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).