We aim to investigate the role of pain perception in consciousness recovery in non-communicative severe brain injury (SBI) patients, during acute and subacute stage after the SBI. Acutely, SBI patients' brains suffer neuroplastic remodeling of key structures that, in favorable cases, support consciousness. Pain can largely alter brain plasticity, especially in chronic painful conditions, as the ones that may follow SBI at all stages (e.g. pain following the trauma itself, muscle pain due to spasticity, etc). We speculate that alterations of pain circuitry may concur to poor recovery of consciousness. Using a personalized source of thermal painful stimulation, in order to avoid useless and harmful stimuli, we will study pain responses in acute SBI patients by using neurophysiological and a task-related and resting state fMRI-based neural signature of pain (consistently developed in healthy subjects). We will support neuroimaging and neurophysiological data with clinical evaluation of pain (Nociception Coma Scale revised) and consciousness (Four Score and Coma Recovery Scale). We expect that differences in brain responses to pain among patients will predict good outcome and suggest possible therapeutic targets.
We aim to characterize the behavioral and functional brain responses to pain perception in SBI patients, according to their level of consciousness, and use them to predict the consciousness recovery, though two setting the cross-sectional (traversal) and the longitudinal designs.
In the cross-sectional, we suppose to better assess pain perception with the NCS-R scale by using a personalized rather than the standard noxious stimulation. We also expect that it could better clarify the relationship between the pain perception and the level of consciousness and highlight a possible role of pain networks in recovering patients.
Based on the data reported in the literature, we expect to confirm the pattern of brain activations found by Wagner and coworkers(11), including wide spread networks, in healthy subjects, in MCS patients and in those acute SBI patients with a better prognosis. By contrast, we expect a narrow but stronger activation of the limbic circuit in VS and poor prognosis patients. In the latter, due to the lack of control of the prefrontal cortices, painful stimuli can induce consolidation of implicit memory traces and stimulus-response automatisms in limbic system, enhancing the occurrence of to chronic painful or anxiety syndromes found in patients, experiencing painful inputs during depressed states of consciousness or other chronic painful conditions(22-24).
Also fMRI RSfC data will offer the opportunity to explore not only the simple activation in these abovementioned networks but also the functional connectivity patterns for both somatosensory and pain responses among groups (e.g. VS, MCS patients vs. healthy) and how these changes are correlated with behavior.
Moreover, for the first time, we will implement the use of SEP in resting condition and during noxious stimulation. Pain-related SEP responses have been proven to be a reliable marker of good outcome, however high-intensity SEP have been used in previous studies and it is impossible to disentangle the contribution of stimulation saliency from the one obtained by pain itself. In our design the SEP stimulation will be kept at sensory threshold during an innocuous and noxious thermal stimulation to observe if pain response in one brain hemisphere enhance the long-latency, widespread SEP responses induced in the contralateral one.
We believe that a quantitative measurement of pain in non-communicative SBI patients and its relationship with consciousness could provide new strategies to recognize, deal, and treat pain both in the first phase after SBI and in rehabilitation setting and possibly help to improve the final outcome.
In the longitudinal design, we aim to define if different pain responses are associated to different outcomes. Finding whether there are different patterns of activation in response to pain stimulation in patients with disorders of consciousness with longitudinal measurements is pivotal to understand if pain responses have an impact on consciousness recovery and pave the way for further research aimed to investigate if treating properly and promptly the pain could improve recovery of consciousness.
This research presents also an ethical value since, besides giving insight on mechanism by which neural networks support consciousness, it discloses the pain perception and eventually sufferance in patients otherwise unable to communicate their discomfort, helping in managing the pain intensity, reducing pain-provoking maneuvers, and improving treatment and rehabilitation efficacy. Collaterally, a validation of a personalized NCS-R with direct pain measurement can provide a valuable tool to use in clinical setting where instrumental investigation may be limited.