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Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States


Abstract and Figures

Background: Persistent vegetative states (PVS) and locked-in syndrome (LIS) are well differentiated disorders of consciousness that can be reached after a localized brain injury in the brainstem. The relations of the lesion topography with the impairment in the whole-brain architecture and functional disconnections are poorly understood. Methods: Two patients (PVS and LIS) and 20 age-matched healthy volunteers were evaluated using diffusion tensor imaging (DTI). Anatomical network was modeled as a graph whose nodes are represented by 71 brain regions. Inter-region connections were quantified through Anatomical Connection Strength (ACS) and Density (ACD). Complex networks properties such as local and global efficiency and vulnerability were studied. Mass univariate testing was performed at every connection using network based statistic approach. Results: LIS patients’ network showed significant differences from controls in the brainstem-thalamus-frontal cortex circuitry, while PVS patients showed a widespread disruption of anatomical connectivity in both hemispheres. Both patients showed a reorganization of network attributes, with decreased global and local efficiency, significantly more pronounced in PVS. Conclusions: Our results suggest that DTI-based network connectivity combined with graph theory is useful to study the long-range effect of confined injuries and the relationship to the degree of consciousness impairment, underlying PVS and LIS.
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Funct Neurol Rehabil Ergon 2013;3(2-3):319-328 ISSN: 2156-941X
© Nova Science Publishers, Inc.
Rafael Rodriguez-Rojas
1,2, Karla Batista1, Yasser Iturria3,
Calixto Machado4, Gerry Leisman5,6,7,8, Robert Melillo5,6,
Mauricio Chinchilla9, Philip DeFina8, Maylen Carballo1,
and Juan M. Morales1
1Brain Imaging Group, International Center for Neurological Restoration, Havana, Cuba
2The Abdus Salam International Centre for Theoretical Physics, Trieste, Italy
3Neuroimaging Department, Cuban Neuroscience Center, La Habana, Cuba
4Institute of Neurology and Neurosurgery, Department of Clinical Neurophysiology,
Havana, Cuba
5F.R. Carrick Institute for Clinical Ergonomics,
Rehabilitation and Applied Neuroscience, Garden City, NY USA
6The National Institute for Brain and Rehabilitation Sciences, Nazareth, Israel
7Biomedical Engineering, ORT-Braude College of Engineering, Karmiel, Israel
8Neuroscience, University of the Medical Sciences of Havana, Faculty Manuel Fajardo
9Neurology Department, Hermanos Ameijeiras Hospital, Havana, Cuba,
10International Brain Research Foundation, New York, USA
Background: Persistent vegetative states (PVS) and locked-in syndrome (LIS) are well-
differentiated disorders of consciousness that can be reached after a localized brain injury in the
brainstem. The relations of the lesion topography with the impairment in the whole-brain
architecture and functional disconnections are poorly understood.
Methods: Two patients (PVS and LIS) and 20 age-matched healthy volunteers were evaluated
using diffusion tensor imaging (DTI). Anatomical network was modeled as a graph whose nodes
are represented by 71 brain regions. Inter-region connections were quantified through Anatomical
Connection Strength (ACS) and Density (ACD). Complex networks properties such as local and
global efficiency and vulnerability were studied. Mass univariate testing was performed at every
connection using network based statistic approach.
Results: LIS patients’ network showed significant differences from controls in the brainstem-
thalamus-frontal cortex circuitry, while PVS patients showed a widespread disruption of
anatomical connectivity in both hemispheres. Both patients showed a reorganization of network
attributes, with decreased global and local efficiency, significantly more pronounced in PVS.
Correspondence: Dr. Rafael Rodriguez-Rojas, International Center for Neurological Restoration, Ave 25 # 15805, CP 11300,
Havana, Cuba. E-mail:
Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
Conclusions: Our results suggest that DTI-based network connectivity combined with graph
theory is useful to study the long-range effect of confined injuries and the relationship to the
degree of consciousness impairment, underlying PVS and LIS.
