Consciousness is a very vague concept with no widely accepted definition. Generally, it can be divided into two aspects: (1) Content-related consciousness (i.e., the local state) and (2) The awakening state (i.e., the global state) [1, 2, 3, 4]. Local states of consciousness include various perceptual experiences, for example, image, affect, body sensations and current thoughts. In the science of consciousness, local states are often referred to as contents of consciousness because they are usually distinguished from others by the objects and features they represent. However, global states of consciousness are not usually distinguished from one another based on the objects or features represented in experience. Rather, they are typically differentiated on the basis of cognitive, behavioral, and physiological factors [5]. The ability to stay awake and awareness of the environment are important characteristics of connection among conscious individuals [6].

Recently, with the rapid development of modern neuroscience and brain science, new technologies and strategies have been developed for the study of human and animal functions of consciousness. For this reason, the 2012 Cambridge Declaration on Consciousness was a turning point in the history of animal consciousness, stating in clear language that nonhuman animals have a similar state of consciousness to humans. Animals like humans, can sense, feel pain and have emotional responses [7]. Here, the main concern is the characteristics of consciousness in nonhuman primates. Ben-Haim et al. [8] used an elegant and simple visual counter-cuing task that found striking similarities between human and monkey behavior. The task required the subjects to shift their eyes from visual cues to reward goals. When the cue was displayed for 250 milliseconds, both subjects easily took their eyes off the cue. Conversely, when the cue was presented so briefly that the human reported not seeing it, neither human nor animal learned to look away and the behavior changed in the opposite direction. The cue captured attention, slightly increasing the amount of time the subjects looked at the reward location opposite the cue. Ben-Haim et al. [8] suggested that monkeys have both conscious and unconscious visual perception patterns based on the similarity between human and monkey eye movements. Conscious behavior suggests that nonhuman primate consciousness can be expressed as phenomenal consciousness. Being able to identify the self in a mirror is thought to be an effective means of verifying self-awareness. Chang et al. [9] found that trained rhesus monkeys spontaneously displayed the ability of mirror self-recognition through a new method of visual ontology position coupling training. Nonhuman primates do not have the ability to use language to express mental feelings. Some researchers have come up with ways to talk to them, with some remarkable results. Some researchers used hand gestures to communicate with them, while others simply spoke to them in American pantomime. The most interesting thing is to talk via the language of a keyboard, which has more than 200 keys, each printed with a different geometric pattern, one pattern representing a word or number. Chimps quickly learned to use this language system to communicate and express their needs [10]. This suggests that nonhuman primates are capable of perceiving external objects and associating with themselves, which is temporarily classified as access consciousness. Nonhuman primates show different awakening states in different brain injury states or different levels of anesthesia and they show different levels of loss of consciousness, as do humans. So, it is concluded feasible to use nonhuman primates as models for studying consciousness.

Nowadays, the survival rate of patients with severe brain injury and stroke has been greatly improved and there has been a large increase in the number of patients with clinical disorders of consciousness [11]. In the United States, approximately 100,000 to 300,000 people have been diagnosed with prolonged DoC, while in Europe the prevalence varies from 0.2 to 6.1 people per 100,000. There is no accurate data on prolonged DoC in China, but it is believed to have increased progressively there over time [12]. These people pose an extremely heavy burden on their families and society. For such reasons, there is strong motivation to seek improved treatments for consciousness disorders.

