The Harder Problem: Functional PET Scanning and Prognosis in the Vegetative State

Cardiac arrest or very severe head injuries are most often fatal, but what of when they are not? Often in such cases we find a person in deep coma, yet one with signs, such as preserved pupillary reflexes, facial movement, or remaining breathing efforts, that they are not brain dead. When this state is prolonged, we may call it the "vegetative state."

Many people who enter the vegetative state never regain consciousness, but others, especially those whose brain injury is from head trauma rather than cardiac arrest, do recover at least some some level of waking consciousness. Prediction of who will recover would be useful in counseling families regarding decisions on how long to maintain artificial means of life support such as mechanical ventilation.

In the Lancet this week, a study has been published which found that functional PET imaging may improve the accuracy of clinical predictions of the potential of waking from a vegetative state.The method seemed more accurate than fMRI in those patients.

Chalmers famously asked the hard problem:  Given a complete materialist description of a thinking, feeling, behaving human, why should those physical processes we have described so completely be accompanied by subjective consciousness? Of course, when engaged in honest conversation with another person, we do not doubt that he is thinking and feeling; the fact that he possesses subjective consciousness is more obvious to us than any physicalist philosophy of mind could ever be!

But what of the person who is vegetative? Here common sense intuitions may fail. This is the harder problem: to find a way of seeing as partially conscious (or denying such) with those who show no outward signs of consciousness.

Related questions for which I have no fixed answers yet:  if one who appears comatose shows partial functional PET signs of conscious awareness, is it correct to say that the patient is in some sense conscious?  If so, where lie our ethical duties? If not, where have we drawn the line, and why?

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ABSTRACT

The Lancet, Early Online Publication, 16 April 2014
doi:10.1016/S0140-6736(14)60042-8Cite or Link Using DOI
This article can be found in the following collections: Neurology (Head injury)

Diagnostic precision of PET imaging and functional MRI in disorders of consciousness: a clinical validation study

Summary

Background

Bedside clinical examinations can have high rates of misdiagnosis of unresponsive wakefulness syndrome (vegetative state) or minimally conscious state. The diagnostic and prognostic usefulness of neuroimaging-based approaches has not been established in a clinical setting. We did a validation study of two neuroimaging-based diagnostic methods: PET imaging and functional MRI (fMRI).

Methods

For this clinical validation study, we included patients referred to the University Hospital of Liège, Belgium, between January, 2008, and June, 2012, who were diagnosed by our unit with unresponsive wakefulness syndrome, locked-in syndrome, or minimally conscious state with traumatic or non-traumatic causes. We did repeated standardised clinical assessments with the Coma Recovery Scale—Revised (CRS—R), cerebral 18F-fluorodeoxyglucose (FDG) PET, and fMRI during mental activation tasks. We calculated the diagnostic accuracy of both imaging methods with CRS—R diagnosis as reference. We assessed outcome after 12 months with the Glasgow Outcome Scale—Extended.

Findings

We included 41 patients with unresponsive wakefulness syndrome, four with locked-in syndrome, and 81 in a minimally conscious state (48=traumatic, 78=non-traumatic; 110=chronic, 16=subacute). 18F-FDG PET had high sensitivity for identification of patients in a minimally conscious state (93%, 95% CI 85—98) and high congruence (85%, 77—90) with behavioural CRS—R scores. The active fMRI method was less sensitive at diagnosis of a minimally conscious state (45%, 30—61) and had lower overall congruence with behavioural scores (63%, 51—73) than PET imaging. 18F-FDG PET correctly predicted outcome in 75 of 102 patients (74%, 64—81), and fMRI in 36 of 65 patients (56%, 43—67). 13 of 42 (32%) of the behaviourally unresponsive patients (ie, diagnosed as unresponsive with CRS—R) showed brain activity compatible with (minimal) consciousness (ie, activity associated with consciousness, but diminished compared with fully conscious individuals) on at least one neuroimaging test; 69% of these (9 of 13) patients subsequently recovered consciousness.

