![Physiological changes observed before and after the administration of zolpidem (10 mg), in patient YOR. A: Sequential histogram of RRI values. Every strip includes 1000 RRI. B:_ Compressed spectral matrix of PSD estimations obtained with the time-frequency spectral analysis method. C:_ Changes observed for sequential estimations of the PSD in the HRV bands LF, MF, HF, and Total frequency range, expressed as zeta-values (ordinates) with respect to the control pre-medication period. Values in the abscissas represent the successive sequential estimations during the control before and after zolpidem administration. Conventionally, a Z-value of 5, corresponds to the mean of the distribution. So, correspondingly, Z-values over 8 or under 2 are significant with p<0.01. D:_ Changes observed in other physiological indices recorded during the experimental session. RF:_ Respiratory frequency, [O2]:_ Pulse oximetry; MAP:_ Mean arterial pressure; CO:_ Cardiac output: W:_ Peripheral vascular resistance. Although these physiological values were actually recorded every minute, in this graphic (only for visual assessment) original measures were interpolated to correspond to the time-sliding value of the TVSPA process. Arrows in all diagrams point to the moment of the administration of zolpidem. In the abscissas are represented the sequential estimations (realizations) for every time displacement of 8 seconds.](https://www.researchgate.net/profile/Calixto-Machado/publication/256499812/figure/fig1/AS:601662783778817@1520458994113/Fig-1-Physiological-changes-observed-before-and-after-the-administration-of-zolpidem_Q320.jpg)
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Machado C, et al. Zolpidem Arousing Effect In Persistent Vegetative State Patients: Autonomic, Eeg And Behavioral Assessment
Abstract and Figures
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.
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... Technical details are published elsewhere. [12][13][14][15]17,[30][31][32] 3 Results Figure 1 shows the A-PSD of all HRV bands for the UWS and MCS groups. When comparing both groups, the most outstanding finding was the Zolpidem vagolitic effect (decrement A-PSD in the HF band) in the UWS patients. ...
... [6,7,[49][50][51][52][53] Dormancy or hibernation of the myocardium after an ischemic insult has been described in cardiology; it is applied to the brain is recognized as neurodormancy. [12][13][14][15]54,55] Nonetheless, in our opinion, neurodormancy does not wholly support Zolpidem's paradoxical arousing effect in UWS cases because the pathological patterns of UWS cases are diverse, and the location of lesions, either focal in different brain regions or widespread brain injury, should be taken into consideration. [56] Schiff and Posner offered a persuasive hypothesis to explain Zolpidem's paradoxical arousing effect. ...
... Hence, Zolpidem might activate GABAergic neurons of the basal forebrain, which provide disinhibition (activation) of cortical neurons. [1,2,12,13,60,61] Another possible target of Zolpidem action is the mesopontine GABAergic column (MPGC). It is a GABAergic neuronal population, appearing as a column of cells, with a long-axis in the sagittal plane, extending through the midbrain and pons. ...
Several reports have been published over recent years about Zolpidem's paradoxical arousing effect in unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) patients. During Zolpidem pharmacological intervention, we emphasized the importance of using the heart rate variability (HRV) methodology to assess the autonomic in a UWS patient. This paper will compare Zolpidem's paradoxical arousing effect on the autonomic system by the HRV methodology, comparing UWS vs. MCS patients. This study included five UWS, five MCS patients, and twenty healthy voluntary subjects, matched by age and gender as a control group. The most striking finding was the significant decrement of A-PSD in the HF band in the UWS group, demonstrating a vagolitic effect of Zolpidem. This group also had a significant increment of slow frequencies (VLF and LF), mainly for VLF. The MCS group showed an early increment of AP for all bands after Zolpidem intake. Later, A-PSD in the frequency band significantly decreased, and A-PSD of LF and VLF trended to increase significantly. In the control group, the Zolpidem effect was characterized by early oscillations in AP values, with a posterior progressive increment of AP indices. In the MCS group of patients, the vagolitic effect and the increment of VLF and LF absolute powers were not so pronounced after Zolpidem intake compared with the UWS cases. We discussed the possible pathophysiological mechanisms to explain these findings in UWS and MCS patients.
