Current Pharmaceutical Design - Volume 20, Issue 26, 2014

The neurobiological approach to consciousness moves from the assumption that all phenomenal experiences are based on neuronal activity in the brain. Consciousness has two main components: wakefulness and awareness. While it may be relatively easy to determine the neuronal correlates of wakefulness, it is not the same for awareness, of which the neural correlates are poorly understood. Knowledge of the circuitry and the neurochemistry of the sleep/wake condition is necessary but not sufficient to understand the circuitry and neurochemistry of consciousness. Disorders of consciousness (DOCs) include coma, vegetative state and minimally conscious state. The study of DOCs and of the electrophysiological changes underlying general anaesthesia-induced loss of consciousness may help in understanding the neuronal correlates of consciousness. In turn, the understanding of the neural bases of consciousness may help in designing interventions aimed at restoring consciousness in DOC patients. Sporadic cases of recovery from a DOC have been reported after the administration of various pharmacological agents (baclofen, zolpidem, amantadine etc.). This review provides an overview of such drugs, which are from various and diverging classes but can be grouped into two main categories: CNS stimulants and CNS depressants. The available data seem to suggest an awakening effect obtained with CNS depressants rather than stimulants, the latter being more effective at improving functional cognitive and behavioral recovery in patients who have spontaneously regained an appreciable level of consciousness. There is a need for more rigorous systematic trials and further investigation of the above treatments, with particular attention paid to their mechanisms of action and the neurotransmitters involved.

Oxygen based neurotransmitters in the synapses of the brain are proposed to play an important role in the generation of consciousness. They include the amino acids glutamate and GABA which use Krebs cycle precursors for their synthesis, and the monoamines dopamine, noradrenalin, adrenalin and serotonin, which are derived from tyrosine and tryptophan. During ischemia after an acute brain injury, a GABA surge often initiates brain suppression. It has been proposed that with chronic ischemia, a secondary, possibly epigenetic response occurs when neurotransmitters deplete, a glucose and oxygen saving mechanism termed neurodormancy that may invoke alternative long term low energy metabolic pathways in the brain, encountered in Disorders of Consciousness. Some medications can reverse Disorders of Consciousness in some patients. Virtually all of them act on neurotransmitter systems that use oxygen as a building block or as an energy source within the brain. Pharmaceuticals that act in the oxygen based amino acid systems of the brain include the GABAergic medications zolpidem and baclofen, while those that act in the monoamine axes include the dopaminergic medications L Dopa, amantadine, bromocriptine, apomorphine and methylphenidate, and the noradrenergic and serotonergic medications desipramine, amitriptyline, protriptyline and fluoxetine. Another group are the cholinesterase inhibitors, responsible for increasing acetylcholine, which is synthesized from the Krebs cycle initiator, acetyl CoA. It appears that pharmaceuticals that are active in the oxygen based neurotransmitter pathways of the brain are successful to arouse to consciousness patients that suffer from its disorders. Research needs to be supported as foundation to understand the biochemical mechanisms that are involved in consciousness disorders and to explore further the pharmacological treatment possibilities for these devastating neurological conditions.

Cases of recovery from vegetative and minimally conscious state after the administration of various pharmacological agents have been recently reported. These agents include CNS depressants (zolpidem, baclofen, lamotrigine) and CNS stimulants (tricyclic antidepressants, selective serotonin reuptake inhibitors, dopaminergic agents, methylphenidate). The action of CNS depressants as awakening agents sounds paradoxical, as they are commonly prescribed to slow down brain activity in the management of anxiety, muscle tension, pain, insomnia and seizures. How these drugs may improve the level of consciousness in some brain-injured patients is the subject of intense debate. Here we hypothesize that CNS depressants may promote consciousness recovery by reversing a condition of GABA impairment in the injured brain, restoring the normal ratio between synaptic excitation and inhibition, which is the prerequisite for any transition from a resting state to goal-oriented activities (GABA impairment hypothesis). Alternative or complementary mechanisms underlying the improvement of consciousness may include the reversal of a neurodormant state within areas affected by diaschisis (diaschisis hypothesis) and the modulation of an informative overload to the cortex as a consequence of filter failure in the injured brain (informative overload hypothesis). A better understanding of how single agents act on neural networks, whose functioning is critical for recovery, may help to advance a tailored pharmacological approach in the treatment of severely brain injured patients.

