Transcranial magnetic stimulation combined with high

Brain Injury
ISSN: 0269-9052 (Print) 1362-301X (Online) Journal homepage: http://www.tandfonline.com/loi/ibij20
Transcranial magnetic stimulation combined
with high-density EEG in altered states of
consciousness
Martino Napolitani, Olivier Bodart, Paola Canali, Francesca Seregni,
Adenauer Casali, Steven Laureys, Mario Rosanova, Marcello Massimini &
Olivia Gosseries
To cite this article: Martino Napolitani, Olivier Bodart, Paola Canali, Francesca Seregni,
Adenauer Casali, Steven Laureys, Mario Rosanova, Marcello Massimini & Olivia Gosseries
(2014) Transcranial magnetic stimulation combined with high-density EEG in altered states of
consciousness, Brain Injury, 28:9, 1180-1189, DOI: 10.3109/02699052.2014.920524
To link to this article: http://dx.doi.org/10.3109/02699052.2014.920524
Published online: 06 Aug 2014.
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Date: 25 March 2016, At: 00:54
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ISSN: 0269-9052 (print), 1362-301X (electronic)
Brain Inj, 2014; 28(9): 1180–1189
! 2014 Informa UK Ltd. DOI: 10.3109/02699052.2014.920524
Transcranial magnetic stimulation combined with high-density EEG in
altered states of consciousness
Martino Napolitani1*, Olivier Bodart2*, Paola Canali1, Francesca Seregni1, Adenauer Casali1, Steven Laureys2,
Mario Rosanova1, Marcello Massimini1,3, & Olivia Gosseries2,4,5
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1
Department of Biomedical and Clinical Sciences ‘Luigi Sacco’, University of Milan, Milan, Italy, 2Coma Science Group, Cyclotron Research Centre
and Neurology Department, University and University Hospital of Liege, Liege, Belgium, 3Istituto Di Ricovero e Cura a Carattere Scientifico,
Fondazione Don Carlo Gnocchi, Milan, Italy, 4Center for Sleep and Consciousness, Department of Psychiatry, and 5Postle Laboratory, Department of
Psychology and Psychiatry, University of Wisconsin, Madison, WI, USA
Abstract
Keywords
Background: This review discusses the advantages of transcranial magnetic stimulation
combined with high-density electroencephalography (TMS-hdEEG) over other current
techniques of brain imaging.
Methods and results: Its application was reviewed, focusing particularly on disorders of
consciousness, in the perspective of recent theories of consciousness. Assessment of
non-communicative patients with disorders of consciousness remains a clinical challenge and
objective measures of the level of consciousness are still needed. Current theories suggest that
a key requirement for consciousness is the brain’s capacity to rapidly integrate information
across different specialized cortical areas. TMS-EEG allows the stimulation of any given cortical
area and the recording of the immediate electrical cortical response. This technique has
recently been successfully employed to measure changes in brain complexity under
physiological, pharmacological and pathological conditions.
Conclusions: This suggests that TMS-EEG is a reliable tool to discriminate between conscious
and unconscious patients at the single subject level. Future works are needed to validate and
implement this technique as a clinical tool.
Consciousness, effective connectivity,
electroencephalography, minimally
conscious state, transcranial magnetic
stimulation, unresponsive wakefulness
syndrome, vegetative state
Introduction
Despite considerable progress, patients with disorders of
consciousness (DOC) such as those in a vegetative state
(recently renamed unresponsive wakefulness syndrome, UWS
[1]) or in a minimally conscious state (MCS [2]) still pose a
challenge to both medical teams and families. After falling
into a coma, patients with UWS recover arousal but not
consciousness, whereas patients in MCS show reproducible
but fluctuating signs of consciousness (e.g. responses to
command, visual pursuit). The diagnosis of consciousness is
mainly based on behavioural evaluation, which can give rise
to misdiagnoses [3]. This problem is only partially resolved
by the introduction of standardized dedicated scales such as
the Coma Recovery Scale–Revised (CRS-R [4]). Numerous
neuroimaging and electrophysiological paradigms have been
developed in recent years, leading to a better understanding of
*contributed equally.
Correspondence: Olivia Gosseries, Coma Science Group, Cyclotron
Research Centre and Neurology Department, University and University
Hospital of Liege, Sart-Tilman B30, 4000 Liege, Belgium.