Keywords: Persistent vegetative state, locked-in syndrome, consciousness, functional disconnection,
diffusion tensor imaging, graph theory
The brainstem plays a key role in cerebral cortex activation as the origin of the ascending reticular
activating system. Severe conditions can arise as a consequence of a traumatic or a non-traumatic
injury in this area. Characteristic clinical symptomatology includes well-differentiated disorders of
consciousness (DOC) such as “vegetative states” (VS) and “locked-in syndrome” (LIS). The VS
encompasses a spectrum of patients who have emerged from coma to exhibit basic orienting response
but show no indication of awareness [1,2]. By contrast, LIS is marked by tetraplegia and anarthria but
consciousness and somatosensory perception are preserved [3,4]. Because patients with LIS show
paralysis of all voluntary motor function except eye movements, they may be mistakenly thought to
be in VS. Behavioral deficits in these patients can be as severe as those produced by diffuse damage to
the cortical areas underlying high-level processing, indicative of awareness. The specific contribution
of individual regions to the clinical performance is determined by their topological integration into
brain networks [2,5]. This highlights the need to delineate the connectivity pattern in specific patients
in order to elucidate how each connection and sub-network is anatomically related to the injured area
and makes specific contribution to the level of consciousness.
Advancements in neuroimaging techniques, such as diffusion tensor imaging (DTI), offer the
potential to probe anatomical connectivity between remote neuronal populations. Recent studies have
suggested that structural networks of the human brain can be characterized by using graph theoretical
approaches [for review, see Bullmore and Sporns [6] and He and Evans [7]. Even though DTI has
provided unique insights on the underlying brain circuitry accounting for the presence of
consciousness and its alterations [5], the relationship of the network topology and efficiency metrics
with specific clinical states such as VS and LIS remains unclear.
On the other hand, recent studies in patients with DOC using functional MRI (fMRI) have shown
impaired connectivity in the thalamo-cortical and fronto-parietal networks, possibly reflecting
interruptions of higher-order processes [8,9]. However, these studies do not provide information about
neuroanatomic connectivity between different network nodes. Furthermore, the complexities of the
association between brain structure and function are not well understood.
To our knowledge, this work introduces for the first time, the use of graph theoretical approaches
and DTI to differentiate the topological organization of white matter network in patients in VS and
with LIS. In order to identify the characteristics properties of injured networks in comparison with
healthy architectures we used network-based statistics. In this study, we therefore sought to suggest
essential differences in reduced global network efficiency and altered nodal efficiency between these
The Ethics Committee of the Institute of Neurology and Neurosurgery, Havana approved this
study. Informed written consent was obtained from the patient’s legal representative and from all
healthy volunteers.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States
Patient in VS: We studied a 24-year-old female patient who suffered a meningoencephalitis when
she was 3 years old, and developed a hydrocephalus requiring several ventricular derivations to
peritoneum, pleura and gallbladder. Four years ago, she suffered an acute hydrocephalus due an
obstruction of the ventricular derivation, causing a central and uncal herniation with a compression of
the brainstem. After being in coma during 4 weeks she was diagnosed as been in a persistent
vegetative state (PVS). Magnetic resonance imaging showed destruction of the rostral part of the
pons, the mesencephalon, and both thalami.
Patient with LIS
We studied a 47-year-old male patient who developed an acute stroke of the basilar artery
territory with sudden loss of consciousness. The patient remained in coma for 3 weeks, but afterwards
opened his eyes and showed sleep-wakefulness cycles. He was diagnosed as having been in a PVS
state. Nonetheless, when our group clinically examined him we noted that we were able to establish
communication with him using through coded messages by blinking or vertical eye movements,
indicating answers of YES or NO. We diagnosed him as being in a Locked-in syndrome (LIS). The
patient demonstrated quadriplegia and the inability to speak, but he was undoubtedly conscious and
aware, with no loss of cognitive function. He only preserved vertical eye movements and the blink
responses. MRI showed ischemic lesions of the pons, corresponding to the basilar artery territory.