Survivors of severe brain injuries may end up in a state of ‘wakeful unresponsiveness’ or in a minimally conscious state. Pharmacological treatments of patients with disorders of consciousness aim to improve arousal levels and recovery of consciousness. We here provide a systematic overview of the therapeutic effects of amantadine, apomorphine and zolpidem in patients recovering from coma. Evidence from clinical trials using these commonly prescribed pharmacological agents suggests positive changes of the patients’ neurological status, leading sometimes to dramatic improvements. These findings are discussed in the context of current hypotheses of these agents’ therapeutic mechanisms on cerebral function. In order to improve our understanding of the underlying pathophysiological mechanisms of these drugs, we suggest combining sensitive and specific behavioral tools with neuroimaging and electrophysiological measures in large randomized, double-blind, placebo-controlled experimental designs. We conclude that the pharmacokinetics and pharmacodynamics of amantadine, apomorphine and zolpidem need further exploration to determine which treatment would provide a better neurological outcome regarding the patient’s etiology, diagnosis, time since injury and overall condition.

Objective. To study the Zolpidem arousing effect in persistent vegetative state (PVS) patients combining clinical evaluation, autonomic assessment by heart rate variability (HRV), and EEG records. Methods. We studied a group of 8 PVS patients and other 8 healthy control subjects, matched by age and gender. The patients and controls received drug or placebo in two experimental sessions, separated by 10-14 days. The first 30 minutes of the session were considered the basal record, and then Zolpidem was administered. All participants were evaluated clinically, by EEG, and by HRV during the basal record, and for 90 minutes after drug intake. Results. We found in all patients, time-related arousing signs after Zolpidem intake: behavioral (yawns and hiccups), activation of EEG cortical activity, and a vagolytic chronotropic effect without a significant increment of the vasomotor sympathetic tone. Conclusions. We demonstrated time-related arousing signs after Zolpidem intake. We discussed possible mechanisms to explain these patho-physiological findings regarding EEG cortical activation and an autonomic vagolytic drug effect. As this autonomic imbalance might induce cardiocirculatory complications, which we didn’t find in any of our patients, we suggest developing future trials under control of physiological indices by bedside monitoring. However, considering that this arousing Zolpidem effect might be certainly related to brain function improvement, it should be particularly considered for the development of new neuro-rehabilitation programs in PVS cases. According to the literature review, we claim that this is the first report about the vagolitic effect of Zolpidem in PVS cases.

General anesthesia-induced pharmacological protection of the central nervous system following injury has been under intense investigations during the past four decades. Indeed, if general anesthetics could provide therapeutic benefit in the event of hypoxia, ischemia or any other kinds of brain lesions, that would be of tremendous clinical importance. The potential for anesthesia-related brain protection, however, has been seriously challenged during the past 10 years. In fact, an increasing number of experimental and, more recently, clinical observations suggest that general anesthetics might exert unwanted, toxic effects on the brain especially when administered to young infants or to the elderly. Of utmost importance, recent data suggest that these same drugs could even have therapeutic effects in some psychiatric disorders. The goal of this review is to highlight these apparent contradictions. We will consider the available experimental evidence arguing for anesthetic-induced neuroprotection and highlight the lack of clinical studies supporting this notion. The biological rational for anesthesia neurotoxicity will then be explored together with existing experimental and clinical evidence in favor of this possibility. Finally, insights into the increasing number of both experimental and clinical data suggesting that general anesthetics, especially ketamine, support the therapeutic value of these drugs in major depressive disorders. When taken together, these seemingly contradictory observations suggest the intriguing possibility that general anesthetics could stand as valuable context-dependent modulators of neural plasticity.