Interpretation

Cerebral 18F-FDG PET could be used to complement bedside examinations and predict long-term recovery of patients with unresponsive wakefulness syndrome. Active fMRI might also be useful for differential diagnosis, but seems to be less accurate.

Robert Kane on Free Will and Determinism


The Intelligibility Question

The problem of intelligibility is an ancient one: if free will is not compatible with determinism, it does not seem to be compatible with indeterminism either. The arguments here are familiar and have been made since ancient times. An undetermined or chance event, it is said, occurs spontaneously and is not controlled by anything, hence not controlled by the agent. If, for example, a choice occurred by virtue of a quantum jump or other undetermined event in one's brain it would seem a fluke or accident rather than a responsible choice. Or look at the problem in another way that goes a little deeper. If my choice is really undetermined, that means I could have made a different choice given exactly the same past right up to the moment when I did choose. That is what indeterminism and probability mean: exactly the same past, different possible outcomes. Imagine, for example, that I had been deliberating about where to spend my vacation, in Hawaii or Colorado, and after much thought and deliberation had decided I prefered Hawaii and chose it. If the choice was undetermined, then exactly the same deliberation, the same thought processes, the same beliefs, desires and other motives--not a sliver of difference--that led up to my favoring and choosing Hawaii over Colorado, might by chance have issued in my choosing Colorado instead. That is very strange. If such a thing happened it would seem a fluke or accident, like that quantum jump in the brain just mentioned, not a rational choice. Since I had come to favor Hawaii and was about to choose it, when by chance I chose Colorado, I would wonder what went wrong and perhaps consult a neurologist. For reasons such as these, people have argued through the centuries that undetermined free choices would be "arbitrary," "capricious," "random," "irrational," "uncontrolled," and "inexplicable," not really free and responsible choices at all.

Defenders of an incompatibilist or libertarian free will have a dismal record of answering these familiar charges. Realizing that free will cannot merely be indeterminism or chance, they have appealed to various obscure or mysterious forms of agency or causation to make up the difference. Immanuel Kant said we can't explain free will in scientific and psychological terms, even though we require it for belief in morality. To account for it we have to appeal to the agency of what he called a "noumenal self" outside space and time that could not be studied in scientific terms. Many other respectable philosophers continue to believe that only some sort of mind/body dualism can make sense of free will. Science might tell us there was indeterminacy or a place for causal gaps in the brain, but a non-material self, or what Nobel physiologist John Eccles calls a "transempirical power center," would have to fill the causal gaps left by physical causes by intervening in the natural order. The most popular appeal among philosophers today is to a special kind of agent- or immanent causation that cannot be explained in terms of the ordinary modes of causation in terms of events familiar to the sciences. Free and responsible actions are not determined by prior events, but neither do they occur merely by chance. They are caused by agents in a way that transcends and cannot be explained in terms of ordinary modes of causation by events involving the agents.

I call these familiar libertarian strategies for making sense of free will "extra factor" strategies. The idea behind them is that, since indeterminism leaves it open which way an agent will choose or act, some "extra" kind of causation or agency must be postulated over and above the natural flow of events to account for the agent's going one way or another. I have been disenchanted with all these traditonal and modern extra factor strategies since my first encounters with free will issues. I agree with virtually all the objections made to them by dozens of able critics, from A. J. Ayer and C. D. Broad to present day critics such as Gary Watson, Ted Honderich, Bernard Berofsky, John Bishop, Susan Wolf and endless numbers of others. I agree with these critics that extra factor strategies--including agent-causal theories which are now so popular--do not solve the problems about indeterminism they are suppose to solve and they create further mysteries of their own. My strategy in writings on free will over the past two decades has been to see what can be done to make sense of incompatibilist free will without appealing to extra factor strategies of any kind, including special forms of agent-causation. If we are going to make progress on the Intelligibility and Existence questions about incompatibilist free will, we have to strike out in entirely new directions....