Tel: +32 4 366 23 16. Fax: +32 4 366 29 46. E-mail: ogosseries@
ulg.ac.be
History
Received 9 August 2013
Revised 28 February 2014
Accepted 12 March 2014
Published online 25 July 2014
the neural correlates of consciousness, thereby allowing for
the detection of differences between patient groups. However,
at the single subject level, all these advancements lack
sensitivity and/or specificity that are required in a clinical
setting. In parallel, new theories of consciousness suggest that
a perturbational approach would bring relevant information
about the brain’s capacity for consciousness [5]. Transcranial
magnetic stimulation (TMS) coupled with high-density electroencephalography (EEG) [6] is a technique that allows the
stimulation of any given cortical area and the recording of the
immediate electrical cortical response. TMS-EEG has been
successfully employed to discriminate between conscious and
unconscious patients under physiological, pharmacological
and pathological conditions.
This review will discuss the recent findings obtained with
TMS-EEG in various states of consciousness, with a particular focus on DOC. These results will be explored along
with the most recent theories of consciousness and this
study concludes with the perspectives of what TMS-EEG can
offer.
Evaluation of consciousness
Current evaluations of the residual level of consciousness rely
on behavioural assessments. These evaluations have an
intrinsic limitation: they need the subject to produce a
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DOI: 10.3109/02699052.2014.920524
motor output, either to a visual, tactile or auditory stimulus.
They also usually require patients to understand the task and
be willing to collaborate [7, 8]. This behavioural approach
leaves the physician unaware of a possible impairment of
motor and/or afferent projections, likely to be present in
patients with severe brain injury [8]. In order to bypass these
limitations, neuroscientists have developed different techniques to assess consciousness without relying on motor
output. Functional magnetic resonance imaging (fMRI) using
mental imagery paradigms can detect consciousness via
wilful activation of specific brain areas in some patients with
DOC [9–12]. However, the lack of response should not be
interpreted as an absence of consciousness. In fact, many
patients in MCS, despite showing some signs of consciousness at the bedside, do not show task-related brain activation,
which might be due to a lack of comprehension, attention,
vigilance or motivation [7, 11]. Besides active task procedures, results from passive paradigms using various external
stimulations have shown differences at the group level
between patients in MCS and UWS, but not at the individual
level [13–15]. Ultimately, the brain can be studied at rest,
without performing any task and without receiving any
stimulation. Recent fMRI studies show that functional
connectivity in the default mode network (which is involved
in self-related processes such as inner speech and mind
wandering) correlates with the level of consciousness in
patients with DOC [16, 17]. However, some have questioned
the validity of such indirect tools to assume one’s consciousness [18]. While functional neuroimaging has an excellent
spatial resolution, it lacks temporal resolution because it
cannot record events shorter than several seconds. This can be
problematic as the time scale for capturing consciousness is
thought to be in the order of hundreds of milliseconds [19].
Moreover, functional connectivity does not provide any causal
interpretation.
Conversely, electrophysiological measurements can detect
neuronal activities in a timescale of milliseconds. Active
paradigms have also been employed with EEG, allowing the
detection of wilful activities following specific instruction in
several patients otherwise considered as unconscious [20–22].
Many sophisticated EEG analyses have been developed, such
as the bispectral index [23, 24], spectral and entropy analyses
[25, 26], neuronal complexity [27], causal density [28] and
Granger causality [29], but these procedures solely deal with
the background neuronal activity and, thus, lack the deterministic value of a perturbational approach.
Although neuroimaging and EEG techniques are able to
bypass some of the behavioural evaluations’ limitations and
some show promising results at the group level, none can
presently be used at the single subject level. Some authors
suggest that TMS-EEG is a good candidate to achieve
accurate evaluation of consciousness at the single subject
level [5, 30].
TMS-EEG techniques
One way to perturb the brain non-invasively is to force
neurons in a small area of the cortex to depolarize, with the
expectation that this excitation would propagate to other brain
regions. TMS allows researchers to do so by means of
TMS-EEG in disorders of consciousness
1181
electromagnetic induction [5]. These magnetic pulses induce
secondary ionic currents in the brain that penetrate the
membranes of the neurons, resulting in an action potential or
excitatory/inhibitory post-synaptic potential. As the magnetic
field falls off rapidly with distance from the coil [5, 31], it
only directly activates neural elements superficially (that is,
on the surface of the cortex) or in the white matter underneath
the stimulation site, limiting the number of brain’s structures
one can reach. The amount of neurons and the layers that are
directly triggered by the TMS remain undetermined.
However, experimental [32] and modelling [33] studies
strongly suggest that axons, rather than cell bodies, are
most likely the targets of the stimulation. Evidently, axons
have the lowest threshold for activation to the brief electrical
currents induced by TMS. The capacity of TMS to depolarize
neurons depends on the ‘activating function’, which causes a
sufficient transmembrane current to flow and depolarize the
membrane. Stimulation will take place at the point where the
spatial derivative of the induced electric field is maximal.
