Brain death and the anencephalic newborn

We will set the stage for our analysis by reviewing selected medical aspects of anencephaly, outlining the history of the use of anencephalics as organ sources, and summarising the results of an important study recently completed at Loma Linda University. We will then employ some of the arguments and justifications underlying the Uniform Determination of Death Act (UDDA) to claim that anencephaly is morally equivalent to brain death, i.e., the reasons for considering brain-dead patients to be dead also apply to anencephalics. Finally, we will critique our proposal and discuss its implications.     

Brain stem death and organ donation.

Organs for donation are in short supply in the United Kingdom, resulting in allegations that relatives of potential donors are not being asked for consent. Legislation on "required request" has been proposed to overcome this. The incidence, causes, complications, and patterns of organ donation in brain stem dead patients in one referral centre were studied over 12 months. Data were collected on all patients fulfilling criteria for brain stem death or considered suitable for donating organs after circulatory arrest. Forty two patients fulfilled the criteria for brain stem death, and in 10 further patients circulatory arrest occurred before formal testing was finished. The major causes of brain stem death were head injury (28) and intracranial haemorrhage (17). Consent to organ donation was obtained for 24 potential donors, and organs were donated by 23 of them. Twenty nine patients did not donate organs. The commonest reasons for failure to donate were medical unsuitability (13) and the coroner not releasing the body (eight). Consent was not sought in three cases, and the relatives refused consent in the remaining five. This study suggests that required request will not considerably increase the supply of donor organs.     

Brain death in three neurosurgical units.

The validity of clinical criteria for diagnosing brain death has been investigated in three ways. A total of 447 published cases were reviewed. In three neurosurgical units (Cambridge, Glasgow, and Swansea) 609 patients diagnosed clinically as brain dead were studied; 326 had final cardiac asystole while still being ventilated, and ventilation was discontinued in the remainder. No patient recovered. The median time in hospital before the heart finally stopped was 3 1/2-4 1/2 days, with 30-40 hours on the ventilator. Analysis of prospective data from three countries on patients with severe head injuries showed that not one of 1003 survivors would ever have been suspected of being brain dead even in their worst state soon after injury. Recovery after supposed brain death has been alleged in patients who were thought to be brain dead but in fact were not and in cases where reflex movements in the limbs were mistaken for signs of life. The safeguards in diagnosing brain death include establishing irreversible structural brain damage, excluding the effects of drugs, and allowing enough time to elapse to establish the diagnosis beyond doubt. The studies reported here show that the clinical criteria used in the United Kingdom are reliable. There is no need for confirmatory tests such as an electroencephalogram provided that all the conditions for clinical diagnosis have been fulfilled and all the tests carried out.     

Brain death and marginal grafts in liver transplantation

It is well known that most organs for transplantation are currently procured from brain-dead donors; however, the presence of brain death is an important risk factor in liver transplantation. In addition, one of the mechanisms to avoid the shortage of liver grafts for transplant is the use of marginal livers, which may show higher risk of primary non-function or initial poor function. To our knowledge, very few reviews have focused in the field of liver transplantation using brain-dead donors; moreover, reviews that focused on both brain death and marginal grafts in liver transplantation, both being key risk factors in clinical practice, have not been published elsewhere. The present review aims to describe the recent findings and the state-of-the-art knowledge regarding the pathophysiological changes occurring during brain death, their effects on marginal liver grafts and summarize the more controversial topics of this pathology. We also review the therapeutic strategies designed to date to reduce the detrimental effects of brain death in both marginal and optimal livers, attempting to explain why such strategies have not solved the clinical problem of liver transplantation.     

Brain death and brain life: rethinking the connection

The connection between brain life and brain death is neither as simple nor as defensible as it might at first appear. The problem rests with the two dominant competing definitions of death:...the loss of that which is necessary for the organism to continue to function as a whole;....the loss of that which is essentially significant to the nature of the organism... If death is understood as the loss of that which is necessary for the continued functioning of the organism as whole, then the apparent symmetry breaks down. If...death could be understood as the loss of that which is essentially significant to the nature of the organism....consciousness, then the symmetry would hold. However, that definition of death is indefensible. Therefore...statements about the status of anencephalic infants and early human embryos based upon a connection between brain death and brain life are unfounded.     

Brain death in Britain as reflected in renal donors.

