A functional near-infrared spectroscopy study on hemodynamic changes of patients with prolonged disorders of consciousness responding to different auditory stimuli

doi:10.21203/rs.3.rs-2611331/v1

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A functional near-infrared spectroscopy study on hemodynamic changes of patients with prolonged disorders of consciousness responding to different auditory stimuli

https://doi.org/10.21203/rs.3.rs-2611331/v1

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published 23 Jun, 2023

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Treating prolonged disorders of consciousness (pDoC) is challenging. Thus, accurate assessment of residual consciousness in patients with pDoC is important for the management and recovery of patients. Functional near-infrared spectroscopy (fNIRS) can reflect brain activity through oxygenated cortical hemoglobin/deoxygenated hemoglobin (HbO/HbR) changes and has recently gained increasing attention for its potential applications in assessing residual consciousness. However, the number of fNIRS studies assessing residual awareness in patients with pDoC is still limited. The following study evaluates the brain function in 18 patients with pDoC (including 14 vegetative states [VS]) and 4 minimally conscious states [MCS]) and 15 healthy controls using two types of external stimuli, i.e., active stimulation (motor imagery) and passive stimulation (subject's own name [SON]) by fNIRS. The results showed that the mean concentrations of HbO/HbR in the prefrontal cortex of the healthy controls during the passive stimulation were significantly lower than those of the active stimulation, and the slope of the best-fit line was high. However, the hemodynamic responses of the patients with pDoC were opposite to the healthy controls. Additionally, the mean concentrations of HbO/HbR increased as the level of consciousness decreased during passive stimulation. Our findings suggest that the residual level of consciousness in pDoC patients can be assessed by measuring brain responses to different stimulations using fNIRS. The present study further demonstrates the feasibility andreliability of fNIRS in assessing residual consciousness in patients with pDoC, providing a basis for its expanded clinical application.

prolonged disorders of consciousness (pDoC)

functional near-infrared spectroscopy (fNIRS)

HbO/HbR

active stimulation

passive stimulation

Disorders of consciousness (DoC) arise from severe acquired brain injuries, which cause an interruption of continuity between the brain arousal and consciousness systems. Common causes of DoC include cerebrovascular disease, craniocerebral trauma, hypoxia, encephalitis, and poisoning. Prolonged disorder of consciousness (pDoC), also known as chronic DoC and defined as consciousness impairment lasting for more than 28 days, mainly including vegetative state (VS)/unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) [1–3]. Unlike coma (unresponsiveness from which the patient cannot be aroused and in which the patient's eyes remain closed), patients in a VS or MCS are awake. Patients in VS open their eyes spontaneously or in response to stimulation and present preserved autonomic functions, but they are not conscious and show only reflexive behaviors. By contrast, patients in MCS present some repeatable or intentional behaviors but cannot establish functional communication or demonstrate functional object use [4]. Therefore, accurate assessment of residual consciousness is important for managing patients with pDoC.

Several evaluation scales, such as the coma recovery scale-revised (CRS-R) [5], the complete overview of unresponsiveness (FOUR) [6, 7], MATADOC [8], and sensory modality assessment and rehabilitation techniques (SMART) [8, 9] are commonly used to clinically assess the residual consciousness in patients with pDoC. Nevertheless, it is difficult to obtain appropriate signs from the patients by these scales because some patients with pDoC are in a state of cognitive-motor dissociation (CMD), i.e., command following during functional magnetic resonance imaging (fMRI) and electroencephalogram (EEG) despite being unresponsive at the bedside [10, 11]. Neuroimaging and electrophysiological techniques have significantly facilitated the studies on the evaluation of residual awareness in patients with pDoC [12, 13]. Some studies have shown that fMRI may provide specific cortical features of loss of consciousness, and various dynamic features of EEG signals, and the level of consciousness can be indicated by amplitude and latency through auditory evoked responses, spectral power and signal complexity, and functional connectivity [14]. However, metal implants, critical conditions, and the use of anesthetics greatly limit the application of fMRI [15]. Craniotomies can result in highly abnormal EEG recordings [16]. Moreover, patients with pDoC result from damage to different brain networks or structures and have a wide range of etiologies. The patients causing specific cognitive abilities may be preserved, which makes different approaches and different stimuli may elicit more covert awareness. However, false negatives may occur in patients who are fatigued, lack understanding, or lack cognitive resources. The misdiagnosis rate of pDoC was be approximately 40% for the problems mentioned above [17–19]. Therefore, various reliable and stable methods are urgently needed to assess residual consciousness in pDoC patients [14, 20–21].

