Pain Perception in Disorder of Consciousness: A Scoping Review on Current Knowledge, Clinical Applications, and Future Perspective

Rocco Salvatore Calabrò, Loris Pignolo, Claudia Müller-Eising, Antonino Naro, Rocco Salvatore Calabrò, Loris Pignolo, Claudia Müller-Eising, Antonino Naro

Abstract

Pain perception in individuals with prolonged disorders of consciousness (PDOC) is still a matter of debate. Advanced neuroimaging studies suggest some cortical activations even in patients with unresponsive wakefulness syndrome (UWS) compared to those with a minimally conscious state (MCS). Therefore, pain perception has to be considered even in individuals with UWS. However, advanced neuroimaging assessment can be challenging to conduct, and its findings are sometimes difficult to be interpreted. Conversely, multichannel electroencephalography (EEG) and laser-evoked potentials (LEPs) can be carried out quickly and are more adaptable to the clinical needs. In this scoping review, we dealt with the neurophysiological basis underpinning pain in PDOC, pointing out how pain perception assessment in these individuals might help in reducing the misdiagnosis rate. The available literature data suggest that patients with UWS show a more severe functional connectivity breakdown among the pain-related brain areas compared to individuals in MCS, pointing out that pain perception increases with the level of consciousness. However, there are noteworthy exceptions, because some UWS patients show pain-related cortical activations that partially overlap those observed in MCS individuals. This suggests that some patients with UWS may have residual brain functional connectivity supporting the somatosensory, affective, and cognitive aspects of pain processing (i.e., a conscious experience of the unpleasantness of pain), rather than only being able to show autonomic responses to potentially harmful stimuli. Therefore, the significance of the neurophysiological approach to pain perception in PDOC seems to be clear, and despite some methodological caveats (including intensity of stimulation, multimodal paradigms, and active vs. passive stimulation protocols), remain to be solved. To summarize, an accurate clinical and neurophysiological assessment should always be performed for a better understanding of pain perception neurophysiological underpinnings, a more precise differential diagnosis at the level of individual cases as well as group comparisons, and patient-tailored management.

Keywords: functional connectivity; minimally conscious state (MCS); neurophysiology; nociception; pain; prolonged disorders of consciousness (PDOC); unresponsive wakefulness syndrome (UWS).

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Illustration of the key brain areas related to pain processing and perception. They comprise densely interconnected sensory or discriminative (yellow tags), affective (blue tags), and associative areas (red tags). Brainstem and diencephalic areas are embedded within the autonomic nervous system (ANS) and can be evaluated using specific measures (including hearth rate variability). Sensory and/or nociceptive evoked potentials (EPs) and gamma-band oscillations (GBO) recorded using EEG can follow nociceptive stimulation (blue shock) combined or not with cortical stimulation using, e.g., transcranial magnetic stimulation (yellow shock). These represent the main neurophysiological paradigms available in the literature to gain objective measures of pain processing in PDOC patients. Legend: PFC, prefrontal cortex; ACC, anterior cingulate cortex; In, insula; Bg, basal ganglia; Am, amygdala; Hi, hippocampus; Th, thalamus; bs, brainstem; SC, spinal cord; SSC, somatosensory cortex; PPC, posterior parietal cortex.
Figure 2
Figure 2
Shows the search strategy we used to select pain assessment studies in patients with PDOC.

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