Functional neuroimaging and neurophysiological patterns during Zolpidem-induced behavioral improvement in akinetic mutism: a pilot study

Akinetic mutism (AM) is a rare, but severe medical condition characterized by
apathy, urinary incontinence and a near-total absence of spontaneous motor
behavior and speech, despite an intact level of consciousness. Typically,
patients have either bilateral thalamic damage or generalized post-anoxic
encephalopathy, although various other focal brain lesions have been described
to cause AM. There is no treatment for AM and its pathophysiology remains
unknown. Zolpidem, a short-acting non-benzodiazepine compound of the
imidazopyridine class is a sedative that is primarily used for the treatment of
insomnia, but is also known to have a paradoxical effect on arousal in a small
subgroup of patients with a severe chronic disorder of consciousness after
traumatic brain injury. In 2007, a case-report was published, describing an AM
patient who markedly improved following Zolpidem administration. However, the
effects were transient and only lasted for a few hours. Moreover, the effects
seemed to 'wear-off' in the long-term. In the Netherlands, two AM patients are
known who also show remarkable, though short-lasting improvements in speech and
motor behavior after administration of Zolpidem. The paradoxical effects of
Zolpidem remain unexplained. Fundamental electrophysiological and functional
neuroimaging research is necessary to analyze the cortical and subcortical
effects of Zolpidem in AM. Unravelling the mechanisms of action of Zolpidem in
AM might hold the key to our understanding of AM and its functional
reversibility. It might thereby open doors to possible future therapies, such
as deep brain stimulation.

To explore the neurophysiological and functional neuroimaging effects of
Zolpidem on brain function in AM patients.

A prospective pilot study.

AM is a rare and severe neurological disorder. There is currently no
evidence-based treatment for definitive improvement or restoration of arousal
in patients suffering from AM. There is only palliative care. In total, two
patients have been identified in Dutch nursing homes. Zolpidem is a last-resort
medical treatment for AM that temporarily improves arousal. Its effects remain
unexplained. In order to discover the therapeutic target areas of Zolpidem in
the brain, it is necessary to explore its underlying neurophysiological effects
with fMRI, EEG, and MEG. The burden of the current study consists of 2x
transportation to the hospital (1x AMC and 1x VUmc) and two mornings with
non-invasive investigations: fMRI and EEG (AMC) and MEG (VUmc). This minimal
burden and minimal risk is considered proportionate while the study might
(in)directly benefit AM patients. After all, the results of the study might
help to define the working mechanism of Zolpidem in AM and determine cortical
and subcortical areas that are a suitable target for additional medicinal or
interventional therapies. Moreover, the study might contribute to further
development of scientific foundations of both AM and Zolpidem-effects in
disorders of consciousness. Thereby, it might indirectly benefit a much larger
group of patients with severe brain damage and (chronic) disorders of
consciousness.