... In the present review, eleven articles presented zolpidem as a treatment strategy for DoC with five discussing its efficacy for patients in PVS/VS (Rodriguez-Rojas et al., 2013;Du et al., 2014;Machado et al., 2011Machado et al., , 2014Calabrò et al., 2015), three discussing its efficacy for patients in MCS (Appu and Noetzel, 2014;Chatelle et al., 2014;Delargy et al., 2019), and three discussing its efficacy for patients in VS/UWS and MCS (Thonnard et al., 2013;Whyte et al., 2014;Khalili et al., 2020). Further, two of eleven articles reported successful treatment (Appu and Noetzel, 2014;Khalili et al., 2020), eight reported some benefits of treatment (Machado et al., 2011(Machado et al., , 2014Rodriguez-Rojas et al., 2013;Chatelle et al., 2014;Du et al., 2014;Whyte et al., 2014;Calabrò et al., 2015;Delargy et al., 2019), and one reported no benefit of treatment (Thonnard et al., 2013). ...
... In the present review, eleven articles presented zolpidem as a treatment strategy for DoC with five discussing its efficacy for patients in PVS/VS (Rodriguez-Rojas et al., 2013;Du et al., 2014;Machado et al., 2011Machado et al., , 2014Calabrò et al., 2015), three discussing its efficacy for patients in MCS (Appu and Noetzel, 2014;Chatelle et al., 2014;Delargy et al., 2019), and three discussing its efficacy for patients in VS/UWS and MCS (Thonnard et al., 2013;Whyte et al., 2014;Khalili et al., 2020). Further, two of eleven articles reported successful treatment (Appu and Noetzel, 2014;Khalili et al., 2020), eight reported some benefits of treatment (Machado et al., 2011(Machado et al., , 2014Rodriguez-Rojas et al., 2013;Chatelle et al., 2014;Du et al., 2014;Whyte et al., 2014;Calabrò et al., 2015;Delargy et al., 2019), and one reported no benefit of treatment (Thonnard et al., 2013). ...
... Further, 50% of VS patients demonstrated an improvement in their level of consciousness and motor function following treatment (Khalili et al., 2020). Calabrò et al. (2015), Du et al. (2014), Machado et al. (2011), Machado et al. (2014), and Rodriguez-Rojas et al. (2013) reported beneficial, but not overtly successful, effects of zolpidem treatment among patients in PVS/VS. Zolpidem was found to increase awareness and wakefulness as well as improve consciousness and arousal in a case report of a 52-year-old female in VS following cardiac arrest (Calabrò et al., 2015). ...
... Among the pharmacological interventions to improve consciousness levels in brain-injured patients, amantadine, zolpidem, and methylphenidate are the only treatments tested in controlled randomized trials, with the currently most promising results for amantadine [33,57,119,129,130,182,200]. ...
Coma is a medical and socioeconomic emergency. Although underfunded, research on coma and disorders of consciousness has made impressive progress. Lesion-network-mapping studies have delineated the precise brainstem regions that consistently produce coma when damaged. Functional neuroimaging has revealed how mechanisms like “communication through coherence” and “inhibition by gating” work in synergy to enable cortico-cortical processing and how this information transfer is disrupted in brain injury. On the cellular level, break-down of intracellular communication between the layer 5 pyramidal cell soma and the apical dendritic part impairs dendritic information integration, with up-stream effects on microcircuits in local neuronal populations and on large-scale fronto-parietal networks, which correlates with loss of consciousness. A breakthrough in clinical concepts occurred when fMRI, and later EEG, studies revealed that 15% of clinically unresponsive patients in acute and chronic settings are in fact awake and aware, as shown by their command following abilities revealed by brain activation during motor and locomotion imagery tasks. This condition is now termed “cognitive motor dissociation.” Furthermore, epidemiological data on coma were literally non-existent until recently because of difficulties related to case ascertainment with traditional methods, but crowdsourcing of family observations enabled the first estimates of how frequent coma is in the general population (pooled annual incidence of 201 coma cases per 100,000 population in the UK and the USA). Diagnostic guidelines on coma and disorders of consciousness by the American Academy of Neurology and the European Academy of Neurology provide ambitious clinical frameworks to accommodate these achievements. As for therapy, a broad range of medical and non-medical treatment options is now being tested in increasingly larger trials; in particular, amantadine and transcranial direct current stimulation appear promising in this regard. Major international initiatives like the Curing Coma Campaign aim to raise awareness for coma and disorders of consciousness in the public, with the ultimate goal to make more brain-injured patients recover consciousness after a coma. To highlight all these accomplishments, this paper provides a comprehensive overview of recent progress and future challenges related to understanding, detecting, and stimulating consciousness recovery in the ICU.
