Pain Perception in Disorder of Consciousness: A Scoping Review on Current Knowledge, Clinical Applications, and Future Perspective

Pain perception in individuals with prolonged disorders of consciousness (PDOC) is still a matter of debate. Advanced neuroimaging studies suggest some cortical activations even in patients with unresponsive wakefulness syndrome (UWS) compared to those with a minimally conscious state (MCS). Therefore, pain perception has to be considered even in individuals with UWS. However, advanced neuroimaging assessment can be challenging to conduct, and its findings are sometimes difficult to be interpreted. Conversely, multichannel electroencephalography (EEG) and laser-evoked potentials (LEPs) can be carried out quickly and are more adaptable to the clinical needs. In this scoping review, we dealt with the neurophysiological basis underpinning pain in PDOC, pointing out how pain perception assessment in these individuals might help in reducing the misdiagnosis rate. The available literature data suggest that patients with UWS show a more severe functional connectivity breakdown among the pain-related brain areas compared to individuals in MCS, pointing out that pain perception increases with the level of consciousness. However, there are noteworthy exceptions, because some UWS patients show pain-related cortical activations that partially overlap those observed in MCS individuals. This suggests that some patients with UWS may have residual brain functional connectivity supporting the somatosensory, affective, and cognitive aspects of pain processing (i.e., a conscious experience of the unpleasantness of pain), rather than only being able to show autonomic responses to potentially harmful stimuli. Therefore, the significance of the neurophysiological approach to pain perception in PDOC seems to be clear, and despite some methodological caveats (including intensity of stimulation, multimodal paradigms, and active vs. passive stimulation protocols), remain to be solved. To summarize, an accurate clinical and neurophysiological assessment should always be performed for a better understanding of pain perception neurophysiological underpinnings, a more precise differential diagnosis at the level of individual cases as well as group comparisons, and patient-tailored management.

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Noninvasive brain stimulation for patients with a disorder of consciousness: a systematic review and meta-analysis

Reviews in the Neurosciences ◽

10.1515/revneuro-2020-0033 ◽

2020 ◽

Vol 31 (8) ◽

pp. 905-914 ◽

Cited By ~ 1

Author(s):

Yali Feng ◽

Jiaqi Zhang ◽

Yi Zhou ◽

Zhongfei Bai ◽

Ying Yin

Keyword(s):

Brain Stimulation ◽

Meta Analysis ◽

Minimally Conscious State ◽

Conscious State ◽

Primary Outcome Measure ◽

Noninvasive Brain Stimulation ◽

Disorder Of Consciousness ◽

Left Dlpfc ◽

Dorsolateral Prefrontal ◽

Minimally Conscious

AbstractNoninvasive brain stimulation (NIBS) techniques have been used to facilitate the recovery from prolonged unconsciousness as a result of brain injury. The aim of this study is to systematically assess the effects of NIBS in patients with a disorder of consciousness (DOC). We searched four databases for any randomized controlled trials on the effect of NIBS in patients with a DOC, which used the JFK Coma Recovery Scale-Revised (CRS-R) as the primary outcome measure. A random-effects meta-analysis was conducted to pool effect sizes. Fourteen studies with 273 participants were included in this review, of which 12 studies with sufficient data were included in the meta-analysis. Our meta-analysis showed a significant effect on increasing CRS-R scores in favor of real stimulation as compared to sham (Hedges’ g = 0.522; 95% confidence interval [CI], 0.318–0.726; P < 0.0001, I2 = 0.00%). Subgroup analysis demonstrated that only anodal transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) significantly enhances the CRS-R scores in patients with a DOC, as compared to sham (Hedges’ g = 0.703; 95% CI, 0.419–0.986; P < 0.001), and this effect was predominant in patients in a minimally conscious state (MCS) (Hedges’ g = 0.815; 95% CI, 0.429–1.200; P < 0.001). Anodal tDCS of the left DLPFC appears to be an effective approach for patients with MCS.

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Functional Brain Network Topology Discriminates between Patients with Minimally Conscious State and Unresponsive Wakefulness Syndrome

Journal of Clinical Medicine ◽

10.3390/jcm8030306 ◽

2019 ◽

Vol 8 (3) ◽

pp. 306 ◽

Cited By ~ 12

Author(s):

Alberto Cacciola ◽

Antonino Naro ◽

Demetrio Milardi ◽

Alessia Bramanti ◽

Leonardo Malatacca ◽

...

