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1.  Measuring consciousness in coma and related states 
World Journal of Radiology  2014;6(8):589-597.
Consciousness is a prismatic and ambiguous concept that still eludes any universal definition. Severe acquired brain injuries resulting in a disorder of consciousness (DOC) provide a model from which insights into consciousness can be drawn. A number of recent studies highlight the difficulty in making a diagnosis in patients with DOC based only on behavioral assessments. Here we aim to provide an overview of how neuroimaging techniques can help assess patients with DOC. Such techniques are expected to facilitate a more accurate understanding of brain function in states of unconsciousness and to improve the evaluation of the patient’s cognitive abilities by providing both diagnostic and prognostic indicators.
doi:10.4329/wjr.v6.i8.589
PMCID: PMC4147439  PMID: 25170396
Disorders of consciousness; Neuroimaging; Magnetic resonance imaging; Transcranial magnetic stimulation/electroencephalography; Minimally conscious state; Vegetative state/unresponsive wakefulness syndrome
2.  Biased binomial assessment of cross-validated estimation of classification accuracies illustrated in diagnosis predictions 
NeuroImage : Clinical  2014;4:687-694.
Multivariate classification is used in neuroimaging studies to infer brain activation or in medical applications to infer diagnosis. Their results are often assessed through either a binomial or a permutation test. Here, we simulated classification results of generated random data to assess the influence of the cross-validation scheme on the significance of results. Distributions built from classification of random data with cross-validation did not follow the binomial distribution. The binomial test is therefore not adapted. On the contrary, the permutation test was unaffected by the cross-validation scheme. The influence of the cross-validation was further illustrated on real-data from a brain–computer interface experiment in patients with disorders of consciousness and from an fMRI study on patients with Parkinson disease. Three out of 16 patients with disorders of consciousness had significant accuracy on binomial testing, but only one showed significant accuracy using permutation testing. In the fMRI experiment, the mental imagery of gait could discriminate significantly between idiopathic Parkinson's disease patients and healthy subjects according to the permutation test but not according to the binomial test. Hence, binomial testing could lead to biased estimation of significance and false positive or negative results. In our view, permutation testing is thus recommended for clinical application of classification with cross-validation.
Highlights
•We assess the influence of cross-validation on significance of classification results.•Classification of random data did not follow binomial distribution.•The permutation test was unaffected by the cross-validation scheme.•Results are illustrated on real-data from BCI and fMRI studies.
doi:10.1016/j.nicl.2014.04.004
PMCID: PMC4053638  PMID: 24936420
classification; cross-validation; binomial; permutation test
3.  Diffusion tensor imaging and white matter abnormalities in patients with disorders of consciousness 
Progress in neuroimaging has yielded new powerful tools which, potentially, can be applied to clinical populations, improve the diagnosis of neurological disorders and predict outcome. At present, the diagnosis of consciousness disorders is limited to subjective assessment and objective measurements of behavior, with an emerging role for neuroimaging techniques. In this review we focus on white matter alterations measured using Diffusion Tensor Imaging on patients with consciousness disorders, examining the most common diffusion imaging acquisition protocols and considering the main issues related to diffusion imaging analyses. We conclude by considering some of the remaining challenges to overcome, the existing knowledge gaps and the potential role of neuroimaging in understanding the pathogenesis and clinical features of disorders of consciousness.
doi:10.3389/fnhum.2014.01028
PMCID: PMC4285098  PMID: 25610388
coma; brain; diffusion tensor imaging; consciousness; tractography
4.  Altered network properties of the fronto-parietal network and the thalamus in impaired consciousness☆ 
NeuroImage : Clinical  2013;4:240-248.
Recovery of consciousness has been associated with connectivity in the frontal cortex and parietal regions modulated by the thalamus. To examine this model and to relate alterations to deficits in cognitive functioning and conscious processing, we investigated topological network properties in patients with chronic disorders of consciousness recovered from coma.