The first step is to note that indeterminism does not have to be involved in all acts done "of our own free wills" for which we are ultimately responsible, as argued earlier. Not all such acts have to be undetermined, but only those by which we made ourselves into the kinds of persons we are, namely "self-forming actions" or SFAs. Now I believe these undetermined self-forming actions or SFAs occur at those difficult times of life when we are torn between competing visions of what we should do or become. Perhaps we are torn between doing the moral thing or acting from ambition, or between powerful present desires and long term goals, or we are faced with a difficult tasks for which we have aversions. In all such cases, we are faced with competing motivations and have to make an effort to overcome temptation to do something else we also strongly want. There is tension and uncertainty in our minds about what to do at such times, I suggest, that is reflected in appropriate regions of our brains by movement away from thermodynamic equilibrium--in short, a kind of "stirring up of chaos" in the brain that makes it sensitive to micro-indeterminacies at the neuronal level. The uncertainty and inner tension we feel at such soul-searching moments of self-formation is thus reflected in the indeterminacy of our neural processes themselves. What is experienced internally as uncertainty then corresponds physically to the opening of a window of opportunity that temporarily screens off complete determination by influences of the past. (By contrast, when we act from predominant motives or settled dispositions, the uncertainty or indeterminacy is muted. If it did play a role in such cases, it would be a mere nuisance or fluke, as critics of indeterminism contend.)

When we do decide under such conditions of uncertainty, the outcome is not determined because of the preceding indeterminacy--and yet it can be willed (and hence rational and voluntary) either way owing to the fact that in such self-formation, the agents' prior wills are divided by conflicting motives. Consider a businesswoman who faces such a conflict. She is on her way to an important meeting when she observes an assault taking place in an alley. An inner struggle ensues between her conscience, to stop and call for help, and her career ambitions which tell her she cannot miss this meeting. She has to make an effort of will to overcome the temptation to go on. If she overcomes this temptation, it will be the result of her effort, but if she fails, it will be because she did not allow her effort to succeed. And this is due to the fact that, while she willed to overcome temptation, she also willed to fail, for quite different and incommensurable reasons. When we, like the woman, decide in such circumstances, and the indeterminate efforts we are making become determinate choices, we make one set of competing reasons or motives prevail over the others then and there by deciding.

Now let us add a further piece to the puzzle. Just as indeterminism need not undermine rationality and voluntariness, so indeterminism in and of itself need not undermine control and responsibility. Suppose you are trying to think through a difficult problem, say a mathematical problem, and there is some indeterminacy in your neural processes complicating the task--a kind of chaotic background. It would be like trying to concentrate and solve a problem, say a mathematical problem, with background noise or distraction. Whether you are going to succeed in solving the problem is uncertain and undetermined because of the distracting neural noise. Yet, if you concentrate and solve the problem none the less, we have reason to say you did it and are responsible for it even though it was undetermined whether you would succeed. The indeterministic noise would have been an obstacle that you overcame by your effort.

There are numerous examples supporting this point, where indeterminism functions as an obstacle to success without precluding responsibility. Consider an assassin who is trying to shoot the prime minister, but might miss because of some undetermined events in his nervous system that may lead to a jerking or wavering of his arm. If the assassin does succeed in hitting his target, despite the indeterminism, can he be held responsible? The answer is clearly yes because he intentionally and voluntarily succeeded in doing what he was trying to do--kill the prime minister. Yet his action, killing the prime minister, was undetermined. Or, here is another example: a husband, while arguing with his wife, in a fit of rage swings his arm down on her favorite glass-top table top intending to break it. Again, we suppose that some indeterminism in his outgoing neural pathways makes the momentum of his arm indeterminate so that it is undetermined whether the table will break right up to the moment when it is struck. Whether the husband breaks the table or not is undetermined and yet he is clearly responsible if he does break it. (It would be a poor excuse for him to say to his wife: "chance did it, not me." Even though indeterminism was involved, chance didn't do it, he did.)

