http://informahealthcare.com/bij ISSN: 0269-9052 (print), 1362-301X (electronic) Brain Inj, 2014; 28(9): 1190–1196 ! 2014 Informa UK Ltd. DOI: 10.3109/02699052.2014.920527
ORIGINAL ARTICLE
Potential applications of concurrent transcranial magnetic stimulation and functional magnetic resonance imaging in acquired brain injury and disorders of consciousness Yelena Guller1 & Joseph Giacino1,2,3 Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Charlestown, MA, USA, 2Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA, and 3Department of Psychiatry, Harvard Medical School, Boston, MA
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Abstract
Keywords
Background: Diagnostic assessment, prognosis and treatment monitoring in patients with disorders of consciousness (DoC) rest largely on behaviorally-based procedures. This approach can lead to misdiagnosis, inaccurate outcome prediction and inappropriate judgements regarding the effectiveness of treatment interventions. Concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) may provide a biological measure of conscious awareness, aid clinicians in clinical decision-making and provide a treatment alternative for DoC. Study: This paper reviews the use of TMS and fMRI in the assessment of patients with DoC and suggests potential applications for concurrent use of these procedures.
Assessment, functional MRI, minimally conscious state, transcranial magnetic stimulation, vegetative state
Introduction Brain injury is a major cause of death and disability worldwide [1]. Following a severe brain injury, some patients will also experience a disorder of consciousness (DoC), a condition that can be classified into the following states: coma (complete failure of the arousal system, no spontaneous eye opening and inability to be awakened even with vigorous sensory stimulation [2]), vegetative state/unresponsiveness wakefulness syndrome (VS/UWS; preserved sleep–wake cycles and capacity for spontaneous or stimulus-induced arousal, but complete absence of behavioural evidence for self or environmental awareness [3, 4], and minimally conscious state (MCS; inconsistent but definitive behavioural evidence of consciousness [5]). Emergence from MCS is signalled by recovery of reliable yes/no responses or the capacity to use objects in a functional manner [6]. Behavioural assessment is the current ‘gold standard’ for diagnosis of patients with DoC. However, this approach may be misleading as it relies on the examiner to determine whether observed behaviours are volitional or random. For example, the examiner may not be aware of underlying sensory, motor, language or cognitive impairments that may
Correspondence: Yelena Guller, PhD, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, 300 First Avenue, Charlestown, MA 02129, USA. Tel: (617) 952-6308. E-mail: [email protected]
History Received 2 October 2013 Revised 10 January 2014 Accepted 26 January 2014 Published online 25 July 2014
mask conscious awareness [7]. Published estimates of misdiagnosis suggest that 3–4 of 10 patients believed to be unconscious based on bedside examination actually retain conscious awareness [8–10]. Establishing an accurate diagnosis is critical to obtaining authorization for rehabilitation and determining the most appropriate plan of care. Recent functional neuroimaging investigations have shown that some patients who appear to be unable to follow commands or communicate at the bedside retain access to language networks and are able to implement these behaviours covertly. Schiff et al. [11] described a small series of patients diagnosed with MCS who activated cortical language networks in response to verbal instructions while undergoing fMRI, despite their inability to follow commands or communicate reliably on bedside examination. Rodriguez-Moreno et al. [12] demonstrated that some non-verbal patients activated language cortex in a manner that approximated healthy controls when instructed to silently name pictures of common objects. In addition, others have used fMRI to demonstrate that some patients in VS/UWS and MCS were capable of performing cognitively-demanding tasks such as mental imagery and selective auditory attention while in the scanner even though bedside examination failed to show consistent responses to simple commands or questions [13–15]. Although these studies are promising, they rely on patients to adequately perceive and process external stimuli and perform complex behaviours to engage functional brain networks. Some patients may retain the functional networks
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necessary to perform these tasks, but may be unable to adequately activate them due to the nature of the stimuli, complexity of the task or fluctuating levels of arousal. To evaluate the integrity of functional brain networks without relying on stimulus perception or comprehension of instructions, a task-free method of brain stimulation is required. The concurrent use of fMRI and transcranial magnetic stimulation (TMS) provides such an opportunity. Below, basic principles of TMS and how TMS and fMRI can aid in measuring network connectivity are reviewed. Potential applications are then suggested of concurrent use of these procedures in DoC and the technical challenges inherent to combining these modalities are addressed.
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TMS TMS is a non-invasive, task-independent method of exciting/ inhibiting the cortex using the principles of electromagnetic induction. In brief, when a charge is passed through the wires of a TMS coil, a perpendicular magnetic field is created. This field easily penetrates the skull and generates an electric current in the underlying cortex [16]. TMS can be delivered in one of two modes. First, single or paired pulse TMS delivers one or two, respectively, pulses of stimulation that cause brief neuronal depolarization and discharge of action potentials. Unlike functional connectivity methods that assess correlational interactions between brain regions, this technique directly perturbs underlying neuronal networks, allowing for the study of effective connectivity and providing insight into causal interaction between brain regions [17]. Delivered over the motor or visual cortex, single pulse TMS can cause motor evoked potentials or phosphenes [18] and is, thus, often used for studying motor and visual systems. Paired-pulse TMS can be used to assess cortical inhibition (decreased cortical excitability), facilitation (increased cortical excitability) and plasticity. The second mode of stimulation, repetitive TMS (rTMS), delivers multiple TMS pulses over a short period of time. Varying rTMS stimulation frequency determines whether cortical neurons will be excited or inhibited. When rTMS is delivered at less than 1 Hz, neuronal excitability is reduced. In contrast, rTMS delivered at greater than 1 Hz facilitates neuronal excitability [19]. Depending on the neuronal population targeted, specific cortical fields may be activated or inhibited and may lead to behavioural changes. rTMS has been used in the context of creating virtual lesions [20] and to facilitate cognitive task performance [21]. Clinically, rTMS has been investigated as a treatment for patients diagnosed with disorders such as depression [22], schizophrenia [23, 24], obsessive compulsive disorder [25], tinnitus [26], aphasia [27], migraine [28] and VS/UWS [29]. Effects of both single/paired pulse and rTMS may be evident in the area directly beneath the coil, in distal brain regions and in peripheral musculature. Consequently, it has become a valuable tool for investigating network connectivity [30]. The concomitant use of TMS and fMRI provides a more direct means of assessing connectivity and establishing causality [31, 32] by directly perturbing underlying neuronal networks and measuring the effects on local and downstream circuits.
