Marco Sarà

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 anti-depressants, 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.

Can reading others' emotional states be shaped by expertise? We assessed processing of emotional facial expressions in professional actors trained either to voluntary activate mimicry to reproduce character's emotions (as foreseen by the "Mimic Method"), or to infer others' inner states from reading the emotional context (as foreseen by "Stanislavski Method"). In explicit recognition of facial expressions (Experiment 1), the two experimental groups differed from each other and from a control group with no acting experience: the Mimic group was more accurate, whereas the Stanislavski group was slower. Neither acting experience, instead, influenced implicit processing of emotional faces (Experiment 2). We argue that expertise can selectively influence explicit recognition of others' facial expressions, depending on the kind of "emotional expertise"

The mass media have recently pointed out the likelihood of diagnostic errors in post-coma patients. Late recoveries of consciousness, even after 20 years, might indicate hidden misdiagnoses that are not corrected over a long period of time. The rate of misdiagnoses of patients in a vegetative state is very high when based on behavioral assessment strategies alone. An extremely restrictive motor repertoire, as occurs in locked-in patients, seems to be the major factor responsible for diagnostic confusion. Functional neuroimaging techniques are regarded as promising tools in unearthing covert awareness in behaviorally unresponsive patients who are unable to produce any motor output. However, unless we believe that these patients persistently live in an unconvincing Cartesian-like state, in which thinking and acting are mutually dissociated, we have to admit that a new taxonomy for low responsive states is called for. This taxonomy should take into account the possible syndromic overlap between disorders of consciousness and locked-in syndrome. We should suspect a "locked-in state" in behaviorally unresponsive patients unless we reach strong evidence that such is not the case; this is the only way to avoid dramatic misdiagnoses.

to the Editors:

I read with interest the article by Machado and colleagues in the January 2012 issue of MEDICC Review (A Cuban Perspective on Management of Persistent Vegetative State). There are two main ways of considering vegetative state: as a pathology of consciousness per se or as a multifaceted ensemble of different neurological syndromes. As reported in their review, the identification of both anatomical and functional impairment may be—and in our opinion must be—the first step in the assessment of these challenging patients. In our work at San Raffaele Cassino Hospital, we see the vegetative state as a matryoshka [a Russian nesting doll—Eds.] syndrome with a pattern of lesions that is rarely the same from one patient to another. All aspects of impairment, or spared functioning, should, therefore, be examined, from motor potential to higher cognitive functions.

In the literature, ​we are seeing a growing emphasis on connectivity as the keystone in the structural and functional foundations of consciousness. However, this conceptual framework seems to collapse in the case of vegetative or minimally conscious states. In a clinical setting, various means of assessment are generally available to us, including functional MRI with various stimuli; standard MRI to assess extent of brain damage; and neurophysiological assessments using very refined techniques of quantitative analysis.

Nonetheless it is rare to read a paper describing both structural lesions and functional aspects in the same cohort of subjects. Failure to do this leads to serious limitations, since neurophysiological data are thus rarely compared with structural data. Functional MRI findings are generally reported in isolation, without corresponding information concerning whether or not the supporting brain structures are anatomically (as opposed to functionally) compromised. In conclusion, we believe there is a need to reinforce anatomical study as the first step in both clinical practice and science. The work of Machado et al. exemplifies this new and necessary approach—starting from the anatomical picture.

Marco Sarà MD
Post-Coma Intensive Care and Rehabilitation Unit San Raffaele Cassino Hospital Cassino, Italy

Calixto Machado Responds for the Authors

We appreciate Dr Sarà’s comments and agree that the literature has a plethora of articles about disorders of consciousness (DOC) emphasizing isolated results from highly refined techniques of quantitative brain function analysis, and that inability to compare functional data with structural-anatomic information is very limiting.[1]

As Dr Sarà affirms, anatomical lesions in DOC are always a mixture of different patterns and vary from patient to patient.[2] Thus, his matryoshka metaphor for lesions found in persistent vegetative state cases is quite apt.