Resting state fMRI data of 34 patients with unresponsive wakefulness syndrome and 25 in minimally conscious state were compared to 28 healthy controls. We investigated global and local network characteristics. Additionally, behavioral measures were correlated with the local metrics of 28 regions within the fronto-parietal network and the thalamus.
In chronic disorders of consciousness, modularity at the global level was reduced suggesting a disturbance in the optimal balance between segregation and integration. Moreover, network properties were altered in several regions which are associated with conscious processing (particularly, in medial parietal, and frontal regions, as well as in the thalamus). Between minimally conscious and unconscious patients the local efficiency of medial parietal regions differed. Alterations in the thalamus were particularly evident in non-conscious patients. Most of the regions affected in patients with impaired consciousness belong to the so-called ‘rich club’ of highly interconnected central nodes. Disturbances in their topological characteristics have severe impact on information integration and are reflected in deficits in cognitive functioning probably leading to a total breakdown of consciousness.
Highlights
•We investigated network properties in patients with a disorder of consciousness.•Patients showed reduced global modularity.•Alterations in regions of the rich club were related to impaired consciousness.•These alterations have severe impact on information integration and segregation.•Disturbances in overall integration may lead to breakdown of consciousness.
doi:10.1016/j.nicl.2013.12.005
PMCID: PMC3895618  PMID: 24455474
DOC, disorders of consciousness; ACC, anterior cingulate cortex; PCC, posterior cingulate cortex; MCS, minimally conscious state; VS/UWS, vegetative state/unresponsive wakefulness syndrome; Consciousness; Vegetative state; Network; Graph theory; Connectivity; Small world
5.  Changes in Effective Connectivity by Propofol Sedation 
PLoS ONE  2013;8(8):e71370.
Mechanisms of propofol-induced loss of consciousness remain poorly understood. Recent fMRI studies have shown decreases in functional connectivity during unconsciousness induced by this anesthetic agent. Functional connectivity does not provide information of directional changes in the dynamics observed during unconsciousness. The aim of the present study was to investigate, in healthy humans during an auditory task, the changes in effective connectivity resulting from propofol induced loss of consciousness. We used Dynamic Causal Modeling for fMRI (fMRI-DCM) to assess how causal connectivity is influenced by the anesthetic agent in the auditory system. Our results suggest that the dynamic observed in the auditory system during unconsciousness induced by propofol, can result in a mixture of two effects: a local inhibitory connectivity increase and a decrease in the effective connectivity in sensory cortices.
doi:10.1371/journal.pone.0071370
PMCID: PMC3747149  PMID: 23977030
6.  Resting State Networks and Consciousness 
In order to better understand the functional contribution of resting state activity to conscious cognition, we aimed to review increases and decreases in functional magnetic resonance imaging (fMRI) functional connectivity under physiological (sleep), pharmacological (anesthesia), and pathological altered states of consciousness, such as brain death, coma, vegetative state/unresponsive wakefulness syndrome, and minimally conscious state. The reviewed resting state networks were the DMN, left and right executive control, salience, sensorimotor, auditory, and visual networks. We highlight some methodological issues concerning resting state analyses in severely injured brains mainly in terms of hypothesis-driven seed-based correlation analysis and data-driven independent components analysis approaches. Finally, we attempt to contextualize our discussion within theoretical frameworks of conscious processes. We think that this “lesion” approach allows us to better determine the necessary conditions under which normal conscious cognition takes place. At the clinical level, we acknowledge the technical merits of the resting state paradigm. Indeed, fast and easy acquisitions are preferable to activation paradigms in clinical populations. Finally, we emphasize the need to validate the diagnostic and prognostic value of fMRI resting state measurements in non-communicating brain damaged patients.
doi:10.3389/fpsyg.2012.00295
PMCID: PMC3427917  PMID: 22969735
default mode network; resting state networks; consciousness; sleep; anesthesia; coma; hypnosis
7.  Resting-state EEG study of comatose patients: a connectivity and frequency analysis to find differences between vegetative and minimally conscious states 
Functional Neurology  2012;27(1):41-47.