Now these examples--of the mathematical problem, the assassin and the husband--are not all we want since they do not amount to genuine exercises of (self-forming) free will in SFAs, like the businesswoman's, where the will is divided between conflicting motives. The woman wants to help the victim, but she also wants to go on to her meeting. By contrast, the assassin's will is not equally divided. He wants to kill the prime minister, but does not also want to fail. (If he fails therefore, it will be merely by chance.) Yet these examples of the assassin, the husband and the like, do provide some clues. To go further, we have to add some new twists.
Imagine in cases of inner conflict characteristic of SFAs, like the businesswoman's, that the indeterministic noise which is providing an obstacle to her overcoming temptation is not coming from an external source, but is coming from her own will, since she also deeply desires to do the opposite. Imagine that two crossing (recurrent) neural networks are involved, each influencing the other, and representing her conflicting motivations. (These are complex networks of interconnected neurons in the brain circulating impulses in feedback loops that are generally involved in higher-level cognitive processing.) The input of one of these neural networks consists in the woman's reasons for acting morally and stopping to help the victim; the input of the other, her ambitious motives for going on to her meeting. The two networks are connected so that the indeterministic noise which is an obstacle to her making one of the choices is coming from her desire to make the other, and vice versa--the indeterminism thus arising from a tension-creating conflict in the will, as we said. In these circumstances, when either of the pathways "wins" (i.e. reaches an activation threshold, which amounts to choice), it will be like your solving the mathematical problem by overcoming the background noise produced by the other. And just as when you solved the mathematical problem by overcoming the distracting noise, one can say you did it and are responsible for it, so one can say this as well, I argue, in the present case, whichever one is chosen. The pathway through which the woman succeeds in reaching a choice threshold will have overcome the obstacle in the form of indeterministic noise generated by the other.

Note that, under such conditions, the choices either way will not be "inadvertent," "accidental," "capricious," or "merely random," (as critics of indeterminism say) because they will be willed by the agents either way when they are made, and done for reasons either way--reasons that the agents then and there endorse . But these are the conditions usually required to say something is done "on purpose," rather than accidentally, capriciously or merely by chance. Moreover, these conditions taken together, I argue, rule out each of the reasons we have for saying that agents act, but do not have control over their actions, (compulsion, coercion, constraint, inadvertence, accident, control by others, etc.). Of course, for undetermined SFAs, agents do not control or determine which choice outcome will occur before it occurs; but it does not follow, because one does control or determine which of a set of outcomes is going to occur before it occurs, that one does not control or determine which of them occurs, when it occurs. When the above conditions for SFAs are satisfied, agents exercise control over their future lives then and there by deciding. Indeed, they have what I call "plural voluntary control" over the options in the following sense: they are able to bring about whichever of the options they will, whenthey will to do so, for the reasons they will to do so, on purpose rather than accidentally or by mistake, without being coerced or compelled in doing so or willing to do so, or otherwise controlled in doing or willing to do so by any other agents or mechanisms. Each of these conditions can be satisfied for SFAs as conceived above. The conditions can be summed up by saying, as we sometimes do, that the agents can choose either way, at will.

Note also that this account of self-forming choices amounts to a kind of "doubling" of the mathematical problem. It is as if an agent faced with such a choice is trying or making an effort to solve two cognitive problems at once, or to complete two competing (deliberative) tasks at once--in our example, to make a moral choice and to make a conflicting self-interested choice (corresponding to the two competing neural networks involved). Each task is being thwarted by the indeterminism coming from the other, so it might fail. But if it succeeds, then the agents can be held responsible because, as in the case of solving the mathematical problem, they will have succeeded in doing what they were knowingly and willingly trying to do. Recall the assassin and the husband. Owing to indeterminacies in their neural pathways, the assassin might miss his target or the husband fail to break the table. But if they succeed, despite the probability of failure, they are responsible, because they will have succeeded in doing what they were trying to do.