Functional near-infrared spectroscopy (fNIRS) is a non-invasive optical neuroimaging technique that can reflect brain activity through cortical oxygenated hemoglobin/deoxygenated hemoglobin (HbO/HbR) changes. With advantages such as portability, compatibility, movement tolerability, and higher safety, fNIRS has recently gained attention for its potential applications in assessing residual consciousness [22–24]. However, the use of fNIRS to assess residual consciousness in patients with pDoC has rarely been reported.

The evaluation of consciousness level is based on the patient's response level to external stimuli. Several studies showed that patients with pDoC respond differently to stimuli, suggesting that the stimulus selection is decisive for accurately evaluating pDoC patient status [14–15, 25]. We hypothesized that pDoC patients would respond differently to different levels of auditory stimulation and detect residual consciousness more accurately. In the present study, fNIRS was used to assess the residual consciousness in pDoC patients as well as healthy controls. We determined the level of consciousness by investigating differences in hemodynamics over the prefrontal cortex in response to name-call (hello, subject's own name [SON]) and motor imagery (MI) stimuli between the healthy controls and the pDoC patients. As expected, the pDoC patients with different residual consciousness presented different brain oxygen response patterns to the passive and the active stimulations. Our findings suggest that fNIRS can assess the residual level of consciousness in pDoC patients. The present study further demonstrates the feasibility and reliability of fNIRS in assessing residual consciousness in patients with pDoC, providing a basis for its expanded clinical application.

2.1 Participants

The participants were recruited from the Department of Neurological Rehabilitation, China Rehabilitation Research Center (Beijing, China) from June 2018 to December 2020. The inclusion criteria were: (1) 18–65 years of age; (2) etiology of stroke, traumatic brain injury (TBI), and anoxic, with a duration of more than one month; (3) normal sleep-wake cycle; (4) diagnosed as VS/UWS or MCS according to the CRS-R scale[26]; (5) intact I-V waves of auditory evoked potentials on at least one side; (6) ability to cooperate with the examination and treatment; (7) right-handed; (8) informed consent signed by the legal guardian.

The exclusion criteria were: (1) subjects who have changed their names; (2) epilepsy, sympathetic hyperexcitability, or spasticity without effective control; (3) treatment with hypnotics, antiepileptics, and/or antipsychotics for 2 weeks; (4) patients with local skull defects who could not wear the NIRS cap or could not cooperate with the examination and treatment for other reasons.

The CRS-R used to evaluate patients were quality controlled. Two clinicians (with 8 years experienced in the treatment of pDoC) trained in formal CRS-R evaluation assessed the patients three times and compared the mean scores. If the two scores differ, the two clinicians would jointly perform another test to obtain a uniform score.

A total of 18 patients with pDoC who met the strict criteria were finally selected to complete the experiment. The clinical characteristics of the patients are illustrated in Table 1. In parallel, healthy controls (7 males and 8 females, aged 25.93 ± 6.62 years) with normal hearing, no neurological disease, and no history of head injury were selected as the control group.

Written informed consent was obtained from each healthy subject or the patient's legal guardian for each patient in this study. This study was approved by the Ethics Committee of the China Rehabilitation Research Center (Ethics Number CRRC-IEC-RF-SC-005-01).