Philosophers have been trying to solve the mind-body problem for hundreds of years. Consciousness is the core of this problem: How do subjective conscious sensations, perceptions, feelings, and thoughts arise out of objective physical brain activities? How is this subjective conscious world in causal interaction with the objective sensory and motor mechanisms of the brain and the body? Although we witness the seamless interaction of the mental and the physical worlds in our everyday lives, no scientific theory can yet fully describe or explain it. The hard problem of consciousness, the question why and how any brain activity should be accompanied by any subjective experiences at all, remains a mystery and a challenge for modern science. Anesthesia offers a unique and safe way to directly manipulate the state of consciousness and can, thus, be used as a tool in consciousness research. With neuroimaging, such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) performed at different states of consciousness, it is possible to visualize the state-related changes and pinpoint the brain structures or neural mechanisms related to changes in consciousness. With these tools, neurosciences now show promise in disentangling the eternal enigma of human consciousness. In this article, we will review the recent advancements in the field.

In this paper, we review the contribution of our research group to the study of human consciousness by quantitative electroencephalographic (EEG) techniques. We posit that EEG techniques can be extremely useful for a direct measurement of brain electrophysiological activity related to human consciousness for their unsurpassable high temporal resolution (milliseconds). This activity can be expressed in terms of event-related potentials as well as changes of EEG rhythms of interest, for example the dominant alpha rhythms (about 8-12 Hz). The results of our studies, and those of several independent groups, lead support to the hypothesis that these techniques provide important insights about the neurophysiologic mechanisms underlying cortical neural synchronization/desynchronization and the regulation of neuromodulatory systems (e.g. dopaminergic, noradrenergic, cholinergic, etc.) at the basis of brain arousal and consciousness in healthy subjects and in patients with impairment of the consciousness. A possible interaction of these mechanisms and the drugs administered to patients with consciousness disorders is discussed.

Twenty-nine patients with Unresponsive Wakefulness Syndrome (UWS), 26 patients in Minimally Conscious State (MCS), and 21 healthy control individuals matched in age and social environment (patients’ relatives) were presented with 80 short sentences half of which were factually correct, and the other half factually incorrect. The diagnosis was made on the basis of repeated neurological examinations as well as the standardized assessment using a Coma Recovery Scale-Revised (CRS-R). fMRI blood oxygen level dependent signal was recorded in an event-related design time-locked to the end word of the sentences. In the contrast “incorrect-minus-correct” significant activations in the relevant brain regions were obtained in 17 (81%) controls and in 16 (29%) patients. Among patients, the 16 responders had a significantly longer time since accident than the 39 non-responders. Responders and non-responders did not differ in terms of the diagnosis (UWS vs. MCS), age, CRS-R score, or the degree of brain atrophy. The data concur with the results of several earlier studies on UWS/MCS patients, with the difference that the critical stimuli in those studies were semantically incongruent or ambiguous propositions rather than factually false ones in the present experiment. The hypothesis is discussed that the differential response of brain language areas to factually correct and incorrect statements does not require conscious perception of the statements.

The last years have witnessed a significant increase in our understanding of brain functions in survivors of severe brain injuries with disorders of consciousness (DOC). Despite there is currently no effective standardized treatment for DOC patients, in the past decade many potential pharmacological as well as non-pharmacological therapies have been proposed. A promising and increasingly growing field of non-pharmacological therapeutic trials has been supported by the application of electrophysiological techniques. This article reviews the most relevant studies in the literature in order to provide the reader with a clear picture of the current available neurophysiological instruments that could be used to treat DOC patients. We will hereinafter briefly discuss the basic principles of deep brain stimulation (DBS), repetitive transcranial magnetic stimulation (rTMS), spinal cord stimulation (SCS) and peripheral nerve stimulation (MNS) that are the main techniques now used by researchers as a treatment and we will explain the rationale of these therapies. Then, we will outline the more relevant studies regarding their application in DOC patients. Finally, due to the fact that only a moderate amount of individual or clinically-dependent approaches are available, we conclude that more standardized studies are necessary to address the role of electrophysiological treatment strategies in DOC as well as to further elucidate their therapeutic effects and define optimal stimulation parameters. Undoubtedly, at present the multidimensional approach is the most interesting.