... Third, we consider the possibility that cortical connectivity, network topology and complexity are true biomarkers of the conscious state, indicating that the level of consciousness of the case examples presented in this paper improved upon exposure to anesthesia. This explanation is supported by previous studies that have shown that a sedative GABAergic drug -zolpidem -can increase arousal in patients with DOC (Du et al., 2014;Machado et al., 2014;Noormandi et al., 2017;Sripad et al., 2020). These observations can be reconciled using the hypothesis that consciousness relies on brain networks which are tuned to criticality, a narrow window between stability and chaos; disorder and order (Tagliazucchi, 2017;Popiel et al., 2020;Toker et al., 2022). ...
Human consciousness is widely understood to be underpinned by rich and diverse functional networks, whose breakdown results in unconsciousness. Candidate neural correlates of anesthetic-induced unconsciousness include: (1) disrupted frontoparietal functional connectivity; (2) disrupted brain network hubs; and (3) reduced spatiotemporal complexity. However, emerging counterexamples have revealed that these markers may appear outside of the state they are associated with, challenging both their inclusion as markers of conscious level, and the theories of consciousness that rely on their evidence. In this study, we present a case series of three individuals in disorders of consciousness (DOC) who exhibit paradoxical brain responses to exposure to anesthesia. High-density electroencephalographic data were recorded from three patients with unresponsive wakefulness syndrome (UWS) while they underwent a protocol of propofol anesthesia with a targeted effect site concentration of 2 μg/ml. Network hubs and directionality of functional connectivity in the alpha frequency band (8–13 Hz), were estimated using the weighted phase lag index (wPLI) and directed phase lag index (dPLI). The spatiotemporal signal complexity was estimated using three types of Lempel-Ziv complexity (LZC). Our results illustrate that exposure to propofol anesthesia can paradoxically result in: (1) increased frontoparietal feedback-dominant connectivity; (2) posterior network hubs; and (3) increased spatiotemporal complexity. The case examples presented in this paper challenge the role of functional connectivity and spatiotemporal complexity in theories of consciousness and for the clinical evaluation of levels of human consciousness.
... B rain death (BD) has been progressively wide-reaching accepted beginning since the late 1950s. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] BD outlines medical and legal standards, and its determination is based on guidelines for children, [21] and adults, [22] that established an orderly set of clinical criteria assessed at the bedside, and the use or not of ancillary tests. However, argumentative braindead cases have recently raised up new disputes, arguing up-to-date BD criteria by questioning accepted medical standards. ...
Background:
New controversies have raised on brain death (BD) diagnosis when lesions are localized in the posterior fossa.
Objective:
The aim of this study was to discuss the particularities of BD diagnosis in patients with posterior fossa lesions.
Materials and methods:
The author made a systematic review of literature on this topic.
Results and conclusions:
A supratentorial brain lesion usually produces a rostrocaudal transtentorial brain herniation, resulting in forebrain and brainstem loss of function. In secondary brain lesions (i.e., cerebral hypoxia), the brainstem is also affected like the forebrain. Nevertheless, some cases complaining posterior fossa lesions (i.e., basilar artery thrombotic infarcts, or hemorrhages of the brainstem and/or cerebellum) may retain intracranial blood flow and EEG activity. In this article, I discuss that if a posterior fossa lesion does not produce an enormous increment of intracranial pressure, a complete intracranial circulatory arrest does not occur, explaining the preservation of EEG activity, evoked potentials, and autonomic function. I also addressed Jahi McMath, who was declared braindead, but ancillary tests, performed 9 months after initial brain insult, showed conservation of intracranial structures, EEG activity, and autonomic reactivity to "Mother Talks" stimulus, rejecting the diagnosis of BD. Jahi McMath's MRI study demonstrated a huge lesion in the pons. Some authors have argued that in patients with primary brainstem lesions it might be possible to find in some cases partial recovery of consciousness, even fulfilling clinical BD criteria. This was the case in Jahi McMath.
... Here, using effective connectivity, we demonstrated that a GABAergic agonist enhanced naturally occurring cortical sigma dominance over vagal autonomic activity. Similar vagolytic findings have been shown with zolpidem in persistent vegetative state patients (47). Furthermore, the magnitude of this central sigma influence on vagal activity predicted the trade-off between overnight LTM and WM improvement. ...