Table 1

Clinical features of patients with pDoC
	Diagnosis	Gender	Age (years)	Duration of DoC (months)	Etiology	CRS-R
Patient 1	VS	M	57	2.8	Stroke	6
Patient 2	VS	M	55	3.4	TBI	6
Patient 3	VS	M	60	2.3	Anoxic	6
Patient 4	VS	M	64	2.2	Stroke	5
Patient 5	VS	M	47	2.8	Stroke	4
Patient 6	VS	M	41	19.9	Stroke	5
Patient 7	VS	M	60	2.8	Anoxic	5
Patient 8	VS	M	31	25.2	Anoxic	7
Patient 9	VS	F	45	15.5	Anoxic	7
Patient 10	MCS	M	65	4.0	TBI	16
Patient 11	MCS	M	48	1.7	Stroke	14
Patient 12	VS	F	23	7.6	TBI	7
Patient 13	MCS	F	45	6.4	TBI	14
Patient 14	VS	M	44	3.1	TBI	6
Patient 15	VS	M	59	8.2	Stroke	7
Patient 16	VS	F	50	2.3	Stroke	7
Patient 17	VS	M	46	4.1	TBI	5
Patient 18	MCS	M	21	14.2	Anoxic	11

VS, vegetative state; MCS, minimally conscious state; CRS-R, coma recovery scale-revised; TBI, traumatic brain injury

2.2 Study design

Each subject was given two different stimuli: the SON command (“hello, name of the subject”) and the MI command (imagine raising his/her right hand). The stimuli were presented using auditory commands. For the sound stimuli, words for dubbing were synthesized using iFlytek dubbing software, standard Mandarin male speech, medium speed, 60–70 decibel (dB). The sound was stored in MP3 format, and the stimulation program was presented using EPRIME2.0 software (Psychology Software Tools, Inc., Pittsburgh, PA, USA). The experimental protocol was block-designed. Specifically, the experimental paradigm for each kind of stimulation was consisted of an initial baseline (60 s) followed by 8 blocks. Each block comprised a task period (30 s) and a recovery period (40 s) [22, 27]. The same auditory instructions were repeated 5 times during the SON and MI task period. The 2 stimuli were randomly presented at 60 s intervals. The experimental protocol of this study is shown in Fig. 1.

2.3 Data acquisition and analysis

The fNIRS signals of the left prefrontal cortex with 5 channels were measured by the Oxymon MK III (Artinis Medical Systems BV, Nijmegen, The Netherlands) at 760 and 830 nm with a sampling rate of 10 Hz. The acquisition of fNIRS signals consisted of three light sources and two receivers, and the layout of the fNIRS optodes is shown in Fig. 2. The midpoint between the light sources and the light detectors was placed 3 cm above the center of the upper edge of the left orbital fossa; the distance between the source and the detector pairs was 3 cm.

fNIRS signals were converted into HbO/HbR signals based on the modified Beer-Lambert law (MBLL). The Z-score method was used to normalize HbO/HbR signals [28]. In order to obtain pure HbO/HbR signals, this study carried out signal pre-processing intending to solve cardiac and respiratory interferences and motion artifacts. There are many physiologic disturbances in human cerebral oxygen signals (respiratory wave interference [0.2–0.5 Hz] and cardiac interference [0.8–1.5 Hz]). In addition, a baseline drift trend of extremely low frequency (< 0.006 Hz) in cerebral blood oxygen signals was observed. Therefore, the normalized HbO/HbR signals were processed by a band-pass filter (frequency band, 0.01–0.2 Hz) to eliminate baseline drift and heartbeat interference. To eliminate motion artifacts in the signal, Correlation-based Signal Improvement (CBSI) was used. CBSI method is a channel-by-channel method used to filter motion artifacts proposed by Cui et al.[29]. This approach builds on the hypothesis of a change in HbO and HbR, assuming that the response of HbO and HbR induced by brain function shows opposite trends, while the response of exercise interference to HbO and HbR leads to consistent trends. Sabrina et al. compared several methods of motion artifact removal and found that CBSI and wavelet methods have a better effect on fNIRS motion artifact removal, and the physiological principle of the CBSI method is clear, simple, and rapid [30]. After pre-processing of HbO/HbR signals, two physiologic indices were obtained, i.e., the mean concentration value and the slope of a line of best fit in the task interval after stimulation. The HbO/HbR signals 3 seconds before task stimulation were used as baseline values to obtain physiologic indices. Then, the baseline values were subtracted from the data between 3 seconds before stimulation and 40 seconds after stimulation, and the brain functional response curves of HbO/HbR signals in the task interval were obtained. The mean concentration was the mean value of the brain functional response curve of HbO/HbR signals from 2–20 seconds after task stimulation. For the slope of a line of best fit, the linear fitting method was used to obtain the best estimate of the slope of a signal segment, calculated as the slope of a line of best fit of the brain functional response curve of HbO/HbR signals from 5–15 seconds after task stimulation [31].

