Neurotransmitters in Coma, Vegetative and Minimally Conscious States, pharmacological interventions

Medical Hypotheses 75 (2010) 287–290

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Neurotransmitters in Coma, Vegetative and Minimally Conscious States, pharmacological interventions R.P. Clauss * Nuclear Medicine Department, Royal Surrey County Hospital, Guildford, Surrey GU2 7XX, United Kingdom

a r t i c l e

i n f o

Article history: Received 1 March 2010 Accepted 6 March 2010

s u m m a r y Articles on pharmacological interventions in disorders of consciousness after brain damage are increasingly appearing in the medical literature. This hypothesis links disorders of consciousness to the depletion of oxygen reliant neurotransmitters based in two biochemical axes, the amino acid axis (glutamate/ GABA) and the monoamine axis (dopamine/noradrenalin and serotonin). After a brain injury, an immediate response inside the brain constitutes a surge of amino acids such as glutamate, GABA and others. Glutamate is excitatory and GABA inhibitory. The inhibitory response dominates and the brain becomes suppressed, leading to a loss in consciousness which reduces oxygen requirements. In time, GABA depletes after increased usage and leakage from the brain into the blood. If it cannot be restored sufficiently in some parts of the brain, a secondary response in these regions occurs which makes GABA receptors oversensitive to GABA, so that decreased GABA levels can maintain their suppressive effect. This occurs in prolonged disorders of consciousness as in the Vegetative State, which can be broken by agents such as zolpidem in some patients. In addition to amino acids, monoamine systems such as dopamine are essential to cognition and motor function. Their depletion or the suppression of brain regions in which they function, are proposed as contributors to disorders of consciousness. Reports of successful arousals after amino acid and monoamine based therapies supports the hypothesis that depletion of these brain chemicals may play a fundamental role in disorders of consciousness. Ó 2010 Elsevier Ltd. All rights reserved.

Introduction A renewed interest has occurred in disorders of consciousness (DOC) following three milestone publications on this subject in 2006. The first was a report on three patients who awoke from the Vegetative State after receiving a sleeping tablet called zolpidem [1]. The second described a patient who awoke from the Minimally Conscious State after 19 years. He was shown to generate new neurological pathways in his brain, following this awakening [2]. The third concerned a patient in the Vegetative State, proven to have conscious thought on MRI investigation [3]. The reports rekindled speculation on neurotransmitter mechanisms in DOC and possible pharmacological interventions. This hypothesis considers consciousness as a balance of outflows of two oxygen reliant biochemical axes of the brain, the amino acid axis (glutamate/GABA) and the monoamine axis (dopamine/noradrenalin/serotonin) (Fig. 1). In a normally functioning brain, there is a daily utilisation and nightly restoration of neurotransmitter function [4]. At night the eyes are closed and neurotransmitter reserves are topped up from * Tel.: +44 1483 571122x2130. E-mail address: [email protected] 0306-9877/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2010.03.005

their lowered levels during the day in parts of the brain [5–8]. With acute brain injury, there is a surge of excitatory and inhibitory neurotransmitters, mostly glutamate and GABA [9–11]. Glutamate, the forerunner of GABA, is excitatory, causing potentially apoptotic brain cells to absorb toxic metabolites which stabilize the ischemic microenvironment after brain damage. GABA is inhibitory, suppressing cellular metabolism, protecting cells from unfavourable surroundings. Inhibition dominates, leading to loss of consciousness. The surge is followed by a depletion of brain produced neurotransmitters such as GABA after utilisation and leakage from the brain into the blood [12]. 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 [13]. When they open their eyes to awake, they move from Coma to the Vegetative State (VS), Minimally Conscious State (MCS) or full consciousness [14,15]. Vegetative State patients are awake, but unaware while those in the Minimally Conscious State are awake and partially aware. It is proposed that awaking from Coma occurs when neurotransmitters, depleted after brain damage, have been restored to 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

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Fig. 1. Oxygen dependent pathways of amino acids and monoamines in disorders of consciousness.

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 [1,16].

The amino acid axis (glutamate/GABA) 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 building block, which limits the supply [17–21]. 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 [22]. Another source of glutamate is amino acids. Transamination of aspartate results in glutamate and oxaloacetate, another Krebs cycle intermediate [23,24]. Glutamate can also be derived from deamination of glutamine resulting in the release of NH3. However, glutamate and glutamine are usually NH3 capturing molecules [22,25]. If there is no oxygen or glucose, 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 [26–30]. Presumably, in such situations other sources of glutamate are used by the brain, for example aspartate [23]. Decreased aspartate levels occur in DOC, improving when the DOC resolves [28,29,31,32]. GABA, the most widespread inhibitory neurotransmitter of the brain, is generated via the GABA shunt from glutamate and succinate, another Krebs cycle intermediate [33]. 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 sensitivity of receptors 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. [30]. Prolonged brain suppression 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 [34]. In another study, this suppression was associated with reorganisation of GABA mediation in the cerebellum [35]. With normal or borderline GABA levels, GABA receptors remain functioning normally, but in depleted regions such receptors may undergo molecular modifications, possibly due to gene expression, as found in other ischemic brain conditions [36]. 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. Medications that act on the glutamate/GABA axis After brain damage, GABA levels can range through a continuum of normal to subnormal levels in different regions of the brain. In this continuum, GABAergic medicines work normally on normal GABA receptors, but unpredictably on ‘abnormal’ GABA receptors that occur in areas of GABA depletion. Zolpidem Zolpidem has featured in several reports, notably reversing the Vegetative State and symptoms of stroke [16,37]. 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 [38]. However, in dormant brain