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Measuring effects of TMS The effects of TMS can be measured using changes in behaviour or task performance, electromyographic (EMG) motor evoked potentials, electroencephalography (EEG) and functional neuroimaging procedures (e.g. fMRI, Positron Emission Tomography [PET], see Table I for strengths and weaknesses of each method). Motor evoked potentials, which are caused by stimulating primary motor cortex, are useful for studying corticospinal tract conduction and are a reference for adjusting intensity of stimulation when targeting regions that do not have an easily measurable behavioural correlate. EEG measures TMS-evoked voltage fluctuations at the scalp level and can provide valuable information on the temporal order (but not spatial specificity) of brain activity. fMRI identifies the location of TMS-evoked brain responses and reveals regions mono- and poly-synaptically coupled to the area of focal stimulation. Previous studies have used a multimodal TMS approach to characterize motor [33–35], sensory [36–40] and attention networks [41, 43] and to show causal interactions between brain areas [33, 34, 37, 38, 42] in healthy subjects. Recently, decreased thalamic activity and thalamo-cortical connectivity was shown in patients diagnosed with schizophrenia by delivering single pulses of TMS to the cortex and concurrently measuring with fMRI the TMS-evoked response in underlying and distal cortical and sub-cortical regions. This finding highlighted the underlying role of the thalamus in schizophrenia and suggested that the thalamus contributes to the patterns of aberrant connectivity characteristic of the disease [44].
Measuring connectivity in DoC Historically, DoC has been discussed in the context of structural or functional network disconnection. Specifically, a breakdown of cortico-subcortical and cortico-cortical connectivity as the biological underpinning of DoC has been proposed [45–47]. In more recent years, this connectivity hypothesis of DoC has been empirically investigated with PET studies, suggesting impaired cortical connectivity as the defining feature of VS/UWS [48] and restoration of corticothalamic connectivity as a precursor to recovery from VS/ UWS [49]. Motor-evoked potential studies suggest, at the group-level, a breakdown in corticospinal connectivity [50, 51] in patients with severe brain injury and DoC; however, a review by Lapitskaya et al. [52] concluded that, currently, this method is better suited for extending knowledge about DoC rather than deriving clinical conclusions. Rosanova et al. [53] demonstrated that TMS-evoked EEG responses in patients diagnosed with VS/UWS were small and local to the area of direct stimulation, similar to that seen in sleeping or anaesthetized subjects. On the other hand, TMSevoked EEG responses in patients diagnosed with MCS were complex and sequentially involved distant cortical regions ipsi- and contralateral to the site of stimulation. This pattern more closely resembled that of patients diagnosed with locked-in syndrome. Longitudinal studies conducted with the patients who recovered consciousness revealed that this change in connectivity pattern could occur prior to recovery of reliable communication and prior to the presence of
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Table I. Methods of assessing TMS-evoked changes in behaviour and neurophysiology. Measure
Definition and description
Pros
Cons
TMS-Behavioural Paradigms
Assessment of conscious awareness by administering cognitive or behavioural tasks
Inexpensive, technically straightforward, can select tests that assess specific brain function, effects are on the order of behaviour or task performance changes
TMS-EMG
Electromyography; assessment of electrical signals from peripheral musculature. EMG sensor often placed on thumb during contralateral TMS to hand area of motor cortex; can analyse amplitude/duration of action potential and number of motor units Electroencephalography; assessment of electrical brain activity; measures, at the scalp, summation of activity in millions of neurons with similar spatial orientation; can analyse event-related potentials (electrophysiologic response time-locked to stimulus) and obtain information about response amplitude, timing and frequency Positron Emission Tomography; assessment of brain metabolism via radionucleotide uptake; measured in ‘standardized uptake value’ units (ratio of actual tissue radioactivity concentration and hypothetical radioactivity concentration if evenly distributed across the entire body)
Technically straightforward, provides measure of cortical excitability and corticospinal connectivity, non-invasive
Indirect measure of brain function, many confounding factors (age, education, attention), typically non-specific to brain region, physiologic changes are assumed but cannot be tested, difficult to design placebo condition Typically used only with motor cortex stimulation, requires assumptions about relationship of muscle action potentials and brain function, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition Poor spatial resolution, non-specific to location of TMS-evoked response, requires specialized equipment and analytic methods for removing TMS artifact, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition
Functional Magnetic Resonance Imaging; assessment of haemodynamic response in the brain; measures ratio of oxygenated to deoxygenated haemoglobin; typically reported in units of percentage signal change
High spatial resolution (on the order of millimetres), reveals causal relationship of specific brain regions in a network, non-invasive
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TMS-EEG
TMS-PET
TMS-fMRI
Temporal resolution on the order of milliseconds, reveals causal time course of brain activity and connectivity, direct measure of electrical activity, non-invasive, portable
Measures causal relationship of metabolic changes at the cellular level across networks, can identify location of specific areas active during rest and task performance
significant changes in spontaneous EEG measures [53]. Ragazzoni et al. [54] showed that local and distal TMS-evoked cortical potentials were severely impaired in patients in VS/UWS and largely preserved (but with abnormal features) in patients in MCS. However, for at least one of five patients in MCS, the TMS-evoked cortical potentials resembled that of patients in VS/UWS [54]. The latter finding may have been the result of stimulating a lesioned or hypometabolized brain region, which may be visualized with PET or fMRI imaging, or it may be a consequence of poor specificity and sensitivity of the measure. Finally, Casali et al. [55] used TMS-EEG measures to develop a Perturbation Complexity Index that relies on thalamocortical networks to discriminate between wakefulness, sleep, anaesthesia and to differentiate patients in MCS and VS/UWS. Taken together, the studies addressed above highlight the presence of disturbed connectivity in patients with DoC. However, PET imaging is an invasive procedure requiring radionucleutide tracers and TMS-EEG studies suffer from poor spatial resolution (on the order of centimetres, compared
Requires exposure to radiation, requires assumptions about relationship of brain metabolism and neuronal activity, average spatial and poor temporal resolution, expensive, requires cyclotron facility to create radionucleotides, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition Poor temporal resolution (on the order of several seconds), requires assumptions about relationship of haemodynamic response and neuronal activity, requires specialized equipment and analytic methods, expensive, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition, patients with ferrous implants or metal in the head causing irreversible artifact are excluded