Significant
Sleep facilitates both long-term episodic memory consolidation and short-term working memory functioning. However, the mechanism by which the sleeping brain performs both complex feats and which sleep features are associated with these processes remain unclear. Using a pharmacological approach, we demonstrate that long-term and working memory are served by distinct offline neural mechanisms and that these mechanisms are mutually antagonistic. We propose a sleep switch model in which the brain toggles between the two memory processes via a complex interaction at the synaptic, systems, and mechanistic level with implications for research on cognitive disturbances observed in neurodegenerative disorders such as Alzheimer’s and Parkinson's disease, both of which involve the decline of sleep.
Traumatic brain injury (TBI) is an acquired injury to the brain caused by external mechanical forces, which can cause temporary or permanent disability. TBI and its potential long-term consequences are serious public health concerns. This review seeks to provide updated information on the current methods of management of patients with TBI to improve patient care.
Major advances have been made over the past few decades in identifying and managing disorders of consciousness (DOC) in patients with acquired brain injury (ABI), bringing the transformation from a conceptualized definition to a complex clinical scenario worthy of scientific exploration. Given the continuously-evolving framework of precision medicine that integrates valuable behavioral assessment tools, sophisticated neuroimaging, and electrophysiological techniques, a considerably higher diagnostic accuracy rate of DOC may now be reached. During the treatment of patients with DOC, a variety of intervention methods are available, including amantadine and transcranial direct current stimulation, which have both provided class II evidence, zolpidem, which is also of high quality, and non-invasive stimulation, which appears to be more encouraging than pharmacological therapy. However, heterogeneity is profoundly ingrained in study designs, and only rare schemes have been recommended by authoritative institutions. There is still a lack of an effective clinical protocol for managing patients with DOC following ABI. To advance future clinical studies on DOC, we present a comprehensive review of the progress in clinical identification and management as well as some challenges in the pathophysiology of DOC. We propose a preliminary clinical decision protocol, which could serve as an ideal reference tool for many medical institutions.
The number of paediatric patients living with a prolonged Disorder of Consciousness (DoC) is growing in high-income countries, thanks to substantial improvement in intensive care. Life expectancy is extending due to the clinical and nursing management achievements of chronic phase needs, including infections. However, long-known pharmacological therapies such as amantadine and zolpidem, as well as novel instrumental approaches using direct current stimulation and, more recently, stem cell transplantation, are applied in the absence of large paediatric clinical trials and rigorous age-balanced and dose-escalated validations. With evidence building up mainly through case reports and observational studies, there is a need for well-designed paediatric clinical trials and specific research on 0–4-year-old children. At such an early age, assessing residual and recovered abilities is most challenging due to the early developmental stage, incompletely learnt motor and cognitive skills, and unreliable communication; treatment options are also less explored in early age. In middle-income countries, the lack of rehabilitation services and professionals focusing on paediatric age hampers the overall good assistance provision. Young and fast-evolving health insurance systems prevent universal access to chronic care in some countries. In low-income countries, rescue networks are often inadequate, and there is a lack of specialised and intensive care, difficulty in providing specific pharmaceuticals, and lower compliance to intensive care hygiene standards. Despite this, paediatric cases with DoC are reported, albeit in fewer numbers than in countries with better-resourced healthcare systems. For patients with a poor prospect of recovery, withdrawal of care is inhomogeneous across countries and still heavily conditioned by treatment costs as well as ethical and cultural factors, rather than reliant on protocols for assessment and standardised treatments. In summary, there is a strong call for multicentric, international, and global health initiatives on DoC to devote resources to the paediatric age, as there is now scope for funders to invest in themes specific to DoC affecting the early years of the life course.