Most authors overemphasize connectivity as the structural and functional mechanism of consciousness generation, [3] but it is only part of the picture. Although it is very important to assess connectivity between thalamus and neocortex in studying DOC, the presence of anatomical—sometimes sizable—lesions in the brainstem, thalamus, or cerebral hemispheres, plays a key role in explaining consciousness impairment. That is, it is important to assess more than connectivity, because grey matter lesions—which usually also involve neighboring white matter disruption—are also fundamental in DOC pathophysiology.[2]

We agree entirely with Dr Sarà that identifying and correlating both anatomical and functional impairments are necessary to recognize, assess and explain DOC in these challenging patients. And yes, the first step is the anatomical picture.

Sarà M, Pistoia F. Defining consciousness: lessons from patients and modern techniques.J Neurotrauma. 2010 Apr;27(4):771–3.
Machado C. Persistent vegetative and minimally conscious states. Rev Neurosci. 2009;20(3–4):203–20.
Vanhaudenhuyse A, Noirhomme Q, Tshibanda LJ, Bruno MA, Boveroux P, Schnakers C, et al. Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients. Brain. 2010 Jan;133(Pt 1):161–71.

April–July 2017, Vol 19, No 2–3 » Letters to the Editor

Research on the so-called " neural correlates of consciousness " (NCC) has come out of its niche, becoming a " trendy " matter both in scientific literature and mass media. It is a consequence of knowledge forthcoming about " vegetative state " (SV) and " minimally conscious state " (MCS). The idea of losing command of ourselves is indeed one of the greatest fears of this century. We are aware of the fact that we can find ourselves in a not-so-defined state (that may be definitive), which could be of more or less complete dependence on the others for an indefinite time. Thus, the reflection on the nature of consciousness, apart from representing one of the central scientific challenges of this new millennium , is also an urgent human necessity. While the problem of consciousness is no longer an exclusive object of philosophy, the discussion on the social consequences of these syndromes where there is impairment of consciousness has begun to raise ethical matters. Generally, all the scientific matters imply two kinds of fundamental questions: (1) those related to the nature of the problem itself; and (2) the possible solutions of this particular problem. Concerning the nature of consciousness, we face a " constitutional dilemma " for consciousness is not defined in a univocal way by various researchers over the world. What are the consequences of this heterogeneity? The most obvious deduction we can draw is that we have not defined yet what exactly is consciousness. This leads to inevitable consequences of scientific procedure: the lack of prerequisites of reproducibility. For example, " apples fall down, " and when Newton gave this phenomenon a certain mathematical description, he referred to something that everybody could observe in an absolutely comparable way. Thereby, if—for example—a Dutch or Australian scientist would have liked to verify the Newton equations, he would not have had problems doing it, confirming the laws of gravity. Unfortunately, with respect to consciousness, the situation is not the same given that a certain discovery made in a Japanese laboratory may not be confirmed by another laboratory where this problem (and also the expected answer) is defined in another way. Contemporary researchers assume consciousness as the condition in which we wake up in the morning after a no-dreams sleep (e.g., John Searle), while for many others, it is a combination of perception, synthesis, subjectivity, and free will. For some scientists (including the neurophilosopher Thomas Metzinger), consciousness itself has a lot of illusive elements, as well as free will (e.g., Benjamin Libet, Martin Heisenberg, and others). According to others, the only element that can be examined in a scientific way is the exact moment when a subject (obviously collaborative) confirms his or her awareness of a certain stimulus. To conclude, it is not easy to reproduce and compare the results achieved in different laboratories of the world: We put forth various questions, and thereby, the possible answers can be incomparable. In our opinion, dividing consciousness in parts implies " the paradox of the parts of an unknown whole " (Sarà & Pistoia, 2010), which leads us to wonder whether it is possible to study the distinct parts of a whole that we have not yet described in its entirety. Another important limit in studying patients with SV and MCS is represented by the considerable heterogeneity of brain damages that cause the above syndromes. However, we can affirm that the scientific literature is moving toward a " connectionist " view of cognitive functions and therefore of consciousness itself. The concept of functional integration is more and more spread in neuroscience. Particularly, the phenomenon of consciousness would emerge from dynamic shaping of neural functional aggregates even between distant cerebral areas. We have used the verb " emerge " to represent the types of phenomena (called " emergence phenomena ") among which, according to different authors, could be also consciousness. An emergent phenomenon is something that draws on what already exists in that space assuming its own identity. For example, a flock of birds (which is a dynamic aggregate of elements previously independent from each other), in aggregate, forms a new and clearly recognizable entity. We know that the aggregate will adopt its own behavior with advantages for itself and, above all, the elements that form it: single birds. The phenomena of emergence can be the subject of studies even when considering the laws of quantum mechanics with important advantages taking into account the matters related to nondeterministic behavior of so-called " voluntary " mental activity. An emergent phenomenon must necessarily be regarded in its entirety (also in line with the paradox of the parts of an unknown whole).