Twenty healthy subjects (13 male, 11 female, age: 35.0 ± 12.1) were selected from the Cuban
Human Brain Mapping Project database [10]. Volunteers reported no history of psychiatric or
neurological disorders. Those studies were selected so as to coincide with the average age of the
patients and the age of these were within the standard deviation of the controls database.
Image Acquisition and Preprocessing
All images were acquired using a MRI scanner Siemens Symphony 1.5 T (Erlangen, Germany).
Using a standard diffusion gradient direction scheme (twelve diffusion-weighted images and a b=0
image), DW-MRI data were acquired using a single shot EPI sequence. To each subject, two
interleaved sets of 25 slices of 6 mm thickness with a distance factor of 100% were acquired with the
following parameters: b=1200 s/mm2; FOV=256×256 mm2; acquisition matrix=128×128;
corresponding to an ‘in plane’ spatial resolution of 2×2 mm2; TE/TR=160 ms/7000 ms. Two
interleaved sets were necessary because it was impossible to cover the whole head with a good spatial
resolution using a single set due to a pulse sequence limitation (max: 35 slices). Both sets were joined
to form a volume of 50 contiguous slices of 3 mm thickness covering the whole brain for each subject.
The aforementioned acquisition was repeated 5 times to improve signal to noise ratio (SNR). In order
to improve EPI quality, magnitude and phase difference images of a T2 gradient echo field mapping
sequence were acquired with TE=7.71 ms and 12.47 ms. Also, a 3D high-resolution T1-weighted
MPRAGE pulse sequence covering the whole brain was acquired with the following parameters: 160
contiguous slices of 1-mm thickness in sagittal orientation; in plane FOV=256×256 mm2, and matrix
size 256×256 yielding an spatial resolution of 1×1×1 mm3. The echo time, repetition time, and
inversion time were set to TE/TR/TI=3.93 ms/3000 ms/1100 ms with a flip angle FA=15°. Lesion
areas were manually segmented on the MPRAGE images using MRIcron software
( to create binary masks in native space.
Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
Network Definition
The graph framework used here has been widely described in Iturria-Medina et al. [11]. In brief,
the cerebral volume is represented as a non-directed weighted graph G in which nodes N correspond
to anatomically defined regions and arcs  to the connections joining them. In DTI-based graphs,
between-regions connectivity can be reasonably restricted to white matter tracts connecting voxels of
the surfaces of the corresponding anatomical areas. This approach significantly reduces the
computational cost of the procedure.
While definition of the network nodes is consubstantial with graph theory, standard image-
matching algorithms to map atlas to brains are challenged in patients with brain injury. To overcome
this inconvenience, MPRAGE volumes were spatially normalized to the T1-MNI template using the
‘unified segmentation’ approach, available in SPM8 ( [12]. This procedure
combines segmentation, bias correction and spatial normalization in the non-linear deformation
model. Lesioned area was excluded from the calculation using a cost function masking to improve
normalization results. Lesion masks for each patient were created using rough drawings of lesion
boundaries. Atlas was registered with the gray matter volume maps in native space and segmented
into 71 regions, using the anatomically labeled template corresponding to the Jacob Atlas developed
by the Montreal Neurological Institute ( and the IBASPM toolbox
(available at [13]. Thus, the topological properties of
the brain anatomical networks were defined on the basis of the 71x71 binary graph G.
Fiber Tracking and Node-Node Connectivity
Figure 1 shows an overview of the methodology used in this study to identify impaired
connections and compromised sub-networks in patients. An iterative streamline fiber tractography
algorithm is employed for finding the most probable trajectory between each pair of gray matter
regions [11]. Streamlines exceeding 20 mm and below 500 mm in length and a curvature threshold of
±90o were used to generate the connectivity matrix for each subject.
The connectivity between a pair of nodes was quantified by two different anatomical connectivity
measures: Anatomical Connection Strength (ACS) and Anatomical Connection Density (ACD) [11].