Disorders of consciousness (DOC) could be the results of acquired brain injury, a term defining all brain damages happening after birth that are not hereditary, congenital, degenerative, or induced by birth trauma. Different mechanisms could lead to acquired brain injury such as infection, anoxia, and traumatic brain injuries, which can induce diffuse or focal injury pathophysiologic processes (e.g., cerebral hematoma, contusion, diffuse axonal injury, etc.). DOC are divided in four categories; coma (no arousal or awareness), unresponsive wakefulness syndrome – UWS – (arousal is present but not awareness), minimally conscious state – MCS – (arousal is present with fluctuant but reproducible cognitively mediated behaviors), and emergence from MCS, that is when the patient achieves functional communication and/or functional object use. Therapeutic approaches to promote consciousness recovery, such as pharmacological and non-pharmacological propositions, have been limited both in number and success. With regard to transcranial direct current stimulation (i.e., tDCS) in DOC, it has been shown that a single session of tDCS over the left DLPFC can improve signs of consciousness in about 43% of patients in MCS. Multiple tDCS sessions showed also positive results mostly with MCS patients and promising results in retaining new signs of consciousness for as long as 3 months post-stimulation. The transient clinical improvement observed in patients in MCS following tDCS seems to require residual gray matter and metabolic activity in the stimulated area and in structures known to be involved in awareness and arousal, such as the precuneus and the thalamus. The best montage has not been determined yet, as it may vary according to the topography of the brain damage. Nonetheless, stimulation with the anode positioned over the left DLPFC has proved to be effective although no comparative study has been published so far. As diagnostic tool, tDCS combined with transcranial magnetic stimulation has been shown to induce different responses in terms of connectivity and excitability in MCS patients compared with UWS patients. This may suggest that some patients are more suited to benefit from tDCS than others. In conclusion, although tDCS on patients with DOC has not been fully investigated, the studies published so far have revealed promising results regarding feasibility, safety, and improvement of signs of consciousness. The present chapter provides an overview of the tDCS studies on patients with DOC.
Abstract
Background: Case reports of the use of zolpidem in Permanent Vegetative States (PVS) have led to interest by the media and court judgements defining treatment with such drugs. It is uncertain whether this paradoxical effect of zolpidem in raising consciousness may be evident in other low awareness states such as Minimally Conscious State (MCS).
Case study: This study treated a 44 year old male with MCS some 4 years after his traumatic brain injury with zolpidem for 1 week on and 1 week off treatment. Assessment with a number of tests by blinded therapists showed that his scores were no better on zolpidem and in some cases were worse on treatment.
Conclusions: Ideally a series of individuals is required to assess the effect of zolpidem, but in the light of positive spin stories in the media, negative case reports should also be highlighted. It is imperative that medical treatment in all instances and certainly in low awareness states and end of life decisions is always based on firm evidence.
Cerebral processing in the minimally conscious state To the Editor: The minimally conscious state (MCS) is considered a transitional phase in the partial recovery of self-awareness or environmental-awareness from the vegetative state (VS). This recognition highlights the crucial role of pathophysiology in elucidating the generation of consciousness in these cases.1 The patient described by Laureys et al. showed contextdependent higher-order auditory processing. The authors previously reported that in the VS, auditory stimulation activates primary auditory cortices but not higher-order associative areas from which they have been disconnected. Their work revealed that functional connectivity between primary and higher-order associative cortices areas can be partially preserved in MCS although disconnected in VS.2 In the original description of the apallic syndrome, extensive bilateral damage to the cerebral cortex was considered the primary pathological finding. However, recent publications have shown that VS results from a complex combination of discrete cortical and subcortical damage. In addition, consciousness requires sufficient thalamocortical and intercortical connections, as demonstrated by the identification of isolated functional activity in diverse parts of the cortex that does not provide awareness of self and the environment.3,4 Patients in VS provide the only circumstance in which there is an apparent dissociation of both components of consciousness. The subjective dimension of awareness is impossible to test because it involves “internal awareness” or a state of mind that cannot be measured in an individual existing in apparent disconnection from the environment.3 Despite limitations in measuring this phenomenon physiologically, subjective awareness might continue in some VS cases.3 The development of rehabilitation techniques for VS patients and others suffering long-lasting effects of brain injury is challenging. The multisensory stimulation approach, the use of deep
brain stimulation and the implementation of prosthetics to treat cognitive disabilities have provided new hope for cognitive rehabilitation from VS.3,5 Beyond these advances, the use of neural stem cells is another hope. Laureys et al. have demonstrated partial recovery in a patient who earlier had been in a persistent vegetative state. As these authors have emphasized, “MCS may be a transitional state on the route to further recovery, just like the patient’s vegetative state was a transitional state earlier in his course.” Neuroimaging could provide a powerful tool to follow up cognitive recovery in patients with PVS or MCS.
Calixto Machado, MD, PhD, Ciudad de La Habana, Cuba
Introduction:
Zolpidem is a non-benzodiazepine drug used for the therapy of insomnia, which has selectivity for stimulating the effect of GABA-A receptors. Recently, a paradoxical arousing effect of zolpidem in patients with severe brain damage has been repeatedly reported.