2.4 Statistical analysis

All data were statistically analyzed using SPSS 22.0 at α = 0.05 significance level. GraphPad Prism 8.0 software was used for statistical charts. The mean ± standard error (SEM) was used for measurement data. Because the data were not normally distributed, the rank-sum test was used for statistical analysis. The comparisons of the two groups were analyzed by means of the nonparametric Mann-Whitney U test. The comparisons of the three groups were analyzed by means of the Kruskal-Wallis test. A p-value < 0.05 was considered statistically significant.

3.1 The time course of the hemodynamic responses during the SON and MI tasks

As shown in Fig. 3A and B, the group-averaged hemodynamic responses of the healthy controls presented the “inverted” pattern (that is negative hemodynamic response) characterized by a decrease in HbO and HbR concentrations. Specifically, for both SON and MI tasks, the hemodynamic responses over the prefrontal cortex were relatively stable during the baseline period. At the task onset, the HbO and HbR concentrations over the prefrontal cortex were decreased.

The group-averaged hemodynamic responses of the pDoC patients were presented different distribution pattern in compared with the healthy controls. Specifically, for both the SON and MI tasks, the hemodynamic responses over the prefrontal cortex were relatively stable during the baseline period. However, after the onset of the task, the changes of the hemodynamic responses of the SON and MI tasks were different from each other. As shown in Fig. 3C, the group-averaged hemodynamic responses of the pDoC patients showed the “typical” hemodynamic response, characterized by an increase in HbO concentration accomplished by a small increase in HbR concentration during the SON task. As shown in Fig. 3D, the hemodynamic responses of group-averaged pDoC patient are characterized by a slightly increase in HbO and HbR concentrations during the MI task.

3.2 Differences in hemodynamic responses between SON and MI stimuli in healthy controls

As shown in Fig. 4, the mean HbO/HbR concentrations over the prefrontal cortex of the healthy controls during the MI condition were much higher than after SON stimulation (HbO, Z=-4.345, p = 0.000; HbR, Z=-2.241, p = 0.025) (Fig. 4A, C). Interestingly, the HbO and HbR concentrations were negative at the group level. In addition, the rates of change in HbO concentrations, namely the fitting slope, were much lower for the MI condition than the SON stimulation (Z=-5.687, p = 0.000) (Fig. 4B). In consistent with the trend of HbO, the HbR fitting slope of MI stimulation was much lower than that of SON stimulation, but there was no significant difference (Z=-0.196, p = 0.845) (Fig. 4D).

For the pDoC patients, the changes in the hemodynamic responses were different from those of the healthy controls. Specifically, as shown in Fig. 5, the mean values of the HbO/HbR concentration during the MI condition were significantly lower than after SON stimulation for the pDoC patients. Unlike the healthy controls, the HbO and HbR concentrations of pDoC were positive during the SON tasks (HbO, Z=-0.712, p = 0.477; HbR, Z=-1.210, p = 0.223) (Fig. 5A, C). The differences in the fitting slopes of HbO/HbR between the two stimuli were not statistically significant (HbO, Z=-1.497, p = 0.134; HbR, Z=-0.132, p = 0.895) (Fig. 5B, D). Thus, these results indicate that healthy controls and the pDoC patients might present different patterns of hemodynamic responses to the SON and MI stimuli. In addition, the response patterns of pDoC patients were opposed to those of the healthy controls when subjected to SON and MI stimulations.