From the site of cortical stimulation, the neuronal signal then
propagates along intra- and inter-hemispheric association
fibres to other cortical areas and to deeper neural structures.
However, the neural signal also, via projecting fibres,
propagates to sub-cortical structures and sometimes to the
spinal cord. The ‘effective connectivity’ measures the causal
interaction between the differently specialized brain
areas, which is different from ‘functional connectivity’
(that measures temporal correlation) and from ‘structural
connectivity’ (that assesses the anatomical links between
brain regions) [34].
While TMS systems have been available for a long time,
EEG amplifiers have not been compatible and recording
artefact-free response was impossible. EEG amplifiers have
then been equipped with sample-and-hold circuits to prevent
the recording of the powerful TMS-related artefact. This
allowed recording the TMS evoked potentials response with
milliseconds time scale, which reliably reflets the state of
excitability of underlying cortical circuits [6, 35–38]. The
EEG cap is often composed of 60 flat open ring carbon
electrodes specially designed to further decrease TMS related
artefacts, along with one reference, one ground and two
electrooculogram electrodes (Figure 1). Muscles artefacts are
also reduced to their minimum by stimulating central scalp
regions, avoiding the temporal muscles masses [39]. In order
to avoid the contamination of the responses by auditory
evoked EEG signal, noise masking is applied through
earphone playing white noise in the frequency band of the
TMS coil ‘click’ [40]. To further standardize stimulation
parameters, ensuring reproducibility and accuracy over cortical areas and across subjects, the experimental set-up should
be equipped with a stereotactic neuronavigation system
(Figure 1) [41]. The neuronavigation system is used with a
structural image of the brain of the subject and locates the
relative position of the subject’s head and the TMS coil.
Moreover, the system may take into account the relative
scalp-to-cortex distance to calculate the electric field induced
by TMS on the cortical surface. This ensures that the effective
stimulation intensity is the same across subjects and stimulation sites. Therefore, the combination of neuronavigation
system, TMS and compatible EEG allows the acquisition of
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Figure 1. Possible set-up, combining a
neuronavigation system (a), the stimulation
coil with tracking elements (b), high-density
EEG net (c) and EEG amplifier (d). The
neuronavigation system is composed of 3D
brain reconstruction (a1), an infrared tracking
camera (a2) and tracking googles (a3).
Table I. Advantages and disadvantages of TMS-EEG.
Advantages
Bypass afferent sensory pathways.
Does not require functioning efferent pathways.
Does not require subject active participation.
Does not require language processing.
Highly reproducible within subject.
Can be use at the patient’s bedside.
Sensitive to changes in stimulation parameters.
Good temporal resolution.
Probes effective connectivity.
Discrimination between conscious and unconscious conditions.
Supported by recent theories of consciousness.
Disadvantages
Dependent on the subject cortical excitability, lowered in case of brain
atrophy (it increases scalp-to-cortex distance) and with several drugs
(including anti-epileptic).
Requires stable state of wakefulness.
Limited spatial resolution.
Acute patients assessment limited by the presence of metallic implant,
external CSF drain or uncontrolled epilepsy.
Requires considerable logistic and subject preparation.
Source modelling possibly inaccurate in cases of extensive brain lesions or
scalp deformations.
CSF, Cerebrospinal fluid.
cortical evoked potentials that are triggered and recorded
from cortical structures. The amplitude, spreading and
morphology of the evoked potentials are the characteristics
considered in order to investigate the brain’s excitability and
connectivity.
Regarding the analysis, the EEG data sets are
pre-processed to remove any trial contaminated with eye
movements, blinks, muscle or movement artefact, before a
source-modelling algorithm is applied. Significant signals
from EEG sensors are transposed to cortical sources, according to the time sequence and the topography of the registered
evoked response. This transposition can be performed on the
subject’s own brain imagery or on a standard model [42].
Casali et al. [42] developed a method to further analyse
TMS-EEG data with three synthetic indices: significant
current density (SCD), significant current scattering (SCS)
and phase locking (PL). SCD sums up the amplitude of
all significant currents induced by TMS, SCS measures the
average distance of significantly activated sources from
the stimulated region, while PL reflects the ability to re-set
the ongoing phase of cortical oscillations; these indices,
therefore, help to assess different aspects of brain responsiveness. Table I summarizes the advantages and disadvantages of the TMS-EEG technique. Considering this evidence,
this technique seems to be a promising tool to assess brain
functions in both healthy subjects and pathological conditions. Specifically, it can be a useful method in the assessment
of non-communicative patients, as discussed in the next
sections.