The design of neurorehabilitation therapy to treat subjects with altered consciousness provides opportunities and challenges to professionals involved with the care for these severely ill patients. While there is an increased interest in determining methods to restore consciousness in these patients, the process is complex and challenging, due in part to the diverse aetiology of these states of consciousness, and also to the intricate cerebral connectivity involved in their treatment. The present case study examines a patient who showed signs of emergence from the vegetative state after neurorehabilitation using The Combined Method Therapy (CMT). In this case, neurorehabilitation therapy was applied simultaneously with pharmacological treatment, stimulation, and neuroimaging techniques to help adjust drug dosage. The results of this study suggest that this combined approach to treatment promoted connectivity among posterior and anterior cortical regions aiding emergence from the vegetative state.

Recovery from traumatic brain injury (TBI) is variable despite similarities in the severity or mechanism of injury. The study of genetic polymorphisms offers an avenue for explaining individual differences in recovery and outcome following TBI. The current paper reviews the role that genetic polymorphisms may play in influencing recovery and quality of life following TBI. Investigating the role of polymorphisms on recovery from TBI may contribute to a better understanding of individual variations in outcome and has the potential to lead to earlier and more targeted interventions and rehabilitation based on a patient’s genetic makeup. By outlining what has been discovered about the relationship between polymorphisms and TBI we hope to both inform the medical community about the potential for polymorphisms to influence recovery following TBI and provide a roadmap to researchers about the gaps in research within this population.

The pathophysiology of degenerative, infectious, inflammatory and traumatic diseases of the central nervous system includes a significant immune component. As to the latter, damage to the cerebral vasculature and neural cell bodies, caused by traumatic brain injury (TBI) activates innate immunity with concomitant infiltration of immunocytes into the damaged nervous system. This leads to proinflammatory cytokine and prostaglandin production and lost synaptic integrity and more generalized neurotoxicity. Engagement of adaptive immune responses follows including the production of antibodies and lymphocyte proliferation. These affect the tempo of disease along with tissue repair and as such provide a number of potential targets for pharmacological treatments for TBI. However, despite a large body of research, no such treatment intervention is currently available. In this review we will discuss the immune response initiated following brain injuries, drawing on knowledge gained from a broad array of experimental and clinical studies. Our discussion seeks to address potential therapeutic targets and propose ways in which the immune system can be controlled to promote neuroprotection.

The growing diffusion of life support procedures, including cardiopulmonary resuscitation (CPR) and advanced cardiac life support (ACLS), allows physicians to keep a person alive almost indefinitely when the person's heart has stopped beating autonomously or spontaneous breathing is precluded. However, in some cases patients are brought back to life but remain in a vegetative state (VS) or in a minimally conscious state (MCS). This prompts reflections on the ‘pros and cons’ of life support procedures and on the recommended conduct to be adopted for the general management of patients who survive in a VS or MCS. Important issues to be debated include the choice of therapeutic management which guarantees for the patient the maximum possible physical and mental well-being; the distinction between ‘worthwhile’ and ‘disproportionate’ treatments; the patient's right to make decisions concerning his or her own health status; the possibility to make ‘advance directives’ when still healthy or when a life-threatening illness has been diagnosed; the role of relatives and caregivers in the choice of the best treatment for unconscious patients and the identification of ethically and scientifically valid criteria for the inclusion of unconscious patients in studies investigating experimental therapies.