3.3 The healthy controls and pDoC patients responded differently to the SON stimulation

To further determine the differences in the hemodynamic response of the healthy controls and pDoC patients when subjected to the same stimulation, we analyzed the mean HbO/HbR concentrations between the controls and patients. As shown in Fig. 6, the HbO/HbR concentrations of pDoC patients were significantly higher than that of the controls under the SON stimulation (HbO, Z=-8.025 p = 0.000; HbR, Z=-3.954, p = 0.000) (Fig. 6A, B). The fitting slope of HbO was significantly lower in patients than that of healthy controls (Z=-3.895, p = 0.000) (Fig. 6E), whereas the fitting slope of HbR was much higher in patients than in healthy controls (Z=-2.132, p = 0.036) (Fig. 6F).

When stimulated by MI, the HbR concentration was significantly higher in pDoC patients (Z=-2.261, p = 0.024) (Fig. 6D), and the HbO concentration had the same trend, but it was not significant (Z=-1.934, p = 0.052) (Fig. 6C). The fitting slope of HbO in patients was much higher than that of the healthy controls (Z=-3.172 P = 0.000) (Fig. 6G). No significant differences were observed in the fitting slope of HbR (Z=-1.559, p = 0.119) (Fig. 6H). These data suggested that the task-evoked hemodynamic responses of the pDoC patients were positive activation, while the task-evoked hemodynamic responses of healthy controls were negative activation. Under the MI condition, a strong trend was observed where the concentrations and fitting slope in pDoC patients were higher than in the controls. The results indicate that the pDoC patients have different responses during SON.

3.4 Differences in the hemodynamic responses among the MCS patients, VS patients, and the healthy controls under the SON stimulation

In order to further investigate the differences in hemodynamic responses under the SON and MI tasks, the mean values and the fitting slope of the HbO/HbR concentrations were quantitatively compared among the MCS, VS, and healthy controls. As shown in Fig. 7, under the SON stimulation, the HbO/HbR concentrations of the VS patients were higher than those of the MCS patients. The HbO/HbR concentrations of the MCS patients were higher than those of the healthy controls (HbO, H = 65.38, p = 0.000; HbR, H = 30.025, p = 0.000) (Fig. 7A, B). The HbO/HbR concentration in healthy controls, MCS, and VS patients went from negative to positive after SON stimulation. The HbO/HbR fitting slope of the MCS patients was higher than that of the other two groups (HbO, H = 40.773, p = 0.000; HbR, H = 38.281, p = 0.000) (Fig. 7E, F). Under the MI condition, there was a trend that the HbO/HbR concentrations of the VS patients were higher than that of the other groups (HbO, H = 6.018, p = 0.052; HbR, H = 6.249, p = 0.043) (Fig. 7C, D). The HbO/HbR fitting slope of the MCS was significantly higher than that of the VS patients and the controls (HbO, H = 26.572, p = 0.000; HbR, H = 33.648, p = 0.000) (Fig. 7G, H). These results indicated that the VS patients, the MCS patients, and the controls respond differently to SON stimuli.

In the present study, we used fNIRS to compare the hemodynamic changes of the prefrontal lobe in patients with pDoC and healthy controls in response to different auditory stimuli, including active stimulation (MI) and passive stimulation (SON). Healthy controls presented negative activations over the prefrontal cortex during both conditions; the negative activations were more pronounced under SON stimulation. The pDoC patients with different levels of residual consciousness showed different patterns of the hemodynamics of the SON and the MI stimulations compared to healthy controls, and prefrontal HbO/HbR gradually changed from negative to positive activation as the level of consciousness decreased.