The diagnostic mix of 1228 brain-dead renal donors in Britain was similar to that of 479 cases of brain death recently reported from three neurosurgical units. About half the donors came from non-teaching hospitals without a neurosurgical unit, many of them small and distant from the centre. The different circumstances that preceded brain deaths were examined--namely, diagnosis and whether the fatal ictus of brain damage occurred when the patient was already in hospital--to explain why donors spend varying times on the ventilator. Head injuries accounted for half the donors, and intracranial haemorrhage for almost a third. While many potential donors are not made available, the size of the pool has been overestimated, particularly in regard to head injury. Reduction in organ donation since "Panorama" has been very uneven, with some places increasing their yield; this suggests reluctance of doctors to initiate donation rather than relatives withholding permission.     

Brain death and organ donation in a neurosurgical unit: audit of recent practice.

OBJECTIVE--To assess the potential for increasing the yield of donors by comparing the current pattern of brain death and organ donation in a neurosurgical unit with that reported in 1981 and with a recent national audit. DESIGN--Retrospective review of all deaths for 1986, 1987, and 1988 and prospective data for 1989. SETTING--A regional neurosurgical unit serving 2.7 million population. RESULTS--Of 553 deaths, 35% (191) patients died while on a ventilator and 17% (92) after discontinuation of ventilation. Medical contraindications to donation were found in 23% (32) of 141 patients tested for brain death, in 38% (19) of 50 patients who died while being ventilated who were not tested, and in 12% (11) of 92 patients no longer being ventilated. Consent for donation was sought in 88% (96) of 109 medically suitable brain dead patients and granted in 70% (67) of these. Half those with permission for multiorgan donation had only the kidneys removed. CONCLUSIONS--More organs may be lost owing to transplant team logistics than by failure to seek consent from relatives of brain dead patients. The estimated size of the pool of potential donors depends on what types of patients might be considered. Ensuring that all who die while being ventilated are tested for brain death and considering the potential for donation before withdrawing ventilation could yield more donors. Ventilating more patients who are hopelessly brain damaged to secure more donors raises ethical and economic issues.     

Death and brain death: a new formulation for Canadian medicine. Canadian Congress Committee on Brain Death.

Between June 1984 and December 1986, 35 patients with acute myocardial infarction received streptokinase intravenously within 3 hours after the beginning of chest pain and underwent percutaneous transluminal coronary angioplasty (PTCA) either immediately (in 2 cases) or 1 to 19 (mean 4.4) days later (in 33). The rate of successful PTCA was 89%. Reocclusion occurred in one patient. The mean percentage of stenosis decreased from 86% to 11%. The mean trans-stenotic gradient was reduced from 41 to 11 mm Hg. The results suggest that in patients whose condition is stable, PTCA performed a few days after thrombolysis is a valuable alternative to more aggressive treatment with immediate PTCA.     