Experimental recordings in healthy awake subjects
Some recent studies employed TMS-EEG to measure cortical
excitability (i.e. the amplitude of the initial response to TMS,
which can also be assessed by SCD) and effective connectivity (i.e. the causal interaction between the stimulated area
and the subsequent activated cortical regions, which can be
assessed by SCS) in healthy awake subjects. The responses
were recorded during rest and various cognitive tasks such
as memory [43, 44], visual attention [45, 46] and motor
planning [47].
Massimini et al. [35, 48] were first to demonstrate that,
during wakefulness, TMS is followed by multiple low
amplitude fast EEG waves, associated with spatially and
temporally differentiated patterns of activation. Brain areas
also respond differently to a given stimulation, as shown by
Rosanova et al. [49], who delivered TMS on different brain
regions of healthy awake subjects. Regardless of the
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stimulation intensity, TMS evoked alpha band oscillations (8–
12 Hz) in the occipital cortex, beta band oscillations
(13–20 Hz) in the parietal cortex and fast beta/
gamma oscillations (21–50 Hz) in the frontal cortex.
TMS-EEG can, therefore, be used to directly investigate the
properties of thalamocortical circuits to produce natural
oscillations.
Huber et al. [50] showed that the cortical excitability
steadily increased in healthy subjects during the course of
prolonged wakefulness. Similarly, attention to motor tasks,
even without actual movement, causes an increase of local
cortical excitability, as assessed by TMS-EEG [47]. During
visual attention tasks, an increase of effective connectivity
has also been observed between the frontal eye field (the site
of stimulation) and posterior brain regions [46]. This effect
is thought to reflect a top-down control over these latter
regions. Another recent study showed that, during a spatial
working memory task, the delivery of TMS on a specific
brain area (i.e. the superior parietal lobule, an area known to
play a role in working memory) during the delay period also
induced a marked increase of both SCD and SCS, as
compared to a condition of rest (where subjects fixated
a static point) [43]. Moreover, Kundu et al. [44] have
recently demonstrated that a long-term training of a working
memory visual task resulted, once again, in an increase in
SCS in the task-related networks. Further evidence of taskrelated network specific change of cortical excitability has
been provided in another recent study on face recognition,
where excitability was modulated in the medial prefrontal
cortex, but not in the premotor cortex [51].
In summary, these findings in healthy awake subjects
converge to the assumption that cognitive functions induce
increased cortical excitability and/or effective connectivity.
It is noted that alcohol intake reduces cortical excitability,
especially on the frontal and prefrontal areas [52].
Reduced brain excitability and decreased effective connectivity have also been observed in various states of altered
consciousness.
TMS-EEG in disorders of consciousness
1183
Experimental recordings in altered states of
consciousness
Physiological and pharmacological states
If awakened from an early non-rapid eye movement (NREM)
or slow-wave sleep, subjects report little or no conscious
content, while, if awakened from REM sleep, they are able
to report dreams, which can be as vivid as conscious
experience during wakefulness [53]. Different thalamocortical networks responses have been recorded with TMS-EEG
during transition from wakefulness to NREM and REM
sleep. In NREM sleep, TMS triggers a larger positive–
negative low frequency wave. Depending on stimulation
parameters such as intensity, this response can stay local and
be transient or can be global and look like typical slow
waves [54]. Sleep-stage one induced an intermediate
response between wakefulness and NREM sleep and low
intensity stimulation evokes a typical slow wave with
disappearance of the latter components [35]. In contrast, in
REM sleep, the brain’s response to TMS is similar to the
one observed during wakefulness, with fast oscillatory
components, especially during the first 100–150 milliseconds post-stimulus [48] (Figure 2). These findings suggest
that TMS-EEG is able to monitor graded changes in the
level of consciousness during normal physiological changes.
Note also that, after a night of sleep, cortical excitability
decreases, as opposed to the increase observed after
prolonged wakefulness [50].