In the present study, we demonstrated that observation of hand rotation had specific facilitation effects on a classical motor imagery task, the hand-laterality judgement. In Experiment 1, we found that action observation improved subjects’ performance on the hand laterality but not on the letter rotation task (stimulus specificity). In Experiment 2, we demonstrated that this facilitation was not due to mere observation of a moving hand, because it was triggered by observation of manual rotation but not of manual prehension movements (motion specificity). In Experiment 3, this stimulus- and motion-specific effect was found to be right hand-specific, compatible with left-hemispheric specialization in motor imagery but not in action observation. These data provided direct support to the idea that different simulation states, such as action observation and motor imagery, share some common mechanisms but also show specific functional differences.

Previous studies have been inconclusive whether dominant resting state alpha rhythms are greater or lower in amplitude in subjects with Down syndrome (DS) when compared to control subjects, ample resting alpha rhythms being considered as a reflection of good mechanisms of cortical neural synchronization. Here we tested the hypothesis that when the effects of head volume conduction are taken into account by the normalization of the cortical sources of resting alpha rhythms, these sources are lower in amplitude in DS subjects than in controls in line with typical findings in Alzheimer's disease patients. Eyes-closed resting electroencephalographic (EEG) data were recorded in 45 DS subjects (25 males; mean age of 22.8years+/-0.7 standard error of mean (SEM)) and in 45 age-matched cognitively normal subjects (25 males; mean age of 22.4years+/-0.5 SEM). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz). Cortical EEG sources were estimated by low resolution electromagnetic tomography (LORETA) and normalized across all voxels and frequencies. Central, parietal, occipital, and temporal cortical sources of resting alpha and beta rhythms were lower in amplitude in the DS than control subjects, whereas the opposite was true for occipital delta cortical sources. A control analysis on absolute source values showed that they were globally larger in amplitude across several frequency bands in DS than control subjects. These results suggest that normalized cortical sources of alpha rhythms are lower in amplitude in DS than control subjects, as it is typically found in Alzheimer's disease. DS is accompanied by a functional impairment of cortical neuronal synchronization mechanisms in the resting state condition.

Previous studies have been inconclusive whether dominant resting state alpha rhythms are greater or lower in amplitude in subjects with Down syndrome (DS) when compared to control subjects, ample resting alpha rhythms being considered as a reflection of good mechanisms of cortical neural synchronization. Here we tested the hypothesis that when the effects of head volume conduction are taken into account by the normalization of the cortical sources of resting alpha rhythms, these sources are lower in amplitude in DS subjects than in controls in line with typical findings in Alzheimer's disease patients. Eyes-closed resting electroencephalographic (EEG) data were recorded in 45 DS subjects (25 males; mean age of 22.8years+/-0.7 standard error of mean (SEM)) and in 45 age-matched cognitively normal subjects (25 males; mean age of 22.4years+/-0.5 SEM). EEG rhythms of interest were delta (2-4Hz), theta (4-8Hz), alpha 1 (8-10.5Hz), alpha 2 (10.5-13Hz), beta 1 (13-20Hz), beta 2 (20-30Hz), and gamma (30-40Hz). Cortical EEG sources were estimated by low resolution electromagnetic tomography (LORETA) and normalized across all voxels and frequencies. Central, parietal, occipital, and temporal cortical sources of resting alpha and beta rhythms were lower in amplitude in the DS than control subjects, whereas the opposite was true for occipital delta cortical sources. A control analysis on absolute source values showed that they were globally larger in amplitude across several frequency bands in DS than control subjects. These results suggest that normalized cortical sources of alpha rhythms are lower in amplitude in DS than control subjects, as it is typically found in Alzheimer's disease. DS is accompanied by a functional impairment of cortical neuronal synchronization mechanisms in the resting state condition.