Modulating Brain Oscillations to Drive Brain Function

Do neuronal oscillations play a causal role in brain function? In a study in this issue of PLOS Biology, Helfrich and colleagues address this long-standing question by attempting to drive brain oscillations using transcranial electrical current stimulation. Remarkably, they were able to manipulate visual perception by forcing brain oscillations of the left and right visual hemispheres into synchrony using oscillatory currents over both hemispheres. Under this condition, human observers more often perceived an inherently ambiguous visual stimulus in one of its perceptual instantiations. These findings shed light on the mechanisms underlying neuronal computation. They show that it is the neuronal oscillations that drive the visual experience, not the experience driving the oscillations. And they indicate that synchronized oscillatory activity groups brain areas into functional networks. This points to new ways for controlled experimental and possibly also clinical interventions for the study and modulation of brain oscillations and associated functions.How does the brain work? How does it code, transfer, and store information? How are conscious experiences generated? These, among others, are long-standing questions neuroscientists try to answer. One way to approach this is to study how the brain orchestrates behaviour, for instance, by measuring brain activity and relating it to behaviour. Yet, studying the brain–behaviour relationship raises another series of questions: What type of brain activity should one look at? Do we need to record directly from single neurons? Or can we make inferences also by recording from larger pools of neurons? And importantly, do these measures of brain activity provide mechanistic accounts of how the brain implements function, or are they just inevitable side-products, with limited explanatory power for the neural mechanisms underlying our experiences, thoughts, or actions?Certainly, one would have a good argument for brain activity causally underlying brain function if (i) this brain activity not only relates to sensory experiences or behavioural performance measures (revealing a correlative brain-behaviour relationship), but (ii) interventions into this brain activity would also modulate our experiences or performance (revealing a causal link). Recent developments allow addressing these central points for oscillatory brain activity, which is what Helfrich et al. [1] did in their study published in this issue of PLOS Biology.At the basis of Helfrich et al.''s study are two lines of research, one of which is concerned with the interpretation of a special type of brain activity, namely, brain oscillations. This type of brain activity represents voltage fluctuations of neuronal elements and was initially observed from one scalp electrode by Hans Berger [2]. Today, brain oscillations are typically recorded from multiple sensors distributed over the scalp or brain, for instance using electro- or magneto-encephalography (EEG/MEG), in order to make inferences about the orchestration of brain activity across distinct neuronal elements [3]. A prominent view is that these oscillations represent essential network activity. They become visible when neuronal elements of a network start to synchronize their oscillatory activity, i.e., temporarily couple together [4]. Notably, brain oscillations vary in frequencies depending on the task that is being executed and the region of the brain they are recorded from [3] (see Box 1 for example frequencies relevant for Helfrich et al.''s study). It is understood that this may reflect nested networks that oscillate at different frequencies and spatial scales [4] and that define functional architecture not only by synchronizing at the same frequency but also through complex cross-frequency interactions; this to allow for integration of processes at different temporal and spatial scales [5]–[7]. With respect to the above questions on how the brain operates, the most exciting aspect of oscillatory brain activity is probably that it offers mechanistic accounts. One example is the communication-through-coherence theory [8], which states that the relative timing of oscillatory activity of two neuronal elements enables the control of information transfer, with communication being maximal when phases of high excitability of these elements cycle in synchrony, and minimal when they cycle out of synchrony (see Fig. 1B Model).Open in a separate windowFigure 1Schematic representation of design, objectives, and insights from the study by Helfrich et al. A. Design and questions: Participants viewed an apparent motion stimulus, which elicits a bistable percept consisting of either horizontal (percept 1) or vertical motion (percept 2). A bi-hemispheric network of two posterior areas (blue and red squares) was interrogated as to the functionality of inter-area synchrony (see “?”) in generating these percepts, by recording of brain oscillations through electro-encephalography (EEG), and interventions into these oscillations through transcranial alternating current stimulation (tACS). B. Results and conclusion: EEG revealed that the horizontal motion percept was associated with enhanced synchrony (coherence) between oscillatory brain activity of the two posterior areas (as compared to vertical motion percept), in line with coupling of the two areas to a functional network by synchronization of their respective phases of high excitability (see Model). This provides information on a correlative relationship between network activation and function but cannot disentangle whether it is the percept that drives the network, or the network that drives the percept. Intervention with tACS supports the latter. Applying tACS in synchrony over the two areas enhances inter-area coherence of oscillatory activity as well as the horizontal motion percept (as opposed to applying tACS out of synchrony). Hence, synchrony of oscillatory brain activity underlies the formation of functional networks and mediates its associated functions.