In clinical practice, recovery of consciousness (ROC) is rigorously assessed, including examination of cortical activity [13], spontaneous behavior and response to stimuli [14]. However, the detailed underlying mechanisms that support these changes remain unknown. Additionally, the lack of such information ultimately limits physicians in the accurate determination of levels of consciousness, which has a negative influence on making treatment plans to assess prognosis and estimated time to recovery from coma [15]. Currently, the understanding of DoC is largely dependent on individual case studies or clinical trials in different patient populations, which have limited ability to export data and implement controlled experimental designs [16]. It is predicted that preclinical models will provide precise control with reduced variability, rich data output and limited ethical complexity. Therefore, using animal models to elucidate unknown mechanisms appears to be the best choice. Rodents play a vital role in the study of disorders of consciousness, but they do not fully explain the mechanisms of disorders of consciousness and it is likely not possible to model certain types of DoCs (such as diffuse axonal injury) [17]. Nonhuman primates have a developmental pathway similar to that of humans in terms of anatomy, physiology, genetics, neurological function as well as their cognitive, emotional and social behavior [18]. Therefore, NHPs have a unique advantage in modeling DoCs.

Although objective techniques such as electroencephalography (EEG) [19], neuroimaging (e.g., positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) [20]) can be used to evaluate consciousness of substitutes. The American Academy of Neurology and the American Clinical Neurophysiology Society define quantitative EEG as: “…the mathematical processing of digitally recorded EEG in order to highlight specific waveform components, transform the EEG into a format or domain that elucidates relevant information, or associate numerical results with the EEG data for subsequent review or comparison” [21]. Spectral power analysis is a standard EEG method, increased low power ($\delta$ and $\theta$) and decreased high power ($\alpha$) in resting EEG are common spectral features in DoC patients [22]. Evoked potentials are “electrical manifestations of the brain’s reception of and response to an external stimulus” [21]. Several EEG markers, such as somatosensory evoked potential (SEP), auditory evoked potential (AEP) and event-related potential (ERP), are used in clinical routine and can be used to evaluate the prognosis of patients with DoC [23]. Functional imaging is able to detect local activity in different brain regions and explore their interactions. Resting-state fMRI and PET-CT analyses of whole-brain multiple network activation and connectivity strength add information to assessment and prognosis [24], however, fMRI and PET-CT studies easily produce motion artifacts, and patients with consciousness disorders have difficulty not moving limb parts, which causes problems with the evaluation of consciousness. Also, MR scanners are uncomfortable for patients with DoC. As a result, because these techniques are expensive, time-consuming and inconvenient to operate, behavioral test remains the best method for assessing human consciousness [25].

Robust operationally defined behavioral markers have been developed to distinguish conscious behaviors in clinical evaluation, particularly those scales that discriminate coma from related disorders of consciousness [26, 27]. However, progress in the assessment of levels of consciousness in nonhuman primates is surprisingly limited compared to the quantitative behavioral assessments used for patient evaluations [28]. When Gennarelli et al. [29] constructed a diffuse axonal injury model of nonhuman primates, they found it difficult to describe the severity of coma. Systems describing human comas are not satisfactory for laboratory animals. For example, the Glasgow Coma Scale cannot be used because it relies on language elements and the assessment of response to motor commands. So a behavioral scale was developed to describe the severity of the coma. Loss of consciousness (LoC) may occur in sleep anesthesia and pathological states. The reconstruction of brain function after consciousness interruption is similar to the recovery of simulated pathological states, so there is positive clinical significance in its study. It is difficult to study the mechanism of the process of recovery of consciousness in both the unpredictability of the recovery of pathological state and the rapidity of the recovery of sleep. General anesthesia is a controllable and repeatable intervention, so the recovery process can be systematically studied by influencing consciousness under anesthesia. Tassie et al. [30] and Redinbaugh et al. [31] have developed evaluation indexes for the anesthetic awakening behavior of nonhuman primates which are based on clinical assessment scales for evaluation of the level of consciousness in nonhuman primates. However, this must be studied further if such evaluation indexes are to have credibility. Alternatively, there is currently no assessment method to test the level of consciousness in nonhuman primate models, which means it is a significant challenge to establish animal models at different levels of consciousness. Therefore, it is necessary to develop a behavioral scale for the evaluation of consciousness disorders in nonhuman primates. Having objective indicators will also allow meaningful comparisons across studies and optimize preclinical results which, as a consequence, are more likely to be successfully translated from the laboratory to the clinic. This will eventually improve the testing of treatments and help in the accurate diagnosis of disorders of consciousness and brain damage. It also helps to elucidate the detailed underlying mechanisms behind the clinical consciousness assessment of behavior scale.