ACS is related to the amount of nervous fibers shared by regions Ai and Aj by counting the nodes on
the surfaces involved in the connection:
 (,
)=() (1)
where () quantifies the conditional weight of the arc . On the other hand, ACD is a measure of
the fraction of the surface involved in the connection with respect to the total surface of both areas.
Thus, it can be estimated as the ratio between ACS and the number of nodes Ni and Nj belonging to
the surfaces of Ai and Aj, respectively:
 (,
 (,)
|| (2)
Z transformation was used to provide probability statements about the deviation of the
connectivity measures from the normal values. Z scores of ACD and ACS were calculated by means
of Z = (x – µ)/
, where x represents the value of ACD or ACS in each patient, while µ and
respectively the mean value and the standard deviation of x in the population of normal subjects.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States
Figure 1. I. Streamline fiber tractography; II. Nodes definition using non-linear transformations and IBASPM
toolbox; III. Anatomical network construction; IV. Calculation of network efficiency using graph theory; and V.
Identification of impaired connections using network based statistic.
Graph Analysis
To characterize the effect of the lesions over the efficiency in information exchange in brain
connectional architecture, we estimated the global and local efficiency of network as organizational
attributes of integration and segregation, respectively. For a graph G with N nodes, the global
efficiency can be computed as
 =
()∈ (3)
where dij is the shortest geodesic lengths between pair of nodes i and j. On the other hand, the local
efficiency Eloc is measured as:
 =
∈ (4)
where Eglob(Gi) is the global efficiency of the local subgraphs, neighbors of node i.
In order to identify disconnected subnetworks in the patients, mass univariate testing was
performed at every connection using network based statistic (NBS) approach [14]. Primary t statistic
threshold for each link was set to 3.1 and 5000 permutations test were used to determine the statistical
significance of differences in network parameters.
Fiber tractography localized connectivity disruption at different levels in the brainstem in patients
in VS and with LIS, showing high consistency with lesion’s topology (Figure 2). In VS patients,
lesion in mesencephalon and rostral pons caused a disruption of cortico-spinal tract and cerebral
peduncle, causing a widespread alteration of thalamus-subcortical and cortico-cortical connectivity.
Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
On the other hand, brain injury in LIS is confined to the ventral pons disrupting the cortico-spinal and
spino-thalamic tracts, while cortical connectivity is preserved.
As shown in figure 3, for Cluster, E_glob and E_loc the values of ACD and ACS in VS subject
were lower than the corresponding mean values of control subjects, as expected. On the contrary, a
trend toward increased clustering and local efficiency accompanied by reduced global efficiency was
found for ACD in patients with LIS, but these differences were not significant.
Figure 2. From left to right: anatomical damage, streamline fiber tractography and spatial correlation of
impairments in patients. Upper: Patient in VS showing a widespread disruption in cortical and subcortical
connectivity. Lower: Patient with LIS showing an injury in pontine crossing tracts and preserved cortical
Figure 3. Differences in area under the global network properties curves: clustering index, global efficiency and
local efficiency. The clustering and efficiency index differences between normal controls and patients for
Anatomical Connection Density (ACD) and Anatomical Connection Strength (ACS) descriptors are depicted.
Bars represent the mean of each network property and black lines represent standard deviations in control
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States
Table 1. Z scores of anatomical connectivity measures for both patients. Note that the patient
with LIS shows a (non-significant) tendency to higher local properties than healthy controls
Cluster E_glob E_loc Cluster E_glob E_loc
% Z % Z % Z % Z % Z % Z
PVS -19.2 2.79* -55.2 8.84* -15.1 2.13* -55.5 1.44 -75.4 2.06* -53.8 1.20
LIS 3.5 -0.51 -5.3 0.85 4.4 -0.62 -3.7 0.09 -2.5 0.07 11.4 -0.26
*statistically significant (Z > 2)
The Z score test showed significantly lower (Z > 2) global and local efficiency, as well as
clustering index in ACD network in patient in VS, while ACS network showed significant reduction
only for global efficiency. On the other hand, anatomical connectivity measures showed no
differences in patients with LIS compared to controls (Table 1). Seeing together, these results suggest
that balance between local specialization, provided by Cluster and E_loc, and global integration
indicated by E-glob, has been spoiled in VS while remains essentially intact in LIS.