Box 1. Glossary

Brain oscillations in the gamma frequency band (gamma-oscillations): This is a class of brain oscillations cycling at rapid frequencies (35–100 Hz). Gamma-oscillations are prominent in visual cortex (among other areas) and become evident also in scalp recordings when participants view specific types of visual stimuli. Alpha-band brain oscillations cycle at 8–12 Hz. Alpha-oscillations can co-occur with gamma-oscillations in visual areas, where these two classes of oscillations show an inverse relationship in terms of amplitude. Transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS) use electrical currents applied through two or more scalp electrodes for transient, non-invasive brain stimulation, whereas transcranial magnetic stimulation (TMS) uses the principle of electromagnetic induction. In tACS, the currents are modulated in an oscillatory (sinusoidal) pattern, and can therefore be frequency-tuned to underlying brain oscillations. Likewise, TMS in its rhythmic form (rhythmic TMS) allows for periodic brain stimulation at frequencies of brain oscillations.The other line of research that is at the heart of Helfrich et al.''s study is concerned with interventions into brain activity by non-invasive brain stimulation techniques; this to probe the brain–behaviour relationship along a more causal dimension [9]. Such techniques are widely used in cognitive and clinical neuroscience, and employ either magnetic or electric fields to stimulate neurons directly (i.e., transcranially) to then test the behavioural consequences. Currently available techniques use transcranial magnetic stimulation (TMS), or a variety of electrical currents such as with transcranial direct current stimulation (tDCS) or transcranial alternating current stimulation (tACS) (see Box 1) [10]. While these techniques have been successfully employed in numerous studies, a recurrent question is how to improve specificity of effects in terms of enhancing focality [11] or targeting specific subpopulations within the stimulated neuronal pool [12]. In addition, simultaneous neuroimaging studies have revealed that the effect of the magnetic or electric field on the stimulated area (under the TMS coil or the stimulation electrode) is spreading to other areas, in many instances along anatomical connections [13],[14]. Hence, any behavioural outcome needs to be interpreted in the context of network effects. Intriguingly, and relevant for interactions with oscillatory brain activity, recent findings indicate that the specificity of these interventions into functionally relevant brain activity may be improved by taking into account not only the spatial dimension (i.e., what anatomical network to stimulate) but also the temporal dimension (what frequency to apply). This is suggested by recent studies using periodic transcranial stimulation protocols (such as tACS or rhythmic TMS) allowing a frequency tuning of stimulation (see Box 1). These studies demonstrate an immediate behavioural effect at specific stimulation frequencies, namely those that match the frequencies of intrinsic brain oscillations[15]–[21]; which may be caused by the periodic stimulation promoting the intrinsic oscillations [22]–[24].Capitalizing on the above, Helfrich et al. convincingly address in healthy human volunteers the long-standing issue of whether oscillatory brain activity indeed coordinates functional brain architecture, as opposed to representing a mere by-product, and thereby bridge a gap between recordings and interventional studies into brain oscillations (see Fig. 1 for a schematic representation of design, objectives, and insights of the study). They do so by examining the link between visual network activity and specific sensory experiences. To manipulate sensory experience (without changing sensory input), Helfrich et al. employed a visual motion paradigm (see Fig. 1A), in which pairs of diagonally opposed dots are presented on a screen in two alternating configurations (upper left/lower right dots followed by lower left/upper right dots, etc.). This leads to a bistable percept, consisting of time periods during which the two dots are perceived as moving horizontally (see Fig. 1A, apparent motion percept 1), alternating with time periods during which the same dots are perceived as moving vertically (Fig. 1A, apparent motion percept 2). Interestingly, recordings of brain oscillations from left and right occipito-parietal EEG sensors, i.e., from areas processing the right- versus left-sided dots respectively, revealed a temporally stable pattern of relative timing between these oscillations, depending on the percept (replicating [25]): during horizontal motion percepts when the demands for interhemispheric communication can be assumed to be high (as opposed to vertical percepts where motion integration can be resolved within each hemisphere) [26], these left and right oscillations show high coherence in the gamma frequency band (at approximately 35–100 Hz) (Fig. 1B EEG). In other words, oscillations in the left and right occipito-parietal areas are synchronized. This is suggestive of these areas forming a temporally stable network during horizontal as opposed to vertical motion integration, in line with models of network coordination by synchronization of brain oscillations (Fig. 1B Model) [8],[27]. Importantly, applying rhythmic brain stimulation in synchrony over the left and right occipito-parietal cortex using tACS at gamma frequency enhances both the gamma-band EEG coherence between the two hemispheres (without affecting gamma-power) and its associated percept (i.e., horizontal motion), as opposed to applying gamma-tACS out of synchrony (Fig. 1B tACS). See also Polania et al. [19] for a conceptually similar tACS result, without the direct evidence for concurrently enhanced EEG synchrony. This shows that in-synchrony tACS versus out-of-synchrony tACS over two elements of an oscillatory visual network can be used to stabilize/destabilize this network, and with meaningful perceptual consequences. This is in accord with brain oscillations not only indexing network coordination and associated functions, but causing them.The findings of Helfrich et al. make an important contribution. They more firmly link the dynamics of oscillatory brain activity to the formation of functional networks, as well as the orchestration of brain function (here phenomenological experience) and this along a causal dimension. This corroborates and extends a growing number of studies showing that brain oscillations can serve as targets for controlled interventions into brain activity and function, by non-invasive brain stimulation in periodic patterns [22]–[24]. The principle idea is to promote brain oscillations that have been associated with specific functions (as inferred from correlative brain-behavioural links) to cause performance changes, provided a causal relationship underlies the correlative data. For instance, it has been shown that promoting oscillations of the parietal cortex known to be related to attentional selection using frequency-tuned rhythmic TMS [22] biases perception towards the expected stimulus dimension [17],[20]. Likewise, tACS (or oscillatory tDCS) tuned to fronto-temporal oscillations, which have been associated with memory consolidation during slow-wave sleep or dream patterns during REM-sleep (e.g., lucid dreaming), have been shown to enhance memory or lucid dream content, respectively [15],[21]. And equivalent effects have been found for oscillatory motor system activity [16],[18]. This opens powerful opportunities for neuroscience and clinical interventions, not only allowing to test models of how brain activity implements function but also how it relates to dysfunction, to inform controlled intervention into the brain–behaviour relationship.These findings are exciting and indicate that it is promising to study brain oscillations, even at a macroscopic scale (such as measured with EEG/MEG), to answer some of the long-standing questions of how the brain works. They also take the emerging new approach of using periodic transcranial stimulation to interact with brain oscillations and function beyond the proof-of-principle stage. However, the usefulness of this approach will depend on the extent to which its specificity can be improved (e.g., up- versus down-regulating oscillations, tailoring to individual differences) and its mechanisms of actions understood. One unresolved point is the spatial extent of stimulation. With tACS, the conventional stimulation electrodes are large (several cm²) and require a “return” electrode which excites widespread areas. To render stimulation more focal, special electrode montages have been proposed [11], as also used by Helfrich et al., and which may explain some of the differences to a previous study of the same group using a less focal electrode montage [28]. Other developments are underway to funnel stimulation to specific target areas by the use of multichannel electrode configurations and computational (forward) models of electrical field distributions [29]. In this context, it will be of interest to compare the efficiency of frequency-tuned tACS with frequency-tuned rhythmic TMS, the latter thought to be more focal, but also more superficial. In addition, it is still largely unknown how these forms of rhythmic stimulation interact with intrinsic brain oscillations. There is growing evidence that the periodic electric or magnetic force may entrain the underlying oscillations during stimulation [22],[23], and that long-lasting effects may arise from this entrainment, possibly by inducing plasticity effects via spike-timing dependent plasticity in the circuits generating these oscillations [30]. It is the former, short-term effects that are of interest for experimental interventions in cognitive neuroscience for testing theory (because of their limited duration), but the latter, longer-lasting effects that are of relevance for clinical interventions. Finally, while Helfrich et al. report cross-frequency effects of gamma-tACS, in particular in the alpha frequency band (8–12 Hz), it remains to be studied in detail how the induced oscillations resonate in other, nested oscillatory networks. These and other points will need to be resolved in future work to be able to fully assess the extent of the impact of this emerging approach.     