with millimetre resolution in fMRI [56, 57]) and, thus, cannot answer questions regarding the locus of disconnection in cortical or subcortical regions. Although resting state fMRI studies (which have high spatial resolution) have also suggested impaired connectivity in DoC in corticothalamic and default mode networks [58–61], the results of these studies are correlational in nature and do not provide information about causal interactions between brain areas. Concurrent TMS-fMRI circumvents the poor spatial resolution limitation of TMS-EEG and the correlational nature of conventional fMRI studies. Moreover, the direct perturb-and-measure properties of TMS-fMRI eliminate confounding variables such as subject participation, attention, perception of stimuli and compliance (Table I). Despite the advantages, this method has not yet been applied to DoC where it may assist with diagnosis, prognosis and treatment evaluation. Furthermore, by evaluating TMS-evoked cortical and subcortical responses with fMRI one may gain a better understanding of the mechanisms involved in conscious
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awareness and may be able to use this knowledge for developing more precise diagnostic tools and treatments.
Potential applications of TMS-fMRI in clinical assessment of patients with DoC
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Diagnosis Empirical evidence that an individual retains the capacity for command-following and communication through demonstration of intact long-range cortico-cortical, cortico-striatal and cortico-thalamic connectivity may serve as a biomarker for discerning level of consciousness. To assess this capacity, single-pulse TMS can be used to directly stimulate neural pathways known to be involved in awareness [48, 49, 62, 63]. The resultant haemodynamic response can be concurrently measured with fMRI and compared to that of healthy subjects and patients in various stages of recovery from severe head injury. An abnormal TMS-evoked haemodynamic response in the region underlying the TMS coil would suggest diminished function in that area and may be used as a marker of level of conscious awareness. A normal TMS-evoked response in the brain region directly underlying the TMS coil in association with abnormal responses in distal regions may support the disconnection hypothesis of DoC and provide an additional metric to distinguish patients with varying levels of awareness. Failure to activate language cortex on an fMRI-based task in the setting of TMS-evoked activity in language networks may further suggest that command-following capacity in patients is preserved and that other factors may account for lack of activation on the language tasks. Intensity or mode of stimulation (i.e. 90% vs. 110% of motor threshold; single pulse vs. rTMS) required to activate specific regions or networks may be yet another measure of capacity for command-following and communication. Patients with lower levels of conscious awareness may require stronger or more frequent stimulation to activate networks than those with higher levels of awareness. Differences in neurophysiology reflected in TMS-evoked regional percentage signal change, time series correlations across networks and stimulation parameters required to induce activity may serve as biomarkers that objectively separate diagnostic groups—a result that cannot be achieved using behavioural assessment. Prognosis and treatment effectiveness Concurrent TMS-fMRI may also have a role in predicting recovery of function and evaluating treatment effectiveness. Prognostic information in patients with DoC is typically based on functional outcome studies of groups of patients and, thus, lacks sensitivity and specificity at the single-case level. This is in part due to the many variables, such as quality of care, that may account for differences in prognosis, but that are not easily measurable or have not been thoroughly studied [64]. Diagnostic group differences in TMS-evoked fMRI percentage signal changes in specific brain regions or correlations in time series across networks may be better predictors of functional outcome than behavioural assessment and may be robust enough to overcome unaccounted for sources of variance attributable to the patient (e.g. under-arousal), examiner (e.g. misinterpretation of prognostic signs) and
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setting (e.g. quality of care). Different patients with similar histories and behavioural profiles may have different outcomes due to neurophysiologic differences that can be probed with concurrent TMS and fMRI. A second prognostic indicator may be derived from the rate of change in local or network TMS-evoked brain activity. While measurable improvement in function may occur over months or years [65], recovery of neuronal or synaptic activity may be reflected in TMS-evoked haemodynamic response changes across days or weeks. Studies correlating the rate or absolute change in neurophysiology to future functional gains may contribute to the development of objective, robust, singlesubject prognostic markers. Similarly, TMS-fMRI may be used to explore whether treatments (pharmacologic, rehabilitation therapy, etc.) modulate TMS-evoked fMRI activity. Currently, methods of evaluating treatment efficacy in DoC are limited to behavioural assessments conducted before and after initiation of an intervention. As discussed previously, behavioural assessment may not be an appropriate marker of level of awareness as it is difficult to distinguish volitional from spontaneous responses and lack of overt behavioural recovery may not accurately reflect changes occurring at the neuronal level. By applying single pulses of TMS and measuring the resultant response with fMRI, an objective pre-treatment measure of brain activity and network connectivity can be determined. This measure can be re-evaluated throughout a treatment course to determine its effectiveness. Early assessment of the modulatory effect of treatment on specific brain regions or networks may guide clinicians to recommend interventions that are shown to be effective at restoring the physiologic substrate underlying cognitive, linguistic and behavioural competencies. Technical challenges Combining two techniques that rely on magnetic fields poses a technical feasibility challenge. First, a special non-ferrous coil must be obtained and the stimulator must be housed in a non-magnetic control room or properly shielded. However, this configuration creates a second challenge. Radiofrequency noise resulting from computers, lights, fans, etc. in the control room travels down the cable and through the patch panel to connect the stimulator to the TMS coil. Both the cable and patch panel require special shielding to avoid image distortion and artifact resulting from radiofrequency noise. Finally, fMRI images are typically acquired continuously. In 2000 milliseconds, enough slices are collected to obtain an image of the whole brain. This process occurs, uninterrupted, for the duration of the scan. However, when a TMS pulse coincides with image acquisition, the image becomes largely distorted. To avoid this problem, a momentary gap in image acquisition, during which TMS pulses are delivered, should be built into the imaging sequence. With assistance from an MRI technician and physicist, these challenges are quite straightforward to overcome.