Summary
The aim of this study was to look for differences in the power spectra and in EEG connectivity measures between patients in the vegetative state (VS/UWS) and patients in the minimally conscious state (MCS).
The EEG of 31 patients was recorded and analyzed. Power spectra were obtained using modern multitaper methods. Three connectivity measures (coherence, the imaginary part of coherency and the phase lag index) were computed. Of the 31 patients, 21 were diagnosed as MCS and 10 as VS/UWS using the Coma Recovery Scale-Revised (CRS-R). EEG power spectra revealed differences between the two conditions. The VS/UWS patients showed increased delta power but decreased alpha power compared with the MCS patients. Connectivity measures were correlated with the CRS-R diagnosis; patients in the VS/UWS had significantly lower connectivity than MCS patients in the theta and alpha bands.
Standard EEG recorded in clinical conditions could be used as a tool to help the clinician in the diagnosis of disorders of consciousness.
PMCID: PMC3812750  PMID: 22687166
connectivity; disorders of consciousness; imaginary part of coherency; minimally conscious state; phase lag index; vegetative state
8.  Reduction in Inter-Hemispheric Connectivity in Disorders of Consciousness 
PLoS ONE  2012;7(5):e37238.
Clinical diagnosis of disorders of consciousness (DOC) caused by brain injury poses great challenges since patients are often behaviorally unresponsive. A promising new approach towards objective DOC diagnosis may be offered by the analysis of ultra-slow (<0.1 Hz) spontaneous brain activity fluctuations measured with functional magnetic resonance imaging (fMRI) during the resting-state. Previous work has shown reduced functional connectivity within the “default network”, a subset of regions known to be deactivated during engaging tasks, which correlated with the degree of consciousness impairment. However, it remains unclear whether the breakdown of connectivity is restricted to the “default network”, and to what degree changes in functional connectivity can be observed at the single subject level. Here, we analyzed resting-state inter-hemispheric connectivity in three homotopic regions of interest, which could reliably be identified based on distinct anatomical landmarks, and were part of the “Extrinsic” (externally oriented, task positive) network (pre- and postcentral gyrus, and intraparietal sulcus). Resting-state fMRI data were acquired for a group of 11 healthy subjects and 8 DOC patients. At the group level, our results indicate decreased inter-hemispheric functional connectivity in subjects with impaired awareness as compared to subjects with intact awareness. Individual connectivity scores significantly correlated with the degree of consciousness. Furthermore, a single-case statistic indicated a significant deviation from the healthy sample in 5/8 patients. Importantly, of the three patients whose connectivity indices were comparable to the healthy sample, one was diagnosed as locked-in. Taken together, our results further highlight the clinical potential of resting-state connectivity analysis and might guide the way towards a connectivity measure complementing existing DOC diagnosis.
doi:10.1371/journal.pone.0037238
PMCID: PMC3358327  PMID: 22629375
9.  Auditory Resting-State Network Connectivity in Tinnitus: A Functional MRI Study 
PLoS ONE  2012;7(5):e36222.
The underlying functional neuroanatomy of tinnitus remains poorly understood. Few studies have focused on functional cerebral connectivity changes in tinnitus patients. The aim of this study was to test if functional MRI “resting-state” connectivity patterns in auditory network differ between tinnitus patients and normal controls. Thirteen chronic tinnitus subjects and fifteen age-matched healthy controls were studied on a 3 tesla MRI. Connectivity was investigated using independent component analysis and an automated component selection approach taking into account the spatial and temporal properties of each component. Connectivity in extra-auditory regions such as brainstem, basal ganglia/NAc, cerebellum, parahippocampal, right prefrontal, parietal, and sensorimotor areas was found to be increased in tinnitus subjects. The right primary auditory cortex, left prefrontal, left fusiform gyrus, and bilateral occipital regions showed a decreased connectivity in tinnitus. These results show that there is a modification of cortical and subcortical functional connectivity in tinnitus encompassing attentional, mnemonic, and emotional networks. Our data corroborate the hypothesized implication of non-auditory regions in tinnitus physiopathology and suggest that various regions of the brain seem involved in the persistent awareness of the phenomenon as well as in the development of the associated distress leading to disabling chronic tinnitus.