Pharmacological agents inducing a loss of consciousness,
such as midazolam at anaesthetic concentrations, have also
been investigated with TMS-EEG. Midazolam targets
GABA-A receptors exclusively, increasing inhibitory postsynaptic currents and possibly causing its anaesthetic effect
[55]. In this condition, TMS evokes a stereotypical large
positive–negative wave, similar to the one evoked in NREM
sleep, which remains localized to the stimulation site
(Figure 2) [36]. Even if the mechanisms of action differ,
Figure 2. Typical response to TMS in different physiological, pharmacological and pathological conditions. For each condition, cortical
responses under the coil (bold black trace) and in seven other brain areas (lighter black traces) following right premotor stimulations (black lightning)
are shown. (A) In NREM sleep, depending of stimulation intensity, TMS can trigger either a global or a local response, but both remain stereotypical
and slow. In REM sleep, the response is complex, spread in time and space, similar to the one of wakefulness. (B) General anaesthesia responses look
like NREM sleep responses. (C) In DOC, the response in patients in UWS is similar to the one in general anaesthesia and NREM sleep. In patients in
MCS, the response is similar to the one observed in REM sleep and in wakefulness. TMS, Transcranial magnetic stimulation; REM, Rapid eye
movement; NREM, non-REM; UWS, Unresponsive wakefulness syndrome; MCS, Minimally conscious state. Adapted with permission from Sarasso
et al. 2014 [76].
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similar responses are expected with other pharmacological
inhibitory agents.
In summary, during wakefulness and REM sleep the brain
is able to sustain long-range and different activity patterns,
marked by a complex, diffuse and long-lasting evoked
response, whilst during NREM sleep and anaesthesia, when
consciousness fades, this ability is lost and, even if the
thalamocortical system remains active, it responds to a direct
TMS perturbation in a stereotypical and short lasting manner
(Figure 2).
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Pathological state
Given these promising results in monitoring different levels of
consciousness in healthy subjects, TMS-EEG was subsequently performed in patients with DOC. In the two studies
published so far, a total of 30 patients were assessed
(15 UWS, 13 MCS and two patients with a locked-in
syndrome) during acute (less than 30 days post-brain injury),
sub-acute (between 1–3 months post-injury) and chronic
(more than 3 months post-anoxia and more than 1 year posttrauma) periods [40, 56]. Nine of the 15 patients with an
unambiguous diagnosis of UWS showed a simple, local and
slow response to TMS, very similar to the one observed in
NREM sleep and general anaesthesia. The other six patients
with UWS did not show any response to TMS (one sub-acute
and five chronic patients). Interestingly, in the Rosanova et al.
[40] study, the only three patients who did not show any
response to TMS were the ones who suffered from anoxia.
Anoxic aetiology might be linked to some extent to the
absence of response in UWS patients. The exact implication
of the aetiology needs, however, to be further studied on a
larger population sample.
In MCS patients, 12 out of 13 showed complex responses
with changing patterns of cortical activation over time. These
responses were similar to the ones observed in the two
patients with locked-in syndrome (conscious patients who are
unable to produce any volitional motor output, except for eye
movements) and very similar to what is observed in normal
wakefulness. One patient in MCS, with an anoxic aetiology,
did not show any response to brain stimulation. Only one
brain area was stimulated in this patient, so one cannot
exclude that, if other brains areas had been perturbed, it would
have induced a complex and widespread response. Moreover,
the stimulus intensity was fixed as a percentage of the
maximum intensity deliverable and not based on actual
intensity at the cortical level; thus, the intensity necessary to
evoke a response may not have been reached in this patient.
Importantly, Ragazzoni et al. [56] compared the TMS-EEG
to other electrophysiological techniques such as somatosensory evoked potentials, oddball auditory ERPs and EEG
power spectrum and showed that only TMS-EEG was able to
discriminate between patients in UWS and MCS at the
group level.
In acute settings, TMS-EEG was also able to detect, in
three patients with DOC, changes in cortical responses
matching those observed with behavioural evaluation [40].
The responses recorded when the patients were in an
unambiguous UWS were very similar to the one observed
previously in chronic UWS, as well as in NREM sleep and
Brain Inj, 2014; 28(9): 1180–1189
general anaesthesia. On the other hand, once the patients
recovered signs of consciousness and, therefore, were
diagnosed as in a MCS, their responses to TMS looked like
those observed in patients with locked-in syndrome and in
conscious healthy subjects. Once the patients emerged from
the MCS (i.e. recovery of functional communication or
functional use of objects—EMCS), their brain responses to
TMS were also complex, as observed in other conscious states
(Figure 2). Interestingly, one patient who had improved to
MCS was behaviourally back in an UWS the day of the TMS
assessment, but complex and widespread brain responses
could still be detected, although, at the bedside, no sign of
consciousness could be observed. Two other acute UWS
patients who did not recover were also evaluated twice,
1 month apart. Each time, TMS triggered no response in one
patient and a simple, slow and local response in the other
patient. This suggests that, in the acute setting, TMS-EEG is
able to monitor recovery of consciousness or absence thereof
and is less sensitive to daily fluctuation in behavioural
diagnosis. However, it is still sensitive to the level of arousal,
as one patient in MCS showed simple and local slow wave in
response to TMS when sleeping, whereas complex brain
responses were recorded when awake [40]. In contrast,
transition from behavioural sleep to wakefulness was not
associated with a modification of the TMS responses in a
patient with an UWS (Figure 3).