Case study This study presents an hypothetical case study intended to suggest examples of how TMS-fMRI may provide objective
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markers of conscious awareness that help guide physicians, therapists and family members in clinical decision-making.
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History Patient MM is a right-handed, 25 year-old male who sustained a traumatic brain injury as the result of a motor vehicle accident 2 months ago. At the scene, Glasgow Coma Scale score was 3. He was transferred to an acute hospital where brain MRI showed severe diffuse brain injury, predilected to the left fronto-parietal region. An intracranial pressure bolt was placed and he was monitored for 72 hours without the need for neurosurgical intervention. He emerged from coma and transitioned into VS/UWS. Daytime arousal fluctuated between periods of wakefulness and somnolence and there was no discernible behavioural evidence of self or environmental awareness. Specifically, standardized bedside assessment using the Coma Recovery Scale-Revised [66] found no evidence of command-following, purposeful motor behaviour, sustained visual pursuit or verbal or gestural communication. Family members reported occasional instances of right lower extremity movement to command, but these episodes were not corroborated by clinical staff. In view of the conflicting reports concerning volitional behaviour, he was referred for TMS-fMRI assessment to investigate the integrity of cortical networks necessary for command-following and comprehension and expression of language. TMS-fMRI procedure Single pulse TMS at 110% of motor threshold (i.e. the stimulation intensity required to produce right thumb movement on five of 10 occasions when TMS is applied to left motor cortex) was applied to the left posterior parietal cortex and resultant fMRI responses were measured underneath the TMS coil, in the contralateral posterior parietal cortex, in the bilateral dorsolateral prefrontal cortex (DLPFC) and in the thalamus. In addition, time series correlations between these regions were assessed as a measure of connectivity. Similarly, TMS was applied to DLPFC and the resultant response evaluated in contralateral DLPFC, bilateral posterior parietal cortex and thalamus, as well as between these regions. Finally, single pulses of TMS were applied to the left superior temporal gyrus (Wernicke’s area) and the left inferior frontal gyrus (Broca’s area). Responses were measured within and between these regions, ipsi- and contralateral to the site of stimulation. TMS-fMRI examination findings Regional TMS-evoked fMRI measures were significantly lower in amplitude in bilateral DLPFC and bilateral posterior parietal cortex than in healthy control subjects, suggesting decreased function in areas involved in mediating self and environmental awareness. Network connectivity measures between DLPFC and parietal cortices (both ipsi- and contralateral to the site of stimulation) were also lower than expected compared to healthy controls, but nonetheless present, suggesting that these regions remained functionally connected. In addition, connectivity between each of the stimulated regions and the thalamus was intact. Taken together, while there are decreases in cortico-cortical and
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cortico-thalamic network activity, these circuits are at least partly preserved. When stimulating the left inferior frontal gyrus, there was a diminished TMS-evoked haemodynamic response under the coil and no response bilaterally in superior temporal or right inferior frontal gyri. When stimulation was targeted to the left superior temporal gyrus, a diminished TMS-evoked haemodynamic response was observed under the coil and no response was observed bilaterally in the inferior frontal of the right superior temporal gyri. Network connectivity was not preserved between the inferior frontal gyrus and the superior frontal gyrus and vice versa, regardless of the hemisphere interrogated. These findings suggest that, while isolated brain regions of the language network remain active, there is partial loss of effective connectivity in the language network, which may account for the failure to detect command-following on bedside examination.
Impression and recommendations TMS-fMRI revealed that, although brain structures and functional networks that support self and environmental awareness and mediate language comprehension and expression retain some functional activity, there is marked loss of connectivity between these regions. This finding could be a result of insufficient activation of downstream areas due to focal injury to the discrete structures in these networks, injury to white matter pathways through which neuronal signals travel from one region to another or a combination of these factors. While discrete nodes within the language circuit may retain some signal-processing capacity, these functional units are isolated from other nodes situated within the widelydistributed language network. It is likely that the global disruption of brain activity brought about by diffuse axonal injury accounts for the diminished connectivity noted in the DLPFC and the locally-diminished activity in left hemisphere language structures (i.e. Broca’s and Wernicke’s areas). Serial TMS-fMRI re-evaluation should be conducted to monitor the nature and rate of recovery of the networks involved in conscious awareness and communication and correlated with standardized behavioural testing for purposes of concurrent validity.
Conclusion Determining where patients lie on the spectrum of conscious awareness and accurately assessing their cognitive capacity is critical for establishing accurate diagnosis and prognosis and evaluating treatment effectiveness. Current methods of assessing diagnosis and treatment effectiveness primarily rely on behavioural examination (supplemented in some cases by neuroimaging and electrophysiologic techniques), while prognosis is based largely on group-level outcome studies. Procedures that rely on the concurrent use of TMS and fMRI may provide objective markers of brain function while circumventing some of the limitations inherent to behavioural, electrophysiologic and conventional fMRI approaches such as reliance on task comprehension, lack of spatial specificity and results that lack causal inference. Changes in the level of TMS-evoked activity in discrete brain regions and across networks over time may assist clinicians in determining appropriate interventions and disposition. This type of
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multimodal assessment strategy may help expand understanding of the neural mechanisms underlying DoC and inform the approach to diagnosis, prognosis and treatment.
