Unconsciousness or unresponsiveness in akinetic mutism? Insights from a multimodal longitudinal exploration

Abstract

The clinical assessment of patients with disorders of consciousness (DoC) relies on the observation of behavioural responses to standardised sensory stimulation. However, several medical comorbidities may directly impair the production of reproducible and appropriate responses, thus reducing the sensitivity of behaviour‐based diagnoses. One such comorbidity is akinetic mutism (AM), a rare neurological syndrome characterised by the inability to initiate volitional motor responses, sometimes associated with clinical presentations that overlap with those of DoC. In this paper, we describe the case of a patient with large bilateral mesial frontal lesions, showing prolonged behavioural unresponsiveness and severe disorganisation of electroencephalographic (EEG) background, compatible with a vegetative state/unresponsive wakefulness syndrome (VS/UWS). By applying an unprecedented multimodal battery of advanced imaging and electrophysiology‐based techniques (AIE) encompassing spontaneous EEG, evoked potentials, event‐related potentials, transcranial magnetic stimulation combined with EEG and structural and functional MRI, we provide the following: (i) a demonstration of the preservation of consciousness despite unresponsiveness in the context of AM, (ii) a plausible neurophysiological explanation for behavioural unresponsiveness and its subsequent recovery during rehabilitation stay and (iii) novel insights into the relationships between DoC, AM and parkinsonism. The present case offers proof‐of‐principle evidence supporting the clinical utility of a multimodal hierarchical workflow that combines AIEs to detect covert signs of consciousness in unresponsive patients.

International survey on the implementation of the European and American guidelines on disorders of consciousness

“…For instance, the creation or the enhancement of specialized hubs of DoCs expertise, at both national and international levels, may be a fruitful strategy to implement [ 21 ]. Elaborating a strategy for improving a multimodal diagnostic approach, particularly the use of neurotechnology (e.g., elaborating clear and consistent recommendations about when to use it, and introducing standards for the interpretation of emerging results) [ 28 , 29 ]. A promising model to further explore is, for instance, a structured approach to DoCs at the national level [ 30 ], possibly complementing it with relevant international collaborations.…”

Behavioral and cortical arousal from sleep, muscimol-induced coma, and anesthesia by direct optogenetic stimulation of cortical neurons

“…However, the perturbational complexity index--the most sensitive and specific maker of consciousness, validated in humans across many conditions of consciousness and unconsciousness—is similarly high in wakefulness and REM sleep in both humans (Massimini et al, 2010; Casarotto et al, 2016) and rodents (Cavelli et al, 2023). This further emphasizes the importance of distinguishing between consciousness and responsiveness (Sanders et al, 2012; Koch et al, 2016; Comanducci et al, 2023).…”

“…When humans dream, whether during REM sleep or NREM sleep, cortical activation, indexed like here by decreased slow wave activity, is observed primarily in posterior cortex, whereas prefrontal cortex remains deactivated (Siclari et al, 2017; Bernardi et al, 2019). Preserved consciousness accompanied by unresponsiveness or minimal responsiveness is also observed in neurological conditions, especially when associated with massive lesions of prefrontal-basal ganglia-thalamic circuits and of the dopaminergic system ((Schiff et al, 2014; Casarotto et al, 2016; Boly et al, 2017); for a striking example of akinetic mutism, see (Comanducci et al, 2023)). Thus, the induction of cortical arousal without behavioral arousal in our deep sevo-dex anesthesia condition may be due to the inability of cortical stimulation to activate prefrontal-basal ganglia-thalamic circuits, which seems to be one of the mechanisms that distinguish disconnected from connected consciousness (Sanders et al, 2012; Comanducci et al, 2023).…”

The reduction of sleep-like perilesional cortical dynamics underlies clinical recovery in stroke

“…Although outside of the realm of brain injuries, these studies support the existence of a causal relationship between the pathological presence of cortical bistability and the severity of cognitive/motor deficits also following focal brain injuries [14] as confirmed by our findings. Further supporting this view is the evidence from longitudinal TMS-EEG measurements in severe brain-injured patients which revealed a progressive reduction of sleep-like dynamics and the recovery of complex network interactions paralleling [11], and occasionally heralding [30, 43], the recovery of consciousness and behavioral responsiveness.…”