编者按: 脑成像与脑网络

揭示脑的奥秘是人类面临的最大挑战之一。神经元是构成神经系统结构与功能的基本单位。神经元与神经元之间通过突触实现信息交互,并构成神经环路或神经网络。神经环路有局部的,也有跨脑区或长程的,甚至全脑尺度的。神经环路则是脑实现神经信息处理的基本单元。若干神经环路构成脑网络。脑网络研究已经成为脑功能与脑疾病研究领域的热点。 在国家自然科学基金委员会和科技部“973计划”等项目的支持下,我国科学家在这一领域已经开展了卓有成效的工作。2011年第393次香山科学会议“脑网络组及其临床应用的前沿科学问题”曾对此进行过比较深入的研讨。为促进对该领域现状及发展的了解,本期汇集了2篇述评和2篇研究论文,作为脑成像与脑网络专题发表,以飨读者。 利用9.4T功能磁共振成像(fMRI)获得轻度麻醉状态下大鼠静息状态及刺激激活的数据,通过互相关分析构建节点之间的相关系数矩阵并计算相应的网络参数,赖永秀等人报道了大鼠感觉运动系统静息态脑网络的研究成果,发现感觉运动系统在静息态时的脑网络具有小世界属性。 扩散磁共振成像(dMRI)的出现为大脑结构与功能研究提供了全新的检测手段,雷皓等报道了小动物高分辨扩散磁共振成像数据分析方法,为小动物脑dMRI研究提供了统一图像模板与完善的计算方法,对于检测神经纤维微观结构的变化,以及临床诊断,将具有极其重要的意义。 神经环路功能变化的实时在体监测是研究脑网络不可或缺的手段,曾绍群等评述了基于声光偏转器的快速无惯性随机扫描双光子显微成像技术的研究进展及发展趋势,指出该技术的进一步发展将为神经活动观测提供一种全新的方法,从而极大地推动脑科学研究的发展。 针对哺乳动物全脑的神经元网络成像,龚辉等从空间分辨率、探测范围、数据配准和成像速度等方面评述了光学显微水平全脑成像方法的研究进展,并讨论所面临的挑战。他们指出,要在全脑尺度获取突起水平分辨率的结构与功能数据,光学成像方法最为成熟。华中科技大学研制的MOST系统,率先获得了一系列高分辨率的完整大脑解剖数据集,该成果将在神经元网络的构建和脑功能与疾病研究中发挥重要作用。 我们期待更多、更好的有关脑成像与脑网络的论文发表,以更广泛和深入地促进我国脑科学研究领域的学术交流。