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Declaration of interest
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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ORIGINAL ARTICLE
Potential applications of concurrent transcranial magnetic stimulation and functional magnetic resonance imaging in acquired brain injury and disorders of consciousness Yelena Guller1 & Joseph Giacino1,2,3 Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, Charlestown, MA, USA, 2Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA, and 3Department of Psychiatry, Harvard Medical School, Boston, MA
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Abstract
Keywords
Background: Diagnostic assessment, prognosis and treatment monitoring in patients with disorders of consciousness (DoC) rest largely on behaviorally-based procedures. This approach can lead to misdiagnosis, inaccurate outcome prediction and inappropriate judgements regarding the effectiveness of treatment interventions. Concurrent transcranial magnetic stimulation (TMS) and functional magnetic resonance imaging (fMRI) may provide a biological measure of conscious awareness, aid clinicians in clinical decision-making and provide a treatment alternative for DoC. Study: This paper reviews the use of TMS and fMRI in the assessment of patients with DoC and suggests potential applications for concurrent use of these procedures.
Assessment, functional MRI, minimally conscious state, transcranial magnetic stimulation, vegetative state
Introduction Brain injury is a major cause of death and disability worldwide [1]. Following a severe brain injury, some patients will also experience a disorder of consciousness (DoC), a condition that can be classified into the following states: coma (complete failure of the arousal system, no spontaneous eye opening and inability to be awakened even with vigorous sensory stimulation [2]), vegetative state/unresponsiveness wakefulness syndrome (VS/UWS; preserved sleep–wake cycles and capacity for spontaneous or stimulus-induced arousal, but complete absence of behavioural evidence for self or environmental awareness [3, 4], and minimally conscious state (MCS; inconsistent but definitive behavioural evidence of consciousness [5]). Emergence from MCS is signalled by recovery of reliable yes/no responses or the capacity to use objects in a functional manner [6]. Behavioural assessment is the current ‘gold standard’ for diagnosis of patients with DoC. However, this approach may be misleading as it relies on the examiner to determine whether observed behaviours are volitional or random. For example, the examiner may not be aware of underlying sensory, motor, language or cognitive impairments that may
Correspondence: Yelena Guller, PhD, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, 300 First Avenue, Charlestown, MA 02129, USA. Tel: (617) 952-6308. E-mail: [email protected]
History Received 2 October 2013 Revised 10 January 2014 Accepted 26 January 2014 Published online 25 July 2014
mask conscious awareness [7]. Published estimates of misdiagnosis suggest that 3–4 of 10 patients believed to be unconscious based on bedside examination actually retain conscious awareness [8–10]. Establishing an accurate diagnosis is critical to obtaining authorization for rehabilitation and determining the most appropriate plan of care. Recent functional neuroimaging investigations have shown that some patients who appear to be unable to follow commands or communicate at the bedside retain access to language networks and are able to implement these behaviours covertly. Schiff et al. [11] described a small series of patients diagnosed with MCS who activated cortical language networks in response to verbal instructions while undergoing fMRI, despite their inability to follow commands or communicate reliably on bedside examination. Rodriguez-Moreno et al. [12] demonstrated that some non-verbal patients activated language cortex in a manner that approximated healthy controls when instructed to silently name pictures of common objects. In addition, others have used fMRI to demonstrate that some patients in VS/UWS and MCS were capable of performing cognitively-demanding tasks such as mental imagery and selective auditory attention while in the scanner even though bedside examination failed to show consistent responses to simple commands or questions [13–15]. Although these studies are promising, they rely on patients to adequately perceive and process external stimuli and perform complex behaviours to engage functional brain networks. Some patients may retain the functional networks
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necessary to perform these tasks, but may be unable to adequately activate them due to the nature of the stimuli, complexity of the task or fluctuating levels of arousal. To evaluate the integrity of functional brain networks without relying on stimulus perception or comprehension of instructions, a task-free method of brain stimulation is required. The concurrent use of fMRI and transcranial magnetic stimulation (TMS) provides such an opportunity. Below, basic principles of TMS and how TMS and fMRI can aid in measuring network connectivity are reviewed. Potential applications are then suggested of concurrent use of these procedures in DoC and the technical challenges inherent to combining these modalities are addressed.
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TMS TMS is a non-invasive, task-independent method of exciting/ inhibiting the cortex using the principles of electromagnetic induction. In brief, when a charge is passed through the wires of a TMS coil, a perpendicular magnetic field is created. This field easily penetrates the skull and generates an electric current in the underlying cortex [16]. TMS can be delivered in one of two modes. First, single or paired pulse TMS delivers one or two, respectively, pulses of stimulation that cause brief neuronal depolarization and discharge of action potentials. Unlike functional connectivity methods that assess correlational interactions between brain regions, this technique directly perturbs underlying neuronal networks, allowing for the study of effective connectivity and providing insight into causal interaction between brain regions [17]. Delivered over the motor or visual cortex, single pulse TMS can cause motor evoked potentials or phosphenes [18] and is, thus, often used for studying motor and visual systems. Paired-pulse TMS can be used to assess cortical inhibition (decreased cortical excitability), facilitation (increased cortical excitability) and plasticity. The second mode of stimulation, repetitive TMS (rTMS), delivers multiple TMS pulses over a short period of time. Varying rTMS stimulation frequency determines whether cortical neurons will be excited or inhibited. When rTMS is delivered at less than 1 Hz, neuronal excitability is reduced. In contrast, rTMS delivered at greater than 1 Hz facilitates neuronal excitability [19]. Depending on the neuronal population targeted, specific cortical fields may be activated or inhibited and may lead to behavioural changes. rTMS has been used in the context of creating virtual lesions [20] and to facilitate cognitive task performance [21]. Clinically, rTMS has been investigated as a treatment for patients diagnosed with disorders such as depression [22], schizophrenia [23, 24], obsessive compulsive disorder [25], tinnitus [26], aphasia [27], migraine [28] and VS/UWS [29]. Effects of both single/paired pulse and rTMS may be evident in the area directly beneath the coil, in distal brain regions and in peripheral musculature. Consequently, it has become a valuable tool for investigating network connectivity [30]. The concomitant use of TMS and fMRI provides a more direct means of assessing connectivity and establishing causality [31, 32] by directly perturbing underlying neuronal networks and measuring the effects on local and downstream circuits.
