Is circadian rhythmicity a prerequisite to coma recovery? Circadian recovery concomitant to cognitive improvement in two comatose patients

Abstract

Circadian rhythmicity (CR) is involved in the regulation of all integrated functions, from sleep‐wake cycle regulation to metabolic function, mood and cognition. However, the interdependence of CR, cognition and consciousness has been poorly addressed. To clarify the state of CR in coma and to determine the chronological relationship between its recovery and consciousness after brain lesions, we conducted a longitudinal observational study investigating how the state of CR was chronologically related with the recovery of behavioural wakefulness, cognition and/or awareness. Among 16 acute comatose patients, we recruited two 37‐year‐old patients with a persistent disorder of consciousness, presenting diencephalic lesions caused by severe traumatic brain injuries. Two biological urinary markers of CR were explored every 2 hours during 24 hours (6‐sulfatoxymelatonin, free cortisol) with a dedicated methodology to extract the endogenous component of rhythmicity (environmental light recording, near‐constant‐routine protocol, control of beta‐blockers). They presented an initial absence of rhythmic secretions and a recovered CR 7‐8 months later. This recovery was not associated with the restoration of behavioural wakefulness, but with an improvement of cognition and awareness (up to the minimally conscious state). MRI showed a lesion pattern compatible with the interruption of either the main hypothalamic‐sympathetic pathway or the accessory habenular pathway. These results suggest that CR may be a prerequisite for coma recovery with a potential but still unproven favourable effect on brain function of the resorted circadian melatonin secretion and/or the functional recovery of the suprachiasmatic nucleus (SCN). Assessing circadian functions by urinary melatonin should be further explored as a biomarker of cognition reappearance and investigated to prognosticate functional recovery.

Circadian Rhythm Dysregulation and Restoration: The Role of Melatonin

“…Historically, Nowak et al stated that both salivary and urinary melatonin measurement methods were strongly correlated with serum concentrations, and would be useful as non-invasive tests for melatonin concentration [66]. More recently in 2020, Rzepka-Migut and Paprocka detailed melatonin measurement considerations in an extensive systematic review, supporting this concept [67]. They found that urinary and salivary melatonin were useful for assessing serum concentrations non-invasively; however, there are a few caveats that must be considered when collecting these data [67].…”

“…More recently in 2020, Rzepka-Migut and Paprocka detailed melatonin measurement considerations in an extensive systematic review, supporting this concept [67]. They found that urinary and salivary melatonin were useful for assessing serum concentrations non-invasively; however, there are a few caveats that must be considered when collecting these data [67]. For urinary collection, liver and kidney function must be considered as melatonin is metabolized in the liver and excreted via urine [67].…”

“…They found that urinary and salivary melatonin were useful for assessing serum concentrations non-invasively; however, there are a few caveats that must be considered when collecting these data [67]. For urinary collection, liver and kidney function must be considered as melatonin is metabolized in the liver and excreted via urine [67]. Previous research has shown that when 6-sulfatoxymelatonin levels are corrected for creatinine, they strongly correlate with serum melatonin levels [67].…”

“…For urinary collection, liver and kidney function must be considered as melatonin is metabolized in the liver and excreted via urine [67]. Previous research has shown that when 6-sulfatoxymelatonin levels are corrected for creatinine, they strongly correlate with serum melatonin levels [67]. Salivary melatonin appears to be both temporally and quantitatively correlated with serum melatonin levels; the main consideration Rzepka-Migut and Paprocka stipulate is that salivary levels are approximately three times less than that of serum levels [67].…”

“…Previous research has shown that when 6-sulfatoxymelatonin levels are corrected for creatinine, they strongly correlate with serum melatonin levels [67]. Salivary melatonin appears to be both temporally and quantitatively correlated with serum melatonin levels; the main consideration Rzepka-Migut and Paprocka stipulate is that salivary levels are approximately three times less than that of serum levels [67]. Because melatonin is cyclically released as part of a circadian rhythm, the timing of collection plays a significant role in the validity of the measurement.…”