Active paradigm studies have suggested that although patients with severe brain injury may not have any signs of awareness at the bedside, some of them can modulate brain activity according to commands and occasionally answer yes/no questions by performing mental imagery tasks [32]. EEG and/or fMRI can detect brain activity in approximately 15% of VS patients when stimulated by an active consciousness paradigm, which is indicative of covert cognitive ability [33, 34]. As a complex advanced auditory stimulus, the active stimulation paradigm often employed by DoC patients is motor imagery (MI), which shares a common neural network with motor execution and requires a higher level of consciousness to complete [25]. Increased HbO characterizes a typical MI-evoked hemodynamic response in movement-related regions [35]. However, because of the complexity, although the detection of covert awareness has high specificity, the sensitivity is very low [3]. In contrast, SON stimulation causes a more intense clinic response and brain activation in patients because it attaches emotion or some kind of familiarity [36, 37]. Therefore, SON is commonly used as a stimulation mode for detecting residual consciousness in patients with pDoC [38]. Accumulating studies based on neuroimaging and electrophysiological techniques have found that the response to the SON task is evident in the temporoparietal occipital lobe in patients with DoC [20, 38]. Therefore, combining the two stimulation modes (SON and MI) and observing the patient's response pattern to cerebral hemodynamics with two different stimulation levels can improve residual consciousness's evaluation accuracy. Peng Gui et al used EGG to detect residual awareness in DoC patients by auditory hierarchical language processing, and the results showed that the difference in the "residual awareness index" between the MCS and UWS groups progressively increased as the level of language hierarchy increased from rest to words, phrase and sentence conditions [14]. This sets the stage for us to detect residual awareness using different auditory stimuli. The prefrontal cortex, which is an important component of the conscious system, has a causal relationship with conscious perception [27, 39, 40]. In addition, the prefrontal skeleton is relatively intact in most patients with pDoC. Moreover, acquiring the hemodynamics over the prefrontal cortex is relatively easy as it is not disturbed by hair and patient’s lying posture and position. Therefore, here we examined hemodynamic changes in the prefrontal cortex of subjects.

HbO is an effective physiologic index used to describe the oxyhemoglobin content and oxygen molecular energy supply in the brain region, which can indirectly indicate the cerebral cortex's metabolic and functional activity intensity [41, 42]. In fNIRS studies, the mean value of the HbO concentration reflects the signal amplitude, while the slope indicates the rate of change in signal amplitude per unit of time [31, 43]. We found that when the three groups (HC, MCS, and VS) were compared, the slope of the hemodynamic responses in the MCS group was higher than in the other groups. Therefore, the reliability of the slope needs further research, and the mean change in the oxygenated hemoglobin concentration is a stable indicator. In the current study, we found that the prefrontal HbO/HbR was negative in healthy controls under two stimuli, which is consistent with previous findings [25, 44]. Holper identified this phenomenon as a decrease in HBO and⁄or an increase in HBR as “inverse oxygenation responses” or “negative activation”, which is often observed during MI tasks or other mental tasks and may be associated with specific tasks or with inhibition of activation in other brain regions [45]. In Kempny's study, motor movement and motor imagery tasks were used to evaluate consciousness in patients with pDoC and healthy controls. Also, the results showed that negative activations were observed in both groups and tasks. The BOLD response in MRI may respond to active inhibition of cortical areas or normal transcallosal inhibition [46]. Combined with the higher absolute value and slope of HbO concentration change during SON stimulation than MI stimulation, it is inferred that the normal brain responds more strongly to SON stimulation. However, the lack of statistically significant consistent response of pDoC patients to different stimulation patterns is related to the large heterogeneity of patients, and previous studies have found that only a small number of pDoC patients have a clear brain response to external stimuli. It cannot be denied that some patients and normal controls did not respond to active stimulation. Multiple tasks and neuroimaging modalities increase the likelihood of detecting covert awareness in patients with disorders of consciousness. Yet, this study first reported that the absolute value of activation change in healthy controls was significantly higher than that in pDoC patients during SON stimulation, and the degree of negative activation decreased or even turned positive with the decrease of the degree of residual consciousness. The possible reason is that the SON stimulation of normal subjects recruits a certain number of neurons for activation, producing a neurovascular coupling response. Yet, with the decrease in consciousness level, the destruction of consciousness-related neurons and neural networks can only cause a small number of brain responses. Even negative activation is a manifestation of brain activation responses. Resting-state fMRI studies have demonstrated high functional connectivity strength and high rates of cerebral blood flow and glucose metabolism of the default mode network, ie, the posterior cingulate cortex/precuneus, the medial prefrontal cortex, and the lateral temporal and parietal cortices, may serve as potential diagnostic biomarkers for consciousness level and for the prediction of recovery outcome [47]. As an optical tool, fNIRS cannot precisely localize brain regions as fMRI, but this study lays the foundation for further exploration of residual levels of consciousness.