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Measuring effects of TMS The effects of TMS can be measured using changes in behaviour or task performance, electromyographic (EMG) motor evoked potentials, electroencephalography (EEG) and functional neuroimaging procedures (e.g. fMRI, Positron Emission Tomography [PET], see Table I for strengths and weaknesses of each method). Motor evoked potentials, which are caused by stimulating primary motor cortex, are useful for studying corticospinal tract conduction and are a reference for adjusting intensity of stimulation when targeting regions that do not have an easily measurable behavioural correlate. EEG measures TMS-evoked voltage fluctuations at the scalp level and can provide valuable information on the temporal order (but not spatial specificity) of brain activity. fMRI identifies the location of TMS-evoked brain responses and reveals regions mono- and poly-synaptically coupled to the area of focal stimulation. Previous studies have used a multimodal TMS approach to characterize motor [33–35], sensory [36–40] and attention networks [41, 43] and to show causal interactions between brain areas [33, 34, 37, 38, 42] in healthy subjects. Recently, decreased thalamic activity and thalamo-cortical connectivity was shown in patients diagnosed with schizophrenia by delivering single pulses of TMS to the cortex and concurrently measuring with fMRI the TMS-evoked response in underlying and distal cortical and sub-cortical regions. This finding highlighted the underlying role of the thalamus in schizophrenia and suggested that the thalamus contributes to the patterns of aberrant connectivity characteristic of the disease [44].
Measuring connectivity in DoC Historically, DoC has been discussed in the context of structural or functional network disconnection. Specifically, a breakdown of cortico-subcortical and cortico-cortical connectivity as the biological underpinning of DoC has been proposed [45–47]. In more recent years, this connectivity hypothesis of DoC has been empirically investigated with PET studies, suggesting impaired cortical connectivity as the defining feature of VS/UWS [48] and restoration of corticothalamic connectivity as a precursor to recovery from VS/ UWS [49]. Motor-evoked potential studies suggest, at the group-level, a breakdown in corticospinal connectivity [50, 51] in patients with severe brain injury and DoC; however, a review by Lapitskaya et al. [52] concluded that, currently, this method is better suited for extending knowledge about DoC rather than deriving clinical conclusions. Rosanova et al. [53] demonstrated that TMS-evoked EEG responses in patients diagnosed with VS/UWS were small and local to the area of direct stimulation, similar to that seen in sleeping or anaesthetized subjects. On the other hand, TMSevoked EEG responses in patients diagnosed with MCS were complex and sequentially involved distant cortical regions ipsi- and contralateral to the site of stimulation. This pattern more closely resembled that of patients diagnosed with locked-in syndrome. Longitudinal studies conducted with the patients who recovered consciousness revealed that this change in connectivity pattern could occur prior to recovery of reliable communication and prior to the presence of
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Table I. Methods of assessing TMS-evoked changes in behaviour and neurophysiology. Measure
Definition and description
Pros
Cons
TMS-Behavioural Paradigms
Assessment of conscious awareness by administering cognitive or behavioural tasks
Inexpensive, technically straightforward, can select tests that assess specific brain function, effects are on the order of behaviour or task performance changes
TMS-EMG
Electromyography; assessment of electrical signals from peripheral musculature. EMG sensor often placed on thumb during contralateral TMS to hand area of motor cortex; can analyse amplitude/duration of action potential and number of motor units Electroencephalography; assessment of electrical brain activity; measures, at the scalp, summation of activity in millions of neurons with similar spatial orientation; can analyse event-related potentials (electrophysiologic response time-locked to stimulus) and obtain information about response amplitude, timing and frequency Positron Emission Tomography; assessment of brain metabolism via radionucleotide uptake; measured in ‘standardized uptake value’ units (ratio of actual tissue radioactivity concentration and hypothetical radioactivity concentration if evenly distributed across the entire body)
Technically straightforward, provides measure of cortical excitability and corticospinal connectivity, non-invasive
Indirect measure of brain function, many confounding factors (age, education, attention), typically non-specific to brain region, physiologic changes are assumed but cannot be tested, difficult to design placebo condition Typically used only with motor cortex stimulation, requires assumptions about relationship of muscle action potentials and brain function, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition Poor spatial resolution, non-specific to location of TMS-evoked response, requires specialized equipment and analytic methods for removing TMS artifact, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition
Functional Magnetic Resonance Imaging; assessment of haemodynamic response in the brain; measures ratio of oxygenated to deoxygenated haemoglobin; typically reported in units of percentage signal change
High spatial resolution (on the order of millimetres), reveals causal relationship of specific brain regions in a network, non-invasive
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TMS-EEG
TMS-PET
TMS-fMRI
Temporal resolution on the order of milliseconds, reveals causal time course of brain activity and connectivity, direct measure of electrical activity, non-invasive, portable
Measures causal relationship of metabolic changes at the cellular level across networks, can identify location of specific areas active during rest and task performance
significant changes in spontaneous EEG measures [53]. Ragazzoni et al. [54] showed that local and distal TMS-evoked cortical potentials were severely impaired in patients in VS/UWS and largely preserved (but with abnormal features) in patients in MCS. However, for at least one of five patients in MCS, the TMS-evoked cortical potentials resembled that of patients in VS/UWS [54]. The latter finding may have been the result of stimulating a lesioned or hypometabolized brain region, which may be visualized with PET or fMRI imaging, or it may be a consequence of poor specificity and sensitivity of the measure. Finally, Casali et al. [55] used TMS-EEG measures to develop a Perturbation Complexity Index that relies on thalamocortical networks to discriminate between wakefulness, sleep, anaesthesia and to differentiate patients in MCS and VS/UWS. Taken together, the studies addressed above highlight the presence of disturbed connectivity in patients with DoC. However, PET imaging is an invasive procedure requiring radionucleutide tracers and TMS-EEG studies suffer from poor spatial resolution (on the order of centimetres, compared
Requires exposure to radiation, requires assumptions about relationship of brain metabolism and neuronal activity, average spatial and poor temporal resolution, expensive, requires cyclotron facility to create radionucleotides, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition Poor temporal resolution (on the order of several seconds), requires assumptions about relationship of haemodynamic response and neuronal activity, requires specialized equipment and analytic methods, expensive, insensitive to changes (i.e. improvement, decline) in task performance, difficult to design placebo condition, patients with ferrous implants or metal in the head causing irreversible artifact are excluded