doi:10.1371/journal.pone.0036222
PMCID: PMC3344851  PMID: 22574141
10.  Tuberculosis Screening before Anti–Hepatitis C Virus Therapy in Prisons 
Emerging Infectious Diseases  2012;18(4):689-691.
doi:10.3201/eid1804.111016
PMCID: PMC3309670  PMID: 22469015
tuberculosis and other mycobacteria; purified protein derivative; PPD; hepatitis C virus; HCV; prisons; pegylated interferon; viruses
11.  Post-anoxic vegetative state: imaging and prognostic perspectives  
Functional Neurology  2011;26(1): 45 - 50 .
Summary
Prognostic determination of patients in coma after resuscitation from cardiac arrest is a common and difficult requirement with significant ethical, social and legal implications.
We set out to seek markers that can be used for the early detection of patients with a poor prognosis, so as to reduce uncertainty over treatment and non-treatment decisions, and to improve relationships with families. We reviewed the medical literature from 1991 to 2010, using key words such as post-anoxic coma, post-anoxic vegetative state, vegetative state prognosis, recovery after cardiac arrest.
Neurological examination, electrophysiology, imaging, and biochemical markers are all useful tools for estimating patients’ chances of recovery from cardiac arrest.
It seems unlikely that any single test will prove to have 100% predictive value for outcome; but the combination of various prognostic markers, as shown in some articles, could increase the reliability of outcome prediction. However, further research is needed.
PMCID: PMC3814506  PMID: 21693088
anoxic brain injury ;  prognostic factors ;  vegetative state
12.  Resting state activity in patients with disorders of consciousness  
Functional Neurology  2011;26(1): 37 - 43 .
Summary
Recent advances in the study of spontaneous brain activity have demonstrated activity patterns that emerge with no task performance or sensory stimulation; these discoveries hold promise for the study of higher-order associative network functionality. Additionally, such advances are argued to be relevant in pathological states, such as disorders of consciousness (DOC), i.e., coma, vegetative and minimally conscious states. Recent studies on resting state activity in DOC, measured with functional magnetic resonance imaging (fMRI) techniques, show that functional connectivity is disrupted in the task-negative or the default mode network. However, the two main approaches employed in the analysis of resting state functional connectivity data (i.e., hypothesis-driven seed-voxel and data-driven independent component analysis) present multiple methodological difficulties, especially in non-collaborative DOC patients. Improvements in motion artifact removal and spatial normalization are needed before fMRI resting state data can be used as proper biomarkers in severe brain injury. However, we anticipate that such developments will boost clinical resting state fMRI studies, allowing for easy and fast acquisitions and ultimately improve the diagnosis and prognosis in the absence of DOC patients’ active collaboration in data acquisition.
PMCID: PMC3814510  PMID: 21693087
coma ;  consciousness ;  default network ;  functional magnetic resonance imaging ;  resting state ;  spontaneous activity
13.  Neural Plasticity Lessons from Disorders of Consciousness 
Communication and intentional behavior are supported by the brain's integrity at a structural and a functional level. When widespread loss of cerebral connectivity is brought about as a result of a severe brain injury, in many cases patients are not capable of conscious interactive behavior and are said to suffer from disorders of consciousness (e.g., coma, vegetative state/unresponsive wakefulness syndrome, minimally conscious states). This lesion paradigm has offered not only clinical insights, as how to improve diagnosis, prognosis, and treatment, but also put forward scientific opportunities to study the brain's plastic abilities. We here review interventional and observational studies performed in severely brain-injured patients with regards to recovery of consciousness. The study of the recovered conscious brain (spontaneous and/or after surgical or pharmacologic interventions), suggests a link between some specific brain areas and the capacity of the brain to sustain conscious experience, challenging at the same time the notion of fixed temporal boundaries in rehabilitative processes. Altered functional connectivity, cerebral structural reorganization as well as behavioral amelioration after invasive treatments will be discussed as the main indices for plasticity in these challenging patients. The study of patients with chronic disorders of consciousness may, thus, provide further insights not only at a clinical level (i.e., medical management and rehabilitation) but also from a scientific-theoretical perspective (i.e., the brain's plastic abilities and the pursuit of the neural correlate of consciousness).
