in this study. Acknowledgments This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (2012R1A1A4A01001873). Conflict of interest We declare that we have no conflict of interest.
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