with millimetre resolution in fMRI [56, 57]) and, thus, cannot answer questions regarding the locus of disconnection in cortical or subcortical regions. Although resting state fMRI studies (which have high spatial resolution) have also suggested impaired connectivity in DoC in corticothalamic and default mode networks [58–61], the results of these studies are correlational in nature and do not provide information about causal interactions between brain areas. Concurrent TMS-fMRI circumvents the poor spatial resolution limitation of TMS-EEG and the correlational nature of conventional fMRI studies. Moreover, the direct perturb-and-measure properties of TMS-fMRI eliminate confounding variables such as subject participation, attention, perception of stimuli and compliance (Table I). Despite the advantages, this method has not yet been applied to DoC where it may assist with diagnosis, prognosis and treatment evaluation. Furthermore, by evaluating TMS-evoked cortical and subcortical responses with fMRI one may gain a better understanding of the mechanisms involved in conscious
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awareness and may be able to use this knowledge for developing more precise diagnostic tools and treatments.
Potential applications of TMS-fMRI in clinical assessment of patients with DoC
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Diagnosis Empirical evidence that an individual retains the capacity for command-following and communication through demonstration of intact long-range cortico-cortical, cortico-striatal and cortico-thalamic connectivity may serve as a biomarker for discerning level of consciousness. To assess this capacity, single-pulse TMS can be used to directly stimulate neural pathways known to be involved in awareness [48, 49, 62, 63]. The resultant haemodynamic response can be concurrently measured with fMRI and compared to that of healthy subjects and patients in various stages of recovery from severe head injury. An abnormal TMS-evoked haemodynamic response in the region underlying the TMS coil would suggest diminished function in that area and may be used as a marker of level of conscious awareness. A normal TMS-evoked response in the brain region directly underlying the TMS coil in association with abnormal responses in distal regions may support the disconnection hypothesis of DoC and provide an additional metric to distinguish patients with varying levels of awareness. Failure to activate language cortex on an fMRI-based task in the setting of TMS-evoked activity in language networks may further suggest that command-following capacity in patients is preserved and that other factors may account for lack of activation on the language tasks. Intensity or mode of stimulation (i.e. 90% vs. 110% of motor threshold; single pulse vs. rTMS) required to activate specific regions or networks may be yet another measure of capacity for command-following and communication. Patients with lower levels of conscious awareness may require stronger or more frequent stimulation to activate networks than those with higher levels of awareness. Differences in neurophysiology reflected in TMS-evoked regional percentage signal change, time series correlations across networks and stimulation parameters required to induce activity may serve as biomarkers that objectively separate diagnostic groups—a result that cannot be achieved using behavioural assessment. Prognosis and treatment effectiveness Concurrent TMS-fMRI may also have a role in predicting recovery of function and evaluating treatment effectiveness. Prognostic information in patients with DoC is typically based on functional outcome studies of groups of patients and, thus, lacks sensitivity and specificity at the single-case level. This is in part due to the many variables, such as quality of care, that may account for differences in prognosis, but that are not easily measurable or have not been thoroughly studied [64]. Diagnostic group differences in TMS-evoked fMRI percentage signal changes in specific brain regions or correlations in time series across networks may be better predictors of functional outcome than behavioural assessment and may be robust enough to overcome unaccounted for sources of variance attributable to the patient (e.g. under-arousal), examiner (e.g. misinterpretation of prognostic signs) and
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setting (e.g. quality of care). Different patients with similar histories and behavioural profiles may have different outcomes due to neurophysiologic differences that can be probed with concurrent TMS and fMRI. A second prognostic indicator may be derived from the rate of change in local or network TMS-evoked brain activity. While measurable improvement in function may occur over months or years [65], recovery of neuronal or synaptic activity may be reflected in TMS-evoked haemodynamic response changes across days or weeks. Studies correlating the rate or absolute change in neurophysiology to future functional gains may contribute to the development of objective, robust, singlesubject prognostic markers. Similarly, TMS-fMRI may be used to explore whether treatments (pharmacologic, rehabilitation therapy, etc.) modulate TMS-evoked fMRI activity. Currently, methods of evaluating treatment efficacy in DoC are limited to behavioural assessments conducted before and after initiation of an intervention. As discussed previously, behavioural assessment may not be an appropriate marker of level of awareness as it is difficult to distinguish volitional from spontaneous responses and lack of overt behavioural recovery may not accurately reflect changes occurring at the neuronal level. By applying single pulses of TMS and measuring the resultant response with fMRI, an objective pre-treatment measure of brain activity and network connectivity can be determined. This measure can be re-evaluated throughout a treatment course to determine its effectiveness. Early assessment of the modulatory effect of treatment on specific brain regions or networks may guide clinicians to recommend interventions that are shown to be effective at restoring the physiologic substrate underlying cognitive, linguistic and behavioural competencies. Technical challenges Combining two techniques that rely on magnetic fields poses a technical feasibility challenge. First, a special non-ferrous coil must be obtained and the stimulator must be housed in a non-magnetic control room or properly shielded. However, this configuration creates a second challenge. Radiofrequency noise resulting from computers, lights, fans, etc. in the control room travels down the cable and through the patch panel to connect the stimulator to the TMS coil. Both the cable and patch panel require special shielding to avoid image distortion and artifact resulting from radiofrequency noise. Finally, fMRI images are typically acquired continuously. In 2000 milliseconds, enough slices are collected to obtain an image of the whole brain. This process occurs, uninterrupted, for the duration of the scan. However, when a TMS pulse coincides with image acquisition, the image becomes largely distorted. To avoid this problem, a momentary gap in image acquisition, during which TMS pulses are delivered, should be built into the imaging sequence. With assistance from an MRI technician and physicist, these challenges are quite straightforward to overcome.
