After a serious brain injury, some patients remain unconscious in coma with their eyes closed for several weeks. They are ‘unawake’ and unaware in this condition (10). When they open their eyes to awake, they move from Coma to the Vegetative State (VS), Minimally Conscious State (MCS) or full consciousness (11, 12). Vegetative State patients are awake, but unaware while those in the Minimally Conscious State are awake and sometimes aware. It is proposed that awaking from Coma occurs when neurotransmitters, depleted after brain damage, have been restored to more physiological levels in cortical and sub cortical brain regions. Lack of awareness in the Vegetative and Minimally Conscious State occurs when restoration remains incomplete in some parts of the brain which remain fully or partially suppressed. Brain SPECT scans have shown that suppressed brain regions are able to start functioning again in some patients, sometimes after many years (13).

 

Normally, neurotransmitters are highly conserved by the impermeable nature of the blood brain barrier and they have to be produced locally in the brain using glutamate as a main building block, which limits the supply (14-18). 

 

Glutamate, the most common and widely spread neurotransmitter of the brain, is provided from intracellular reserves and by local production in the brain when NH3 combines with alpha ketoglutarate, a Krebs cycle intermediate (19). Another source of glutamate is amino acids. Transamination of aspartate results in glutamate and oxaloacetate, another Krebs cycle intermediate (20, 21). Glutamate can also be derived from deamination of glutamine resulting in the release of NH3. However, glutamate and glutamine are usually produced by NH3 capturing (19, 22).

 

If there is no oxygen, alpha ketoglutarate and glutamate production will cease and pyruvate and lactate will accumulate outside a disrupted Krebs cycle. Increased lactate levels are commonly detected after anoxic brain damage and they can remain increased for many years (23- 27). Presumably, in such situations other sources of glutamate are used by the brain, for example aspartate (20).  Decreased aspartate levels occur in disorders of consciousness (DOC), improving when the DOC resolves (25, 26, 28, 29).

 

GABA, the most widespread inhibitory neurotransmitter of the brain, is generated via the GABA shunt from glutamate and succinate, another Krebs cycle intermediate (30).  If the Krebs cycle does not function or if glutamate is not replenished or remains in short supply after brain damage, GABA will eventually diminish, particularly in ischemic brain regions that lack oxygen and glucose.

 

With a shortage of GABA, the brain needs to maintain inhibition with low levels of metabolic activity in the face of reduced oxygen and nutrient supplies. It is proposed that a secondary response then occurs which appears to increase the receptor sensitivity for the available GABA. In this way, low GABA levels continue to maintain their suppressive stranglehold on the brain, a response that we have termed neurodormancy.  Neurodormancy is a protective mechanism that can manifest as synchronised slow wave activity in the brain, as measured in a recent MEG study by Hall et al (27).

 

Prolonged brain suppression and neurodormancy is the manifestation of a re-modulated GABA receptor metabolism. A previous study has shown that certain types of brain suppression are associated with an altered composition of GABA(A) receptor subunits (31). In another study, this suppression was associated with reorganisation of GABA mediation in the cerebellum (32). With normal or borderline GABA levels, GABA receptors remain functioning normally, but in depleted regions such receptors may undergo molecular modifications or changes in abundance, possibly due to gene expressions that are initiated under hypoxic conditions and that can influence the GABA(A) receptor subunit composition (33, 34). At cellular and subcellular level this may involve messenger feedback pathways that respond to reduced GABA levels in the cellular environment. It may take weeks or months or longer to re-grow blood vessels to repair a deficient blood supply to affected brain areas.  Due to varied locations of brain damage, there may be varied restoration efforts that may be intermittent.

 

Zolpidem has featured in several reports, notably reversing the Vegetative State, symptoms of stroke and anoxic brain injury (35, 36).  In a normal brain zolpidem enhances GABA action. It is used for sleep induction, binding preferentially to omega 1 sub receptors which form part of the normal GABA(A) receptor (37).  However, in dormant brain after brain damage zolpidem may do the reverse – it increases brain function within 30 minutes after oral application. This rapid effect distinguishes it from other medicines in DOC such as the dopaminergic medicines that take several weeks to achieve a response.

 

Imaging studies using 99mTcHMPAO Brain SPECT or 18F FDG PET in patients after brain damage have shown that non-functioning areas start to function again after zolpidem (35, 36, 38). Multiple responders to zolpidem have now been reported in the medical literature. The first case in 2000 documented a patient who was classified to the Vegetative State, attaining consciousness after zolpidem (39). A further case showed that zolpidem was effective in a minimally conscious patient after hanging and another showed that the medicine is effective in relieving symptoms in long standing brain anoxia after cardiac arrest (38, 40). Recently, prospective multi-patient studies showed similar findings. In a study by Du et al, 7 patients in the Vegetative State were investigated with significant improvements in cerebral state index, electromyographic index, burst suppression and cerebral perfusion after zolpidem (41). In a study by Whyte et al on 15 patients, a marked improvement was reported in an MCS patient (42). Nyakale et al found improvement after zolpidem in 10 out of 23 neurologically dependent patients who scored less than 100/100 on the Barthel Index (43). Zolpidem’s proposed  mode of action is the modulation of ‘abnormal’ GABA receptors that are responsible for the neurodormant state (13).

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