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after brain damage zolpidem may do the reverse – it increases brain function within 30 min 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 99mTc HMPAO Brain SPECT or 18F FDG PET in patients after brain damage have shown that non-functioning areas start to function again after zolpidem [1,16,37,39]. 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 [40]. 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 [39,41]. Recently, prospective multi-patient studies showed similar findings. In a study by Du et al., seven patients in the Vegetative State were investigated with significant improvements in cerebral state index, electromyographic index, burst suppression and cerebral perfusion after zolpidem [42]. In a study by Whyte and Myers on 15 patients, a marked improvement was reported in an MCS patient [43]. Nyakala et al. found improvement after zolpidem in 10 out of 23 neurologically dependent patients who scored less than 100/100 on the Barthel Index [44]. Zolpidem’s proposed mode of action is the modulation of ‘abnormal’ GABA receptors that are responsible for the neurodormant state [1]. Baclofen Baclofen is an analogue of GABA, agonistic at the GABA (B) receptors of the central nervous system, primarily used for the treatment of spasticity after spinal chord injury. Case reports have documented that intrathecal baclofen can arouse patients from the Vegetative State [45–47]. The mechanism of this action is not known, but two possibilities have been proposed. One is that low baclofen concentrations may favour a functional restoration among the cortico–thalamo–cortical connection, stimulating wakefulness and awareness. The other is centripetal input stimulation from the peripheral spinal region with stimulation of the central nervous system [45]. The monoamine axis (dopamine/noradrenalin/serotonin) The monoamines dopamine and noradrenalin are produced in the brain via oxygen reliant pathways. Dopamine, synthesized from L-DOPA and its forerunner L-tyrosine, is found mainly in the basal ganglia. It is important in cognition, movement, memory and emotion [48]. Noradrenalin is widely available throughout the brainstem, basal ganglia and neocortex. It is synthesized by the oxidation of dopamine and plays a major role in alertness and arousal [49]. Serotonin plays a role in depression and anxiety. It is synthesized in the brain from five hydroxy-tryptamine, a metabolite of the amino acid L-tryptophan [50–52]. It is proposed that the functions of monoamines are compromised in disorders of consciousness, either due to depletion or due to suppression of brain regions that use these neurotransmitters to execute their functions. It is proposed that replenishing these supplies pharmacologically may help to arouse some patients suffering from DOC. Medications that act on the dopamine/noradrenalin/serotonin axis Dopaminergic agents The role of dopaminergic medicines in DOC is well known and several studies have confirmed their efficacy for this condition. In

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2005 Matsuda et al. described five patients in the Vegetative State who responded to L-DOPA [53]. In another study, the dopamine agonist Bromocriptine was shown to improve awareness in five Vegetative State patients after traumatic brain injury [54]. Recently, there has been a case where the dopamine agonist apomorphine has been shown to arouse a patient from the MCS [55]. Amantadine, a dopamine re-uptake inhibitor has also been shown to be effective in the MCS as has methylphenidate, another dopamine re-uptake inhibitor that has been shown to improve attention deficits in patients after brain injury [56,57]. Tri-cyclic antidepressants Tri-cyclic antidepressants are a group of medicines that prevent re-uptake of noradrenalin or serotonin in the brain. Amitriptyline and desipramine form part of this group of medicines which have been shown to improve arousal in patients after severe traumatic brain injury [58]. Another tri-cyclic antidepressant, protriptyline, was also used to arouse patients after brain injury [59]. Conclusion There is evidence for a fundamental role of amino acids and monoamines in disorders of consciousness. It is proposed that consciousness is based in an intact biochemistry of the brain, particularly in those systems that produce neurotransmitters such as glutamate, GABA and dopamine. Pharmacological interventions that can influence biochemical changes in these systems should undergo closer scrutiny in brain pathologies and in disorders of consciousness. Conflicts of interest statement None declared. Grants No support from grants or other sources of support. Acknowledgement The author wishes to thank Drs. A. Sutton and H.W. Nel for their editorial contributions. References [1] Clauss RP, Nel HW. Drug induced arousal from permanent Vegetative State. Neurorehabilitation 2006;21:23–8. [2] Voss HU, Uluç AM, Dyke JP, Watts R, Kobylarz EJ, McCandliss BD, et al. Possible axonal regrowth in late recovery from the minimally conscious state. J Clin Invest 2006;116:2005–11. [3] Owen AM, Coleman MR, Boly M, Davis MH, Laureys S, Pickard JD. Detecting awareness in the Vegetative State. Science 2006;313(5792):1402. [4] Siegel JM. Why we sleep. Sci Am 2003;291:92–7. [5] Cardinali DP, Golombek DA. The rhythmic GABAergic system. Neurochem Res 1998;23:607–14. [6] Castaneda TR, Marquez de Prado B, Prieto D, Mora F. Circadian rhythms of dopamine, glutamate and GABA in the striatum and nucleus accumbent of the awake rat: modulation by light. J Pineal Res 2004;36:177–85. [7] Grimes MA, Cameron JL, Fernstrom JD. Cerebrospinal fluid concentrations of large neutral and basic amino acids in Macca mulatta: diurnal variations and responses to chronic changes in dietary protein intake. Metabolism 2009;58:129–40. [8] Marquez de Prado B, Castaneda TR, Galindo A, DedArco A, Segovia G, Reiter RJ, et al. Melatonin disrupts circadian rhythms of glutamate and GABA in the neostriatum of the awake rat: a microdialysis study. J Pineal Res 2000;29:209–16. [9] Nilsson GE, Lutz PL. Release of inhibitory neurotransmitters in response to anoxia in turtle brain. Am J Physiol Reg Integ Comp Physiol 1991;261:R32–7. [10] Nilsson GE, Lutz PL. Anoxia tolerant brains. J Cereb Blood Flow Metab 2004;24:475–86.

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