Keyword(s):

Functional Connectivity ◽

Network Topology ◽

Minimally Conscious State ◽

Conscious State ◽

Clustering Coefficient ◽

Unresponsive Wakefulness Syndrome ◽

Topological Network ◽

Functional Brain Network ◽

Minimally Conscious ◽

Nodal Level

Consciousness arises from the functional interaction of multiple brain structures and their ability to integrate different complex patterns of internal communication. Although several studies demonstrated that the fronto-parietal and functional default mode networks play a key role in conscious processes, it is still not clear which topological network measures (that quantifies different features of whole-brain functional network organization) are altered in patients with disorders of consciousness. Herein, we investigate the functional connectivity of unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS) patients from a topological network perspective, by using resting-state EEG recording. Network-based statistical analysis reveals a subnetwork of decreased functional connectivity in UWS compared to in the MCS patients, mainly involving the interhemispheric fronto-parietal connectivity patterns. Network topological analysis reveals increased values of local-community-paradigm correlation, as well as higher clustering coefficient and local efficiency in UWS patients compared to in MCS patients. At the nodal level, the UWS patients showed altered functional topology in several limbic and temporo-parieto-occipital regions. Taken together, our results highlight (i) the involvement of the interhemispheric fronto-parietal functional connectivity in the pathophysiology of consciousness disorders and (ii) an aberrant connectome organization both at the network topology level and at the nodal level in UWS patients compared to in the MCS patients.

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Functional cortico-subcortical reorganization after complete hemispheric disconnection for intractable epilepsy

10.1101/707539 ◽

2019 ◽

Author(s):

Thomas Blauwblomme ◽

Athena Demertzi ◽

Jean-Marc Tacchela ◽

Ludovic Fillon ◽

Marie Bourgeois ◽

...

Keyword(s):

Functional Connectivity ◽

Right Hemisphere ◽

Intractable Epilepsy ◽

Minimally Conscious State ◽

Conscious State ◽

Subcortical Structures ◽

Drug Resistant Epilepsy ◽

Classification Probability ◽

The Right ◽

Minimally Conscious

AbstractHemispherotomy is a treatment for drug-resistant epilepsy with the whole hemisphere involved in seizure onset. As recovery mechanisms are still debated, we characterize functional reorganization with multimodal MRI in two children operated on the right hemisphere (RH). We found that interhemispheric functional connectivity was abolished in both patients. The healthy left hemispheres (LH) displayed focal hyperperfusion in motor and limbic areas, and preserved network-level organization. The disconnected RHs were hypoperfused despite sustained network-level organization. Functional connectivity was increased in the left thalamo-cortical loop and between the cerebelli. The classification probability of the RH corresponding to a minimally conscious state was smaller than for the LH. We conclude that after hemispherotomy, neurological rehabilitation is sustained by cortical disinhibition and reinforcement of connectivity driven by subcortical structures in the remaining hemisphere. Our results highlight the effect of vascularization on functional connectivity and raise inquiries about the conscious state of the isolated hemisphere.

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Disrupted Pallido-Thalamo-Cortical Functional Connectivity in Chronic Disorders of Consciousness

Brain Sciences ◽

10.3390/brainsci11030356 ◽

2021 ◽

Vol 11 (3) ◽

pp. 356

Author(s):

Anna Sontheimer ◽

Bénédicte Pontier ◽

Béatrice Claise ◽

Carine Chassain ◽

Jérôme Coste ◽

...

Keyword(s):

Functional Connectivity ◽

Minimally Conscious State ◽

Brain Structures ◽

Conscious State ◽

Disorders Of Consciousness ◽

Subcortical Structures ◽

Cortical Networks ◽

Chronic Disorders ◽

Minimally Conscious ◽

Chronic Disorders Of Consciousness

Chronic disorders of consciousness (DOC) encompass unresponsive wakefulness syndrome and minimally conscious state. Their anatomo-functional correlates are not clearly defined yet, although impairments of functional cortical networks have been reported, as well as the implication of the thalamus and deep brain structures. However, the pallidal functional connectivity with the thalamus and the cortical networks has not been studied so far. Using resting-state functional MRI, we conducted a functional connectivity study between the pallidum, the thalamus and the cortical networks in 13 patients with chronic DOC and 19 healthy subjects. We observed in chronic DOC patients that the thalami were no longer connected to the cortical networks, nor to the pallidums. Concerning the functional connectivity of pallidums, we reported an abolition of the negative correlation with the default mode network, and of the positive correlation with the salience network. The disrupted functional connectivity observed in chronic DOC patients between subcortical structures and cortical networks could be related to the mesocircuit model. A better understanding of the DOC underlying physiopathology could provide food for thought for future therapeutic proposals.