Nonhuman primates are very similar to humans in terms of genetic, neuroanatomical, cognitive and behavioral characteristics [18]. The authors’ efforts are focused on the development of a suitable tool for assessing levels of consciousness in nonhuman primate models based on a clinically typically consciousness assessment scale.

The aim is to form a behavioral scale to evaluate levels of consciousness in nonhuman primates, in the expectation that it will assist in progression of verification of the foregoing hypothesis. Meanwhile, it is proposed that the Delphi technique and level analysis method may be used as an effective way to select and include assessment indexes for the level of consciousness in nonhuman primates. Finally, for nonhuman primate model animals with disorders of consciousness, it is proposed that a combination of behavioral analysis and fMRI, EEG and PET-CT will suitably test the reliability and validity the of scale developed.

Loss of consciousness is a good model to study consciousness, including sleeping, anesthesia, coma and other disorders of consciousness. Currently, there are few studies on the assessment of consciousness in nonhuman primates. Tasserie [30] and Redinbaugh [31] proposed to evaluate the consciousness level of nonhuman primates in the process of anesthesia awakening based on clinical scales, but their evaluation method has not been confirmed to be accurate. Here, the interest is in loss of consciousness caused by disorders of consciousness such as coma. Although the hypothesis given above is also compiled based on clinical scales, the evaluation indicators proposed can be systematically verified by the Delphi method and associated objective techniques. A successful development of a behavioral scale for assessing the level of consciousness in nonhuman primates would be widely accepted in neuroscience. Meanwhile, it could overcome the difficulty of identifying the level of consciousness in the process of consciousness modeling of nonhuman primates and provide a valuable development to the field of consciousness and consciousness disorders.

The hypothesis described here is that nonhuman primate consciousness assessment scales can be constructed through literature review and Delphi method, with the main process being to extract indicators suitable for nonhuman primate consciousness assessment from existing consciousness assessment tools. Of course, it is not sufficient to construct a nonhuman primate consciousness scale by only a literature review, the selection of some indicators and evaluation of the importance of each indicator by experts. However, if behavioral changes of nonhuman primates can be observed in the process of consciousness recovery in combination with specific experiments, so as to explore the corresponding behavioral characteristics of different states of consciousness, a qualitative leap to the consciousness assessment scale constructed by Delphi method may be achieved.

Currently, it is difficult to construct a universally accepted scale for assessing the level of consciousness of nonhuman primates. Nonhuman primates are so valuable that studies are often limited by small sample sizes. And under the impact of the epidemic, it is difficult to carry out this work. So we want to use this hypothesis to call on a group of researchers who are interested in this research to do this work together. If a scientifically operable scale for assessing consciousness in nonhuman primates can be successfully developed, it may come into wide use and remove a further barrier to consciousness research.

DoC, disorders of consciousness; RoC, recovery of consciousness; EEG, electroencephalography; PET, positron emission tomography; fMRI, functional magnetic resonance imaging; PET-CT, positron emission tomography-computed tomography; SEP, somatosensory evoked potential; AEP, auditory evoked potentials; ERP, event-related potential; LoC, Loss of consciousness.

WMS and CLM designed the study. CL performed the part research of nonhuman primates. XLD and CHL performed the part research of rehabilitation medicine. WMS and GXL wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Not applicable.

We would like to express our gratitude to all those who helped us during the writing of this manuscript.

The work was supported in part by grants from the National Natural Science Foundation of China (31760276 and 31960171), the Jiangxi Natural Science Foundation (20171BAB204019 and 20192ACB20022), and the Jiangxi Provincial Special Fund for Postgraduate Innovation (YC2021-B021).

The authors declare no conflict of interest.