Methods:
A placebo-controlled magnetic resonance study was conducted to evaluate its effect on BOLD and metabolites spectral signals in a patient with severe brain injuries and an age-matched healthy volunteer. A multi-modal analysis was used to assess aspects in the pharmacologically-induced changes in the resting-state brain metabolism.
Results:
A significantly increased BOLD signal was transiently localized in the left frontal cortices, bilateral anterior cingulated areas, left thalamus and right head of the caudate nucleus. The healthy subject showed a deactivation of the frontal, parietal and temporal cortices. BOLD signal changes were found to significantly correlate with concentrations of extravascular metabolites in the left frontal cortex. It is discussed that, when zolpidem attaches to modified GABA receptors of neurodormant brain cells, brain activation is induced. This might explain the significant correlations of BOLD signal changes and proton-MRS metabolites in this patient after zolpidem.
Conclusion:
It was concluded that proton-MRS and BOLD signal assessment could be used to study zolpidem-induced metabolic modulation in a resting state.
Heart rate variability (HRV) is frequently used to measure autonomic nervous system (ANS) activity. However, little is known about the mechanism underlying pharmacologically induced changes in HRV. Previous research has shown that nicotine exposure stimulates the ANS, mediating a wide spectrum of physiological and behavioral effects, including altered respiratory sinus arrhythmia and enhanced arousal and attention. Using Lomb-Welch periodograms, the effect of nicotine on the ANS in 14 nicotine- naive human subjects are studied. Results showed an increase in the low frequency (LF) to high frequency (HF) ratio with little change in mean heart rate. Results suggest that nicotine affects both sympathetic and parasympathetic reactivities and that the LF/HF best characterizes early ANS activated nicotine changes in HRV. The Lomb-Welch periodogram of the HRV is also compared to the conventional interpolated Welch periodogram. The attenuation of the high frequency components due to interpolation of the non-uniform R-R intervals is found to be a function of the power of the high frequency components, increasing with increasing power. Thus analyses using Welch periodograms that make use of the high frequency components may yield erroneous results.
On land, fur seals predominately display bilaterally synchronized electroencephalogram (EEG) activity during slow-wave sleep (SWS), similar to that observed in all terrestrial mammals. In water, however, fur seals exhibit asymmetric slow-wave sleep (ASWS), resembling the unihemispheric slow-wave sleep of odontocetes (toothed whales). The unique sleeping pattern of fur seals allows us to distinguish neuronal mechanisms mediating EEG changes from those mediating behavioral quiescence. In a prior study we found that cortical acetylcholine release is lateralized during ASWS in the northern fur seal, with greater release in the hemisphere displaying low-voltage (waking) EEG activity, linking acetylcholine release to hemispheric EEG activation (Lapierre et al. 2007). In contrast to acetylcholine, we now report that cortical serotonin release is not lateralized during ASWS. Our data demonstrate that bilaterally symmetric levels of serotonin are compatible with interhemispheric EEG asymmetry in the fur seal. We also find greatly elevated levels during eating and hosing the animals with water, suggesting that serotonin is more closely linked to bilateral variables, such as axial motor and autonomic control, than to the lateralized cortical activation manifested in asymmetrical sleep.