And so it is, I suggest, with self-forming choices, except that in the case of self-forming choices, whichever way the agents choose they will have succeeded in doing what they were trying to do because they were simultaneously trying to make both choices, and one is going to succeed. Their failure to do one thing is not a mere failure, but a voluntary succeeding in doing the other. Does it make sense to talk about the agent's trying to do two competing things at once in this way, or to solve two cognitive problems at once? Well, we now know that the brain is a parallel processor; it can simultaneously process different kinds of information relevant to tasks such as perception or recognition through different neural pathways. Such a capacity, I believe, is essential to the exercise of free will. In cases of self-formation (SFAs), agents are simultaneously trying to resolve plural and competing cognitive tasks. They are, as we say, of two minds. Yet they are not two separate persons. They are not dissociated from either task. The businesswoman who wants to go back to help the victim is the same ambitious woman who wants to go to her meeting and make a sale. She is torn inside by different visions of who she is and what she wants to be, as we all are from time to time. But this is the kind of complexity needed for genuine self-formation and free will. And when she succeeds in doing one of the things she is trying to do, she will endorse that as her resolution of the conflict in her will, voluntarily and intentionally, not by accident or mistake.

--from Robert Kane, published in various places, currently in print in Contemporary Debates in Metaphysics, Ch. 7.1

Pathogenesis of SOD-1 related ALS reportedly found.

In a paper in Cell, Stem Cell this month, abstract below, the researchers say that they have found a plausible cause for ALS in persons with the mutant SOD1 gene. It seems that SOD1 modulates neurofilament composition, and that the mutant SOD1 enzyme causes one of the three protein subnits (MF-L, the smallest subunit of the proteins which make up the microscopic filament used to transport nourishment down the axon of the motor nerve cell) to be in such a short supply that the transport mechanism fails, eventually leading, it is supposed, to complete motor neuron failure.

This currently would only apply to persons with the rarer, hereditary form of ALS. The further question is whether in the more common forms of the disease that the neurofilament subunit misproportions will also be seen, or not.

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ABSTRACT

Pathways Disrupted in Human ALS Motor Neurons Identified through Genetic Correction of Mutant SOD1

Evangelos Kiskinis, Jackson Sandoe, Luis A. Williams, Gabriella L. Boulting, Rob Moccia, Brian J. Wainger, Steve Han, Theodore Peng, Sebastian Thams, Shravani Mikkilineni, Cassidy Mellin, Florian T. Merkle, Brandi N. Davis-Dusenbery, Michael Ziller, Derek Oakley, Justin Ichida, Stefania Dicostanza, Nick Atwater, Morgan L. Maeder, Mathew J. Goodwin, James Nemesh, et al.

Although many distinct mutations in a variety of genes are known to cause Amyotrophic Lateral Sclerosis (ALS), it remains poorly understood how they selectively impact motor neuron biology and whether they converge on common pathways to cause neuronal degeneration. Here, we have combined reprogramming and stem cell differentiation approaches with genome engineering and RNA sequencing to define the transcriptional and functional changes that are induced in human motor neurons by mutant SOD1. Mutant SOD1 protein induced a transcriptional signature indicative of increased oxidative stress, reduced mitochondrial function, altered subcellular transport, and activation of the ER stress and unfolded protein response pathways. Functional studies demonstrated that these pathways were perturbed in a manner dependent on the SOD1 mutation. Finally, interrogation of stem-cell-derived motor neurons produced from ALS patients harboring a repeat expansion in C9orf72 indicates that at least a subset of these changes are more broadly conserved in ALS.

Aloha Friday: Kawailiʻulā at Merrie Monarch,2013

The annual Merrie Monarch festival and international hula contest in later this month. Last year's men's winning dance is shown here (from YouTube):

Multiple sclerosis and the Gut Microbiome: Some Preclinical Results

The gut microbiome is measured by assessing the prokaryotic DNA of a stool sample, which reflects the various types of bacteria that are g...