Relationship Between Injured Cingulum and Impaired Consciousness in Patients with Hypoxic-Ischemic Brain Injury

We investigated the relationship between cingulum injury and impaired consciousness in patients with hypoxic-ischemic brain injury (HI-BI) by using diffusion tensor tractography (DTT). Methods We recruited 29 patients with HI-BI and 25 normal control subjects. The patients were classied as intact consciousness (group A, 13 patients) or impaired consciousness (group B, 16 patients). The DTT parameters of fractional anisotropy (FA) and tract volume (TV) were estimated for both cinguli. Glasgow Coma Scale (GCS) and Coma Recovery Scale-Revised (CRS-R) scores were also evaluated. The FA and TV values of the cinguli in groups A and B were lower than those of the control group (p < 0.05), and the FA and TV values of group B were lower than those of group A (p < 0.05). The FA and TV values of the cinguli in group A were not signicantly correlated with GCS and CRS-R scores (p > 0.05); however, regarding the group B, the FA correlations with GCS (r = 0.457, p < 0.05) and CRS-R (r = 0.494, p < 0.05) and those of TV with GCS (r = 0.500, p < 0.05) and CRS-R (r = 0.491, p < 0.05) were moderately positive. Our results suggest that an injured cingulum could be an appropriate target for neurointervention or in


Introduction
Hypoxic-ischemic brain injury (HI-BI) may be caused by strangulation, cardiopulmonary arrest, respiratory failure, carbon monoxide poisoning, etc. Patients with HI-BI exhibit various sequelae, and impaired consciousness is a major sequela that is reported to have a high incidence rate; only 27% of HI-BI patients recover consciousness and the other 73% of patients either exhibit impaired consciousness or die Human consciousness is mainly controlled by the actions of the ascending reticular activating system (ARAS) (Paus, 2000;Zeman, 2001;Daube, 1986;A et al., 2005). However, several studies have reported that brain areas other than the ARAS are also involved in human consciousness (Horovitz et  We hypothesized that there would be a close relationship between injury of the cingulum and impaired consciousness in patients with HI-BI. Thus, in the current study, we investigated the relationship between injury of the cingulum and impaired consciousness in patients with HI-BI by assessing DTT parameters.

Subjects
Twenty-nine consecutive patients (19 men, 10 women; mean age, 45.9 ± 16.4 years, range, 18-74) were recruited according to the following inclusion criteria: (1) with an obvious HI-BI history (e.g., cardiac arrest, strangulation, CO intoxication, etc.), (2)  . The patients were classi ed into two groups according to consciousness status: intact consciousness (group A; GCS score ≥15 and CRS-R score ≥23) and impaired consciousness (group B; GCS score <15 or CRS-R score <23). Thirteen patients (8 men, 5 women; mean age 48.3 ± 17.3 years, range 18-66) were assigned to group A and sixteen patients (11 men, 5 women; mean age 47.5 ± 14.5 years, range 18-74) were assigned to group B. Twenty-ve age-and sex-matched healthy control subjects (14 men, 11 women; mean age 42.4 ± 13.5 years, range 21-72) were also recruited for the study. The demographic and clinical data of the patient and control groups are summarized in Table 1. No signi cant differences in age or sex composition were observed between the patient and control groups or between groups A and B. This study was conducted retrospectively, and written consent was obtained from the control subjects. The institutional review board of a university hospital approved the study protocol. Diffusion Tensor Imaging and Tractography DTI data were acquired at 6.13 ± 6.46 months after onset by using a 6-channel head coil on a 1.5 T Philips Gyroscan Intera (Philips, Best, Netherlands) with 32 non-collinear diffusion sensitizing gradients by single-shot echo-planar imaging. Imaging parameters were as follows: acquisition matrix = 96 × 96, reconstructed to matrix = 192 × 192, eld of view = 240 × 240 mm 2 , TR = 0.398 ms, TE = 72 ms, parallel imaging reduction factor = 2, echo-planar imaging factor = 59, b = 1000 s/mm 2 , NEX = 1, slice gap = 0 mm, and slice thickness = 2.5 mm. Each DTI replication was intra-registered to baseline "b0" images for correction of residual eddy-current image distortions and head motion effects by using a diffusion registration package (Philips Medical Systems). Fiber tracking was performed by using the ber assignment continuous tracking (FACT) algorithm implemented within the DTI task card software. The Statistical analysis SPSS software (v.15.0; SPSS, Chicago, IL, USA) was used for data analysis. The chi-squared test was used to assess differences in sex composition and an independent t-test was used to assess age differences between groups A and B. Paired t-tests were used to assess differences in DTT parameters of the cingulum between groups A and B. The Pearson correlation test was used to identify correlations between DTT parameters of the cingulum and the consciousness data (GCS and CRS-R). Results were considered signi cant when the p value was <0.05. A correlation coe cient of more than 0.60 indicated strong correlation, a correlation coe cient between 0.40 and 0.59 indicated moderate correlation, while that between 0.20 and 0.39 indicated weak correlation, and one less than 0.19 indicated a very weak correlation (Cohen J, 1988).