Case study This study presents an hypothetical case study intended to suggest examples of how TMS-fMRI may provide objective
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markers of conscious awareness that help guide physicians, therapists and family members in clinical decision-making.
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History Patient MM is a right-handed, 25 year-old male who sustained a traumatic brain injury as the result of a motor vehicle accident 2 months ago. At the scene, Glasgow Coma Scale score was 3. He was transferred to an acute hospital where brain MRI showed severe diffuse brain injury, predilected to the left fronto-parietal region. An intracranial pressure bolt was placed and he was monitored for 72 hours without the need for neurosurgical intervention. He emerged from coma and transitioned into VS/UWS. Daytime arousal fluctuated between periods of wakefulness and somnolence and there was no discernible behavioural evidence of self or environmental awareness. Specifically, standardized bedside assessment using the Coma Recovery Scale-Revised [66] found no evidence of command-following, purposeful motor behaviour, sustained visual pursuit or verbal or gestural communication. Family members reported occasional instances of right lower extremity movement to command, but these episodes were not corroborated by clinical staff. In view of the conflicting reports concerning volitional behaviour, he was referred for TMS-fMRI assessment to investigate the integrity of cortical networks necessary for command-following and comprehension and expression of language. TMS-fMRI procedure Single pulse TMS at 110% of motor threshold (i.e. the stimulation intensity required to produce right thumb movement on five of 10 occasions when TMS is applied to left motor cortex) was applied to the left posterior parietal cortex and resultant fMRI responses were measured underneath the TMS coil, in the contralateral posterior parietal cortex, in the bilateral dorsolateral prefrontal cortex (DLPFC) and in the thalamus. In addition, time series correlations between these regions were assessed as a measure of connectivity. Similarly, TMS was applied to DLPFC and the resultant response evaluated in contralateral DLPFC, bilateral posterior parietal cortex and thalamus, as well as between these regions. Finally, single pulses of TMS were applied to the left superior temporal gyrus (Wernicke’s area) and the left inferior frontal gyrus (Broca’s area). Responses were measured within and between these regions, ipsi- and contralateral to the site of stimulation. TMS-fMRI examination findings Regional TMS-evoked fMRI measures were significantly lower in amplitude in bilateral DLPFC and bilateral posterior parietal cortex than in healthy control subjects, suggesting decreased function in areas involved in mediating self and environmental awareness. Network connectivity measures between DLPFC and parietal cortices (both ipsi- and contralateral to the site of stimulation) were also lower than expected compared to healthy controls, but nonetheless present, suggesting that these regions remained functionally connected. In addition, connectivity between each of the stimulated regions and the thalamus was intact. Taken together, while there are decreases in cortico-cortical and
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cortico-thalamic network activity, these circuits are at least partly preserved. When stimulating the left inferior frontal gyrus, there was a diminished TMS-evoked haemodynamic response under the coil and no response bilaterally in superior temporal or right inferior frontal gyri. When stimulation was targeted to the left superior temporal gyrus, a diminished TMS-evoked haemodynamic response was observed under the coil and no response was observed bilaterally in the inferior frontal of the right superior temporal gyri. Network connectivity was not preserved between the inferior frontal gyrus and the superior frontal gyrus and vice versa, regardless of the hemisphere interrogated. These findings suggest that, while isolated brain regions of the language network remain active, there is partial loss of effective connectivity in the language network, which may account for the failure to detect command-following on bedside examination.
Impression and recommendations TMS-fMRI revealed that, although brain structures and functional networks that support self and environmental awareness and mediate language comprehension and expression retain some functional activity, there is marked loss of connectivity between these regions. This finding could be a result of insufficient activation of downstream areas due to focal injury to the discrete structures in these networks, injury to white matter pathways through which neuronal signals travel from one region to another or a combination of these factors. While discrete nodes within the language circuit may retain some signal-processing capacity, these functional units are isolated from other nodes situated within the widelydistributed language network. It is likely that the global disruption of brain activity brought about by diffuse axonal injury accounts for the diminished connectivity noted in the DLPFC and the locally-diminished activity in left hemisphere language structures (i.e. Broca’s and Wernicke’s areas). Serial TMS-fMRI re-evaluation should be conducted to monitor the nature and rate of recovery of the networks involved in conscious awareness and communication and correlated with standardized behavioural testing for purposes of concurrent validity.
Conclusion Determining where patients lie on the spectrum of conscious awareness and accurately assessing their cognitive capacity is critical for establishing accurate diagnosis and prognosis and evaluating treatment effectiveness. Current methods of assessing diagnosis and treatment effectiveness primarily rely on behavioural examination (supplemented in some cases by neuroimaging and electrophysiologic techniques), while prognosis is based largely on group-level outcome studies. Procedures that rely on the concurrent use of TMS and fMRI may provide objective markers of brain function while circumventing some of the limitations inherent to behavioural, electrophysiologic and conventional fMRI approaches such as reliance on task comprehension, lack of spatial specificity and results that lack causal inference. Changes in the level of TMS-evoked activity in discrete brain regions and across networks over time may assist clinicians in determining appropriate interventions and disposition. This type of
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multimodal assessment strategy may help expand understanding of the neural mechanisms underlying DoC and inform the approach to diagnosis, prognosis and treatment.
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Declaration of interest
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The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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