There are some limitations in the present study. First, the sample of subjects is small and the heterogeneity is large. Strict inclusion criteria for pDoC patients, such as stable vital signs, minimal head and body movements, and normal cardiopulmonary function, limit the expansion of the sample size. Whether damage and loss of brain structures can cause inaccurate results needs to be further clarified. Second, this study's number of available optical channels was limited, so only the hemodynamics over the left prefrontal cortex was investigated. Moreover, the possible causes of the negative activation should also be explored. In further explorative study, advanced experimental design and improved techniques should be used to comprehensively investigate the residual awareness of the patient with DoC. We hope that, with the accumulation of patients, and the development of neuroimaging techniques and health care, the current findings will be tested soon.

As a pilot fNIRS study, we hope our study could provide useful insights into evaluating residual cognitive ability in this challenging patient population. Additionally, the experimental protocol used in this study has promising clinical utility in the field of disorders of consciousness.

The present findings demonstrate that pDoC patients with different residual consciousness present different patterns in hemodynamic response to different auditory stimuli. In addition, the active command-following task and the passive task based on fNIRS provide useful insights for assessing residual awareness in patients with pDoC. In further studies, we plan to apply this method to ICU patients to look for non-DoC patients presenting with locked-in syndrome and other causes that fail to make a visible clinical response to environmental stimuli. This will further validate the conclusions of this study and await the generation of new findings.

Ethics approval and consent to participate:

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the China Rehabilitation Research Center (Ethics Number CRRC-IEC-RF-SC-005-01) that informed consent was obtained from all subjects and their legal guardian(s)

Consent for publication: All authors have read and agreed to the published version of the manuscript.

Availability of data and materials: The raw data used to support the findings of this study are available at https://www.jianguoyun.com/p/DWpZLSsQ_ZWgChiRhKwE (Access Password：fQnKaq) or contact from the corresponding author upon request.

Competing interests: The authors declare no conflict of interest.

Funding: This work was supported by the Capital Special Project for Featured Clinical Application (Z181100001718066), Beijing Natural Science Foundation (Grant No. 4214080), and the R&D Program of Beijing Municipal Education Commission (Grant No. KM202011232008)

Authors' contributions: H.L. and J.J. conceptualized and designed the research experiment; H.L. wrote the original/revised drafts; J.J., J.S., and Y.W. designed and verified data analysis; H.L. J.S., and F.H. guided the direction of the work and collected data. All authors have read and agreed to the published version of the manuscript.

Acknowledgements: Thanks to all the subjects who participated in the experiments.

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No competing interests reported.

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A functional near-infrared spectroscopy study on hemodynamic changes of patients with prolonged disorders of consciousness responding to different auditory stimuli

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Journal Publication

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Abstract

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1. Introduction

2. Materials And Methods

2.1 Participants

2.2 Study design

2.3 Data acquisition and analysis

2.4 Statistical analysis

3. Results

3.1 The time course of the hemodynamic responses during the SON and MI tasks

3.2 Differences in hemodynamic responses between SON and MI stimuli in healthy controls

3.3 The healthy controls and pDoC patients responded differently to the SON stimulation

4. Discussion

5. Limitations And Future Directions

6. Conclusions

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1