Differences have also been observed between patients who
suffered mild traumatic brain injury and healthy subjects.
Some of the patients remained symptomatic, while some fully
recovered. None of them had, however, obvious structural
lesions on the MRI. In the symptomatic group, stimulation of
the dorsolateral prefrontal cortex elicited delayed peaks and
increased amplitude of some of the TMS-EEG components
[57]. In the asymptomatic group, stimulation of the same site
elicited responses of shortened latency. In both mild traumatic
brain injury groups, TMS recordings also revealed an
increased motor threshold (as defined by the minimum
TMS intensity required to elicit a 50 mV response on
electromyography in 5 out of 10 stimulations), as well
as differences in the effect of increasing stimulation intensity
as compared to healthy control. This increased motor
threshold has also been observed in patients in UWS and
MCS [58].
Patients with psychiatric disorders also show altered brain
responses to TMS. For instance, while stimulating frontal and
prefrontal brain regions, patients with schizophrenia demonstrated a clear deficit in the production of fast EEG
oscillations, as compared to healthy subjects [59]. Frantseva
et al. [60] also found an abnormal widespread activation of
the EEG response to TMS in schizophrenia, which was
associated with higher global voltage between 400–750
milliseconds post-stimulation, as compared to healthy controls [60]. Both findings revealed a correlation between EEG
gamma band abnormalities and positive symptoms in
schizophrenia.
TMS-EEG could also be an effective tool to assess
altered excitability and connectivity in neurodegenerative
diseases. Casarotto et al. [61] demonstrated a lower
frontal cortical excitability in patients with Alzheimer’s
disease compared to healthy elderly individuals. All these
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TMS-EEG in disorders of consciousness
1185
Figure 3. (A) Effect of arousal on TMS-EEG findings in UWS and in MCS. Behavioural sleep or wakefulness does not influence the response observed
in the patient in UWS, whereas in the patient in MCS there is a clear difference between eyes opened (EO) and eye closed (EC) conditions The response
under the coil (black trace) and the stimulation site (white cross), with the significance threshold (p50.01, pink band) are depicted. The 10 most
activated sources during the significant post-stimulus activation are plotted and colour-coded according to the location. (B) Effect of increasing level of
consciousness. The same graphs are plotted for an acute UWS patient who improved behaviourally until emergence from MCS. Note that
the complexity of the responses improves parallelly. (C) Typical findings in a patient with locked-in syndrom (LIS) showing very similar results
to those observed in wakefulness, REM sleep and EMCS. EC, eyes closed; EO, eyes opened; UWS, Unresponsive wakefulness syndrome;
MCS, Minimally conscious state; EMCS, emergence from minimally conscious state; LIS, Locked-in syndrome; TMS, transcranial magnetic
stimulation. Adapted from Rosanova et al. [40] with permission.
applications of TMS-EEG clearly demonstrate its ability to
investigate the status of various cortical networks. However,
it is important to follow clear guidelines in order to
accurately perform TMS-EEG assessment, especially in
patients with DOC.
How to conduct a good experiment in patients with
disorders of consciousness?
As patients with DOC often have significant brain lesions,
one needs to carefully check the patient brain MRI or CT scan
prior to deciding the stimulation target. Stimulations should
be performed on intact brain areas, as direct stimulation of a
brain lesion is likely to trigger no or very little response,
hence increasing the risk of misdiagnosis. Stimulation of
several sites can avoid such a risk in the absence of recent
neuroimaging data. The experimenter has also to make sure
the patient stays awake for the duration of the TMS-EEG, for
example with the help of the CRS-R arousal protocol and by
positioning seated. If no responses or very little response is
observable online, intensity of the stimulation should be
increased, as responses are sometimes very subtle in this
population.
It is important to acknowledge the risk of inducing a
seizure in patients with a history of epilepsy. Although this is
rare and was mostly seen with high frequency stimulation
(more than 1 Hz) [62], patients with severe brain injuries
often had at least one episode of seizure and, thus, are at
higher risk to present another one. This issue should be
discussed with the local ethic committee, tempered by the
facts that (i) the stimulation parameters typically used are less
susceptible to trigger a seizure than high frequency repeated
stimulations, (ii) patients who had only one contextual seizure
and since then have been treated efficiently (i.e. have had
none since the treatment was started) are unlikely to present
another one and (iii) that TMS is performed while EEG is
recorded and, thus, a seizure would be rapidly noticed.