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Structural and functional connectivity of the ascending arousal network for prediction of outcome in patients with acute disorders of consciousness

Scientific Reports ◽

10.1038/s41598-021-98506-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Cesar O. Enciso-Olivera ◽

Edgar G. Ordóñez-Rubiano ◽

Rosángela Casanova-Libreros ◽

Diana Rivera ◽

Carol J. Zarate-Ardila ◽

...

Keyword(s):

Functional Connectivity ◽

Diffusion Tensor ◽

Cardiopulmonary Arrest ◽

Univariate Analysis ◽

Minimally Conscious State ◽

Predictive Biomarkers ◽

Conscious State ◽

Blood Oxygen Level Dependent ◽

Imaging Biomarkers ◽

Minimally Conscious

AbstractTo determine the role of early acquisition of blood oxygen level-dependent (BOLD) signals and diffusion tensor imaging (DTI) for analysis of the connectivity of the ascending arousal network (AAN) in predicting neurological outcomes after acute traumatic brain injury (TBI), cardiopulmonary arrest (CPA), or stroke. A prospective analysis of 50 comatose patients was performed during their ICU stay. Image processing was conducted to assess structural and functional connectivity of the AAN. Outcomes were evaluated after 3 and 6 months. Nineteen patients (38%) had stroke, 18 (36%) CPA, and 13 (26%) TBI. Twenty-three patients were comatose (44%), 11 were in a minimally conscious state (20%), and 16 had unresponsive wakefulness syndrome (32%). Univariate analysis demonstrated that measurements of diffusivity, functional connectivity, and numbers of fibers in the gray matter, white matter, whole brain, midbrain reticular formation, and pontis oralis nucleus may serve as predictive biomarkers of outcome depending on the diagnosis. Multivariate analysis demonstrated a correlation of the predicted value and the real outcome for each separate diagnosis and for all the etiologies together. Findings suggest that the above imaging biomarkers may have a predictive role for the outcome of comatose patients after acute TBI, CPA, or stroke.

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Disruption in structural-functional network repertoire and time resolved subcortical-frontoparietal connectivity in disorders of consciousness

10.1101/2021.12.10.472068 ◽

2021 ◽

Author(s):

Rajanikant Panda ◽

Aurore Thibaut ◽

Ane Lopez-Gonzalez ◽

Anira Escrichs ◽

Mohamed Ali Bahri ◽

...

Keyword(s):

Functional Connectivity ◽

Minimally Conscious State ◽

Underlying Mechanism ◽

Conscious State ◽

Functional Network ◽

Time Resolved ◽

Potential Marker ◽

Network States ◽

Minimally Conscious ◽

Recovery Of Consciousness

Understanding recovery of consciousness and elucidating its underlying mechanism is believed to be crucial in the field of basic neuroscience and medicine. Ideas such as the global neuronal workspace and the mesocircuit theory hypothesize that failure of recovery in conscious states coincide with loss of connectivity between subcortical and frontoparietal areas, a loss of the repertoire of functional networks states and metastable brain activation. We adopted a time-resolved functional connectivity framework to explore these ideas and assessed the repertoire of functional network states as a potential marker of consciousness and its potential ability to tell apart patients in the unresponsive wakefulness syndrome (UWS) and minimally conscious state (MCS). In addition, prediction of these functional network states by underlying hidden spatial patterns in the anatomical network, i.e. so-called eigenmodes, were supplemented as potential markers. By analysing time-resolved functional connectivity from fMRI data, we demonstrated a reduction of metastability and functional network repertoire in UWS compared to MCS patients. This was expressed in terms of diminished dwell times and loss of nonstationarity in the default mode network and fronto-parietal subcortical network in UWS compared to MCS patients. We further demonstrated that these findings co-occurred with a loss of dynamic interplay between structural eigenmodes and emerging time-resolved functional connectivity in UWS. These results are, amongst others, in support of the global neuronal workspace theory and the mesocircuit hypothesis, underpinning the role of time-resolved thalamo-cortical connections and metastability in the recovery of consciousness.