doi:10.3389/fpsyg.2010.00245
PMCID: PMC3153849  PMID: 21833298
neural plasticity; recovery; unresponsive wakefulness syndrome; vegetative state; minimally conscious state; consciousness; functional neuroimaging; deep brain stimulation
14.  Default network connectivity reflects the level of consciousness in non-communicative brain-damaged patients 
Brain  2009;133(1):161-171.
The ‘default network’ is defined as a set of areas, encompassing posterior-cingulate/precuneus, anterior cingulate/mesiofrontal cortex and temporo-parietal junctions, that show more activity at rest than during attention-demanding tasks. Recent studies have shown that it is possible to reliably identify this network in the absence of any task, by resting state functional magnetic resonance imaging connectivity analyses in healthy volunteers. However, the functional significance of these spontaneous brain activity fluctuations remains unclear. The aim of this study was to test if the integrity of this resting-state connectivity pattern in the default network would differ in different pathological alterations of consciousness. Fourteen non-communicative brain-damaged patients and 14 healthy controls participated in the study. Connectivity was investigated using probabilistic independent component analysis, and an automated template-matching component selection approach. Connectivity in all default network areas was found to be negatively correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative then coma patients. Furthermore, precuneus connectivity was found to be significantly stronger in minimally conscious patients as compared with unconscious patients. Locked-in syndrome patient’s default network connectivity was not significantly different from controls. Our results show that default network connectivity is decreased in severely brain-damaged patients, in proportion to their degree of consciousness impairment. Future prospective studies in a larger patient population are needed in order to evaluate the prognostic value of the presented methodology.
doi:10.1093/brain/awp313
PMCID: PMC2801329  PMID: 20034928
Default mode; fMRI; coma; vegetative state; minimally conscious state
15.  Brain Connectivity in Pathological and Pharmacological Coma 
Recent studies in patients with disorders of consciousness (DOC) tend to support the view that awareness is not related to activity in a single brain region but to thalamo-cortical connectivity in the frontoparietal network. Functional neuroimaging studies have shown preserved albeit disconnected low-level cortical activation in response to external stimulation in patients in a “vegetative state” or unresponsive wakefulness syndrome. While activation of these “primary” sensory cortices does not necessarily reflect conscious awareness, activation in higher-order associative cortices in minimally conscious state patients seems to herald some residual perceptual awareness. PET studies have identified a metabolic dysfunction in a widespread frontoparietal “global neuronal workspace” in DOC patients including the midline default mode network (“intrinsic” system) and the lateral frontoparietal cortices or “extrinsic system.” Recent studies have investigated the relation of awareness to the functional connectivity within intrinsic and extrinsic networks, and with the thalami in both pathological and pharmacological coma. In brain damaged patients, connectivity in all default network areas was found to be non-linearly correlated with the degree of clinical consciousness impairment, ranging from healthy controls and locked-in syndrome to minimally conscious, vegetative, coma, and brain dead patients. Anesthesia-induced loss of consciousness was also shown to correlate with a global decrease in cortico-cortical and thalamo-cortical connectivity in both intrinsic and extrinsic networks, but not in auditory, or visual networks. In anesthesia, unconsciousness was also associated with a loss of cross-modal interactions between networks. These results suggest that conscious awareness critically depends on the functional integrity of thalamo-cortical and cortico-cortical frontoparietal connectivity within and between “intrinsic” and “extrinsic” brain networks.
doi:10.3389/fnsys.2010.00160
PMCID: PMC3010745  PMID: 21191476
disorders of consciousness; connectivity; anesthesia; fMRI; PET; coma; default mode network; consciousness

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