Moreover, TMS-EEG on patients with DOC is performed
most of the time in a setting where adequate management is
immediately available. The recorded response should also be
interpreted in light of the most recent theories of
consciousness.
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Figure 4. Pertubational Complexity Index (PCI) values in patients with DOC and healthy subjects. (A) PCI rise is matching increasing CRS-R and
level of consciousness. UWS values are in the NREM sleep and general anaesthesia range, while EMCS and LIS are in the healthy awake subjects
range. Patients in MCS show intermediate values, but never below the threshold of unconsciousness of healthy subjects (horizontal blue dashed
line, PCI ¼ 0.31). (B) Differences in group mean PCI values are significant between each pair of possible state of consciousness in DOC.
CRS-R, Coma Recovery Scale-Revised; PCI, Perturbational Complexity Index; UWS, Unresponsive Wakefulness Syndrome; MCS, Minimally
Conscious State; EMCS, Emergence from MCS; LIS, Locked-In Syndrome; NREM, Non-Rapid Eye Movement. *p ¼ 0.002, **p ¼ 0.0001. Adapted
from Casali et al. [70] with permission.
Theories of consciousness and the perturbational
approach
In order to establish an objective and reliable marker of
human consciousness, there is a need to design a theoretical
framework that allows making hypothesis about the brain
mechanisms underlying conscious experiences. Although
different hypotheses exist, the most recent ones, such as the
global workspace theory of consciousness [63, 64], the
information integration theory of consciousness – IITC
[65]—and the cognitive binding theory [66], converge to
the necessity of a neural basis of consciousness matching the
temporal dynamic of conscious perception and cognitive
abilities (as described in Ortinski and Meador [67]), while
keeping in mind that these neural processes can be modulated
by other brain structures (e.g. the amygdala for emotional
stimuli [68]).
According to the IITC [65], consciousness can only arise if
its supporting neural network has the ability to differentiate
and integrate information. Indeed, the conscious events
experienced are at the same time different from any past
event and integrated into their context and are impossible to
isolate as such. At the neural level, this conscious event
results in a specific neuronal activation pattern among an
infinite number of possible states. For consciousness to
emerge, the brain, therefore, needs an integrated and
differentiated network, consisting of several specialized
modules that are effectively connected. To infer the brain
capacity for consciousness, one would then need to assess
effective connectivity between these brain regions and the
TMS-EEG technique seems to be the perfect tool to do so, as
seen above. The complex and widespread distributed response
observed in normal wakefulness, in patients in MCS or during
dreams, reflects that the underlying network is integrated
(the response spreads across distant cortical regions) and
specialized, providing information (the response is complex
and not stereotypical). On one hand, if the system’s modules
operate as independent sub-sets, being effectively disconnected from the rest of the network, no information can be
integrated; on the other hand, if there is no specialization and
the system behaves stereotypically, integration occurs without
differentiation. In both cases, the loss of information would
lead to a loss of consciousness. In NREM sleep, general
anaesthesia and UWS, the loss of integration gives rise to the
simple, local and short lasting response observed [35, 36, 40].
During general seizures, where the entire cortex is firing
anarchically, there is no specialization and, hence, no
information, leading to an alteration of consciousness [69].
The aforementioned results are mainly based on qualitative
comparisons between response shapes. To implement the
TMS-EEG technique in a clinical routine for the assessment
of consciousness, there is a need to objectively quantify those
responses. This has previously been done, to some extent,
with the SCD and SCS indices [42]. However, these indices
do not allow the direct comparison between individual
subjects and do not reflect complexity per se. A new
complexity measure, the Perturbational Complexity Index
(PCI), has been recently developed to assess the brain
capacity for consciousness. This ingenious measure is in
line with the IITC theory and allows comparison of different
subjects and different levels of consciousness [70]. Briefly,
based on TMS-EEG artefact-free recordings, statistically
significant sources are modelled and a binary matrix is
generated. This matrix is then compressed using algorithmic
complexity compression and normalized by the source
entropy, resulting in the PCI. PCI is low in cases of loss of
integration (as its time course would be quite short) and in
cases of loss of differentiation (because the information
contained would be extremely redundant and, thus, highly
compressible).