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Dissecting the coma spectrum using Bayesian classification

10.1101/832824 ◽

2019 ◽

Author(s):

Martin J. Dietz ◽

Bochra Zareini ◽

Risto Näätänen ◽

Morten Overgaard

Keyword(s):

Vegetative State ◽

Minimally Conscious State ◽

Conscious State ◽

Small Sample ◽

Control Group ◽

Disorder Of Consciousness ◽

Clinical Disorder ◽

Electrophysiological Responses ◽

Alternative Hypotheses ◽

Minimally Conscious

AbstractA patient who does not regain full consciousness after coma is typically classified as being in a vegetative state or a minimally conscious state. While the key determinants in this differential diagnosis are inferred uniquely from the observed behaviour of the patient, nothing can, in principle, be known about the patient’s awareness of the external world. Given the subjective nature of current diagnostic practice, the quest for neurophysiological markers that could complement the nosology of the coma spectrum is becoming more and more acute. We here present a method for the classification of patients based on electrophysiological responses using Bayesian model selection. We validate the method in a sample of fourteen patients with a clinical disorder of consciousness (DoC) and a control group of fifteen healthy adults. By formally comparing a set of alternative hypotheses about the nosology of DoC patients, the results of our validation study show that we can disambiguate between alternative models of how patients are classified. Although limited to this small sample of patients, this allowed us to assert that there is no evidence of subgroups when looking at the MMN response in this sample of patients. We believe that the methods presented in this article are an important contribution to testing alternative hypotheses about how patients are grouped at both the group and single-patient level and propose that electrophysiological responses, recorded invasively or non-invasively, may be informative for the nosology of the coma spectrum on a par with behavioural diagnosis.

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Selegiline in Patients With Disorder of Consciousness: An Open Pilot Study

Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques ◽

10.1017/cjn.2018.315 ◽

2018 ◽

Vol 45 (6) ◽

pp. 688-691

Author(s):

Orsola Masotta ◽

Luigi Trojano ◽

Vincenzo Loreto ◽

Pasquale Moretta ◽

Anna Estraneo

Keyword(s):

Vegetative State ◽

Minimally Conscious State ◽

Conscious State ◽

Clinical Effects ◽

Disorder Of Consciousness ◽

Brain Injured ◽

Minimally Conscious ◽

Injured Patients ◽

Open Pilot

AbstractThis open study investigated the clinical effects of 10-week selegiline administration in six patients in vegetative state and in four patients in a minimally conscious state, at least 6 months after onset. Clinical outcome was assessed by Coma Recovery Scale-Revised once a week during selegiline administration and 1 month later. Three patients stopped treatment because of possible side effects. After treatment and at 1 month of follow-up, four patients showed improvements in clinical diagnosis, and three patients showed an increase in arousal level only. Selegiline might represent a relatively safe option to enhance arousal and promote recovery in brain-injured patients with disorders of consciousness.

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Results of a prospective study (CATS) on the effects of thalamic stimulation in minimally conscious and vegetative state patients

Journal of Neurosurgery ◽

10.3171/2015.7.jns15700 ◽

2016 ◽

Vol 125 (4) ◽

pp. 972-981 ◽

Cited By ~ 29

Author(s):

Lorenzo Magrassi ◽

Giorgio Maggioni ◽

Caterina Pistarini ◽

Carol Di Perri ◽

Stefano Bastianello ◽

...

Keyword(s):

Vegetative State ◽

Minimally Conscious State ◽

Conscious State ◽

Cortical Activation ◽

Disorder Of Consciousness ◽

Chronic Stimulation ◽

Thalamic Stimulation ◽

Minimally Conscious ◽

Deep Brain ◽

Stimulation Of

OBJECTIVE Deep brain stimulation of the thalamus was introduced more than 40 years ago with the objective of improving the performance and attention of patients in a vegetative or minimally conscious state. Here, the authors report the results of the Cortical Activation by Thalamic Stimulation (CATS) study, a prospective multiinstitutional study on the effects of bilateral chronic stimulation of the anterior intralaminar thalamic nuclei and adjacent paralaminar regions in patients affected by a disorder of consciousness. METHODS The authors evaluated the clinical and radiological data of 29 patients in a vegetative state (unresponsive wakefulness syndrome) and 11 in a minimally conscious state that lasted for more than 6 months. Of these patients, 5 were selected for bilateral stereotactic implantation of deep brain stimulating electrodes into their thalamus. A definitive consensus for surgery was obtained for 3 of the selected patients. All 3 patients (2 in a vegetative state and 1 in a minimally conscious state) underwent implantation of bilateral thalamic electrodes and submitted to chronic stimulation for a minimum of 18 months and a maximum of 48 months. RESULTS In each case, there was an increase in desynchronization and the power spectrum of electroencephalograms, and improvement in the Coma Recovery Scale–Revised scores was found. Furthermore, the severity of limb spasticity and the number and severity of pathological movements were reduced. However, none of these patients returned to a fully conscious state. CONCLUSIONS Despite the limited number of patients studied, the authors confirmed that bilateral thalamic stimulation can improve the clinical status of patients affected by a disorder of consciousness, even though this stimulation did not induce persistent, clinically evident conscious behavior in the patients. Clinical trial registration no.: NCT01027572 (ClinicalTrials.gov)

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