Results
A summary of the comparison of DTT parameters of cingulum between subgroup A and subgroup B and control groups is shown in Table 2. The values of FA and TV of the cingulum in the subgroup A and B were signi cantly different with those of the control group (p<0.05). The values of FA and TV of cingulum were signi cantly different between the subgroup A and B (p<0.05). Values represent mean ± standard deviations * : signi cant differences between patient and control groups, p<.05.
The correlations between DTT parameters, and GCS and CRS-R scores in the group A and B are shown in Table 3. In the group A, no correlation was observed between DTT parameters and GCS and CRS-R scores (p>0.05). However, regarding the group B, the moderate positive correlation was observed between GCS and the FA of the cingulum (r=0.457, p<0.05), and the TV of the cingulum (r=0.500, p<0.05). In terms of CRS-R, the moderate positive correlation was also observed in the value of FA of the cingulum (r=0.494, p<0.05), and the value of TV of the cingulum (r=0.491, p<0.05).

Discussion
In this study, we investigated the relationship between injury of the cingulum and impaired consciousness integrity (e.g., loss of myelination, axon diameter, ber density, or ber organization) and a low FA value suggest loss of white matter integrity (Assaf et al., 2008;Neil, 2008). The TV value is determined by the number of voxels included in a neural tract, thereby suggesting the total number of bers within the tract, and a low TV value re ects a loss of bers. Therefore, decrements in FA or TV levels in the cinguli of patient groups A and B indicate the presence of cingulum injuries (Jang et al., 2013).
Regarding the correlation between DTT parameters (FA and TV) and GCS and CRS-R scores, we observed that only patient group B showed correlations between DTT parameters and GCS or CRS-R scores.
Previous studies have demonstrated that the cingulate cortex, which is connected to other brain areas through the cingulum, is connected to thalamic nuclei, which is an area important for consciousness (Cauda et al., 2010;Assaf et al., 2008). In addition, many studies have demonstrated that the cingulate cortex, which is located above the cingulum, has an important role in consciousness (Horovitz et al., To the best of our knowledge, the current study is the rst to demonstrate, by using DTT, a relationship between injury of the cingulum and impaired consciousness in a large number of patients with HI-BI. However, some limitations of this study should be considered. First, DTT of the white matter of the brain can produce false negative results due to the presence of crossing bers and/or the result of the partial volume effect (Parker et al., 2005). Second, this retrospective study included a relatively small number of subjects. Thus, prospective studies including a larger number of subjects should be encouraged.
In conclusion, we found a signi cant relationship between injury of the cingulum and impaired consciousness in patients with HI-BI. Our results suggest that an injured cingulum should be a target during neurointervention or neurorehabilitation of patients with impaired consciousness following HI-BI.