PCI is able to discriminate between conscious and
unconscious conditions regardless of the strength and extent
in duration of the cortical response, the stimulation site and
intensity (given that the latter is sufficient to evoke an EEG
response). PCI is also sensitive to graded changes of
consciousness (in different sleep stages, degree of general
anaesthesia and DOC). In conclusion, as shown in Figure 4,
this measure allows clear-cut differences in intracortical
effective connectivity between patients with severe brain
injury in UWS and those who recover consciousness
TMS-EEG in disorders of consciousness
DOI: 10.3109/02699052.2014.920524
(MCS, EMCS, locked-in syndrome), representing for the first
time a reliable assessment of consciousness at the single
subject level [70].
Downloaded by [Universita degli Studi di Modena e Reggio Emilia ] at 00:54 25 March 2016
Future perspectives
TMS-EEG and its derived measures have shown interesting
results in the field of DOC. PCI has demonstrated its consistent
ability in determining brain’s capacity for consciousness in a
significant number of subjects under many conditions.
However, it would be interesting to verify the consistency of
these results in a larger group of patients and also using
different set-ups. To be more easily implemented in a clinical
setting, the whole equipment should be more portable: easy to
bring and set up at the patients’ bedside. The pre-processing
and analyses of TMS-EEG derived measures should ideally be
more straightforward, possibly automated and a standard
procedure should be available. This would allow different
centres to obtain directly comparable measures of consciousness and to elaborate guidelines for the diagnosis of DOC using
more than behavioural scales. Larger longitudinal studies of
patients with DOC are also needed to confirm the sensitivity to
graded changes in consciousness, as only three patients have
been studied during the course of their recovery, so far.
Early prognostic markers should be implemented to identify
earlier patients who are more likely to recover consciousness.
The effect of brain injury aetiology on TMS-EEG response and
its implication on the prognosis could also be studied.
Similarly, TMS-EEG should be used to assess the effect of
pharmacological treatments including zolpidem, amantadine
and apomorphine, which have been shown to promote
functional recovery in a sub-set of patients with DOC
[71–73]. This would allow researchers to better understand
the mechanisms by which such treatments work and perhaps
determine early on the patients who are likely to respond.
Repetitive TMS, which has not been discussed in this review,
can modulate brain excitability and potentially connectivity.
These effects could also be quickly assessed by TMS-EEG.
Finally, TMS-EEG results could be combined with those
obtained with other techniques in order to study neural
correlates of consciousness. For example, correlating effective
connectivity with structural connectivity (using diffusion
tensor imaging) or functional connectivity (using EEG or
fMRI [74]). In fact, structural data would provide prior
information as input for the source-modelling algorithm,
possibly increasing its power and making it closer to reality,
as effective connectivity is supported by structural connectivity [34]. Intracranial EEG recordings in patients evaluated for
pharmacoresistant epilepsy, for instance, would also extend
the spatial capacity of this approach and allow studying of
the deeper structures of the thalamocortical networks.
Previous studies have demonstrated the safety of using TMS
with implanted electrodes, although some recommendations
have been released; such as avoiding stimulation near
electrodes loops and avoiding repetitive TMS in a chronic
setting due to lack of data on potential tissue damage [75].
Conclusion
The concomitant development of combined TMS-EEG
technique and new theories of consciousness has led to a
1187
promising evolution in the way of investigating brain
processes. In acute and chronic DOC, TMS-EEG is uncovering new aspects of the brain physiology. Most importantly, for
the first time, one has the potential to assess the residual level
of consciousness of patients with severe brain injuries at the
single subject level and at the bedside. Further developments
such as the PCI are likely to improve the feasibility of a daily
practical application of TMS in evaluation of consciousness.
However, as with every new technique, several questions
remain to be answered, such as the exact sensitivity and
specificity of this tool or its potential prognostic value and the
exact physiology of TMS responses, which has not yet been
determined.
Acknowledgements
The authors would like to thank Simone Sarasso and
Chanyoung Kang for their constructive comments about this
manuscript.
Declaration of interest
This research was funded by the University and University
Hospital of Liège, the Léon Fredericq Funds, the Belgian
National Funds for Scientific Research (FRS-FNRS), the
European Commission (COST, DISCOS, MINDBRIDGE,
DECODER), the James McDonnell Foundation, the Mind
Science Foundation, Wallonie-Bruxelles International (WBI)
the French Speaking Community Concerted Research Action
(ARC 06/11-340), the Belgian American Educational
Foundation (BAEF) the Foundation Médicale Reine
Elisabeth, the Public Utility Foundation ‘Université
Européenne du Travail’ and ‘Fondazione Europea di
Ricerca Biomedica’. OG received support from NIH grant
MH064498 and MH095984 to Bradley R. Postle and Giulio
Tononi. OB is a research fellow, OG a postdoctoral researcher
and SL a research director at the FNRS.
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