Background: Several studies have reported the use of zolpidem for induced arousal after permanent vegetative states. However, changes in brain function and EMG after zolpidem treatment requires further investigation. Objective: To investigate the effect of zolpidem, an unconventional drug, on inducing arousal in patients in a permanent vegetative state after brain injury using visual single photon emission computerized tomography and digitized cerebral state monitor. Design: A self-controlled observation. Setting: Shenzhen People's Hospital. Participants: Seven patients in a permanent vegetative state were selected from the Department of Neurosurgery, Shenzhen People's Hospital from March 2005 to May 2007. The group included 5 males and 2 females, 24-55 years of age, with a mean age of 38.5 years. All seven patients had been in a permanent vegetative statement for at least six months. The patient group included three comatose patients, who had sustained injuries to the cerebral cortex, basal ganglia, or thalamus in motor vehicle accidents, and four patients, who had suffered primary/secondary brain stem injury. Informed consents were obtained from the patients' relatives. Methods: The patients brains were imaged by 99TCm ECD single photon emission computerized tomography prior to treatment with zolpidem [Sanofi Winthrop Industrie, France, code number approved by the State Food & Drug Administration (SFDA) J20040033, specification 10 mg per tablet. At 8:00 p.m., 10 mg zolpidem was dissolved with distilled water and administered through a nasogastric tube at 1 hour before and after treatment and 1 week following treatment, respectively. Visual analysis of cerebral perfusion changes in the injured brain regions before and after treatment was performed. Simultaneously, three monitoring parameters were obtained though a cerebral state monitor, which included cerebral state index, electromyographic index, and burst suppression index. Main outcome measures: Comparison of the three brain function indices, cerebral perfusion in the areas of brain injury, and clinical indices before and after treatment. Results: All seven patients were included in the final analysis. 1 Following treatment, the parameters of cerebral state index and electromyographic index were significantly higher than before treatment (P < 0.05). The burst suppression index was significantly lower than before treatment (P < 0.05). 2 Cerebral perfusion in areas of brain injury improved significantly in all subjects compared to before treatment. Conclusion: The findings of visual single photon emission computerized tomography and digitized cerebral state monitor reveal that Zolpidem appears to be an effective treatment for restoring brain function to certain patients in a permanent vegetative state.
This chapter considers the use of central thalamic deep brain stimulation (CT/DBS) to support arousal regulation mechanisms in the minimally conscious state (MCS). CT/DBS for selected patients in a MCS is first placed in the historical context of prior efforts to use thalamic electrical brain stimulation to treat the unconscious clinical conditions of coma and vegetative state. These previous studies and a proof of concept result from a single-subject study of a patient in a MCS are reviewed against the background of new population data providing benchmarks of the natural history of vegetative and MCSs. The conceptual foundations for CT/DBS in selected patients in a MCS are then presented with consideration of both circuit and cellular mechanisms underlying recovery of consciousness identified from empirical studies. Directions for developing future generalizable criteria for CT/DBS that focus on the integrity of necessary brain systems and behavioral profiles in patients in a MCS that may optimally response to support of arousal regulation mechanisms are proposed.
Localization of the messenger RNAs that encode the α1, β2 and γ2 subunits of GABAA showed a distinct topographic pattern in rat brain which corresponded with [3H]zolpidem binding in most brain regions. The close topographic correspondence between the specific receptor subunits examined and the distribution of [3H]zolpidem binding sites provides support for the hypothesis that this benzodiazepine type 1 selective ligand binds to a GABAA receptor that consists of α1, β2 and γ2 subunits in the rat brain. Brain regions with relatively high densities of α1, β2 and γ2 subunits of GABAA and [3H]zolpidem binding included olfactory bulb, medial septum, ventral pallidum, diagonal band, inferior colliculus, substantia nigra pars reticulata and specific layers of the cortex. Two areas with low [3H]zolpidem binding and a virtual absence of these GABAA receptor subunit messenger RNAs were the lateral septum and the striatum. In contrast to the discrete pattern observed for α1 and β2 subunit messenger RNAs, the γ2 subunit messenger RNA was distributed more diffusely in brain. Only the hippocampus, layer 2 of the piriform cortex and the cerebellum showed a strong concentration of the γ2 subunit messenger RNA. It was determined with a polymerase chain reaction assay that both long and short variants of the γ2 subunit messenger RNAs were present within several of the brain sites selected for examination. Sites with high densities of [3H]zolpidem binding sites had a greater relative abundance of the γ2 long splice variant, compared to the γ2 short variant. There were some regions that expressed high levels of α1, β2 and γ2S subunit messenger RNAs but low [3H]zolpidem binding, suggesting that γ2 splice variant expression may modulate high-affinity [3H]zolpidem binding. To determine relationships between in vitro [3H]zolpidem binding and functional sensitivity in vivo, interactions between zolpidem and GABA were assessed in brain regions that contained high and low densities of [3H]zolpidem binding sites. In the medial septum, a brain region with a high concentration of [3H]zolpidem binding sites, iontophoretic application of zolpidem enhanced the inhibitory effect of GABA responses on 70% of the neurons examined. In the lateral septum, which contains very low densities of [3H]zolpidem binding sites, neurons were not sensitive to zolpidem enhancement of GABA-induced inhibition. These electrophysiological results demonstrate a correspondence between the regional distribution of [3H]zolpidem binding in vitro and functional sensitivity to the drug in vivo.