Akinetic mutism, parkinsonism and the mesocircuit hypothesis
Syndromes in the AM spectrum are among the clinical conditions that may hamper the bedside detection of consciousness (Pincherle et al. , 2021). AM causes a specific impairment of initiating motor responses even after prompting, despite a preserved intrinsic capacity to move (Freemon, 1971). As such, the spectrum of clinical presentation may range from a total unresponsiveness (complete variant) to a sporadic production of words and volitional movements, though with a delay in the initiation and poor reproducibility (Arnts et al. , 2020).
Although AM is often discussed under the umbrella of “DoC” (Némethet al. , 1986; Wijdicks & Cranford, 2005; Shetty et al. , 2009), there are only few studies specifically aimed at disentangling the impairment of responsiveness from the impairment of consciousness in these patients (Kotchoubey et al. , 2003; Naccache et al. , 2004). In fact, a comprehensive multimodal assessment including the currently recommended conventional and advanced tools for DoC diagnosis has not been systematically conducted so far.
Due to the low incidence of AM, the majority of studies were single-case reports, mostly with CT-scan (Ure et al. , 1998; Nagaratnamet al. , 2004; Shetty et al. , 2009), and more advanced techniques, such as TMS-EEG to longitudinally track capacity for consciousness or fMRI to identify residual volitional abilities have not been employed before this case.
An intriguing aspect of the present exploration is the remarkable degree of overlap, both at the anatomical and at the clinical level, between the unresponsiveness typical of a DoC and the severe akinesia related to a dopamine depletion of an advanced parkinsonism (Formisano et al. , 2011; Formisano & Zasler, 2014; Comanducci et al. , 2022). Indeed, “akinetic” symptoms represent the end point on a clinical continuum including abulia (i.e., lack of will and motor initiative) and apathy (i.e. lack of emotional involvement) (Niedermeyer, 2008). This is perhaps not surprising as the neural circuits most affected in AM intersect both with those often involved in DoC (activating projections from the midbrain to the thalamus) and with those typically accounting for parkinsonism (mesolimbic, mesocortical and nigrostriatal dopaminergic projections) (Mega & Cohenour, 1997; Arnts et al. , 2020).
In this case, despite the behavioral unresponsiveness, clinical extrapyramidal symptoms such as the diffuse rigidity, Myerson’s sign and hypomimia after painful stimuli suggest a shared mechanism with parkinsonism based on dopaminergic dysfunction. Moreover, the role of amantadine in promoting recovery of consciousness further corroborated the hypothesis of a critical pathophysiological dysfunction within the dopaminergic projections (Spindler et al., 2021) and the midbrain(substantia nigra)-striatal-thalamic-frontal pattern of dysconnectivity which well matched the network proposed by the mesocircuit model (Schiff, 2010)
In this vein, the covert (fMRI-based) and then overt improvements in motor control and response initiative could be explained by a progressive restoration of function within the anterior forebrain mesocircuit network reflecting a spontaneous and amantadine-related re-activation of fronto-thalamic and basal ganglia outflow (Kraus & Maki, 1997; Thibaut et al., 2019; Formisano & Zasler, 2014).