Figure 4. Nodes and streamline representation of impaired connections in VS (A), and LIS (B). Each node is
depicted as a black circle positioned at its node’s center of gravity. Gray circle is positioned in brainstem where
structural injury is located. Significance of differences was calculated using network-based statistics.
A network based statistical analysis was used to identify particular node pairs that were
abnormally connected in patients. NBS reveals that the architectural network presents anomalous
organization in both patients compared with the corresponding healthy values, but is suggestively
different between them. Streamlines interconnecting each of these node pairs are visualized in Figure
4. A widespread network was found to be significantly impaired in VS patient (p<0.05, corrected)
interconnecting several nodes comprising all cerebral lobes. Only two sub-networks were found to be
significantly impaired in the patient with LIS (p<0.05, corrected), corresponding to the basal ganglia-
thalamus-frontal cortex circuitry.
Rafael Rodriguez-Rojas, Karla Batista, Yasser Iturria et al.
An accurate and reliable assessment of the level and content of consciousness in DOC is critical
for the subsequent management and rehabilitation, as well as legal and ethical decision-making. To
date, the gold standard for diagnosis of the level of consciousness is behavioral. However, the scope
and reliability of available scales, examiner experience and overlapping of impairments in
consciousness limit clinical diagnosis. These concerns may lead to misdiagnosis in patients with LIS,
where cortical functions are preserved but the inability of production of voluntary motor behavior may
resemble patients in VS.
This study provides supports that DTI is a potent tool for dissecting the complex neuroanatomic
substrate of different DOC. Although the result of brain fiber tracking was not necessarily parallel to
the clinical symptoms, essential differences between patients in VS and LIS are evidenced in Figure 4.
Viewed as a network disorder, vegetative state has been found widespread impairment in cortico-
cortical connectivity in addition to the brainstem connections. This result suggests that the loss of
awareness in patients with lesions in the brainstem might be associated with aberrant neuronal
connectivity among widely distributed brain regions, and provide structural evidence for the notion of
VS as a disconnection syndrome. Significant reduction of all structural network attributes in this
pathological condition might be interpreted as a considerable decline in the amount of possible
nervous information that can be exchanged over the brain, and how deficiently it can be managed at
local and global levels.
On the contrary, patient with LIS showed a cortical connectivity pattern that was comparable with
that observed in healthy controls. This is in agreement with previous studies showing a near-to-normal
functional connectivity in LIS [15,16]. Disruption of connections between brainstem, basal ganglia
and frontal motor regions is consistent with quadriplegia, aphonia and quadriplegia and paralysis of
the cranial nerves, while cortical networks supporting consciousness remain intact. Those results are
highly consistent with remarkable functional and cognitive differences between these pathological
states, extensively reported in previous studies [1,3,16-20].
Curiously, ACD shows a higher sensitivity to differentiate network properties of pathological
states, especially VS, from healthy connectivity patterns. This is an unexpected result, considering that
differences in ACS exceed 50% for all the network parameters. More likely, this apparent
contradiction could be a result of the comparison of single subject against a normalized database. The
relatively large range of age in a small population of healthy subjects induces an overstated standard
deviation, which decreases the predictive ability of the Z score. A seminal study made by Iturria et al.
[11] found significant correlations among these connectivity matrixes. However this high correlation
was obtained between gray matter structures of healthy subjects, which may support our conclusion.
By definition, ACD is searched as a measure of the fraction of the surface involved in the connection
with respect to the total surface of both areas, while ACS give an estimate of the amount of nervous
fibers shared by these areas [11]. Thus, ACD normalize for the differences in surface area and volume
of brain regions (network nodes) related with normal inter-subject variability and/or aging [21].
Our MRI configuration allows for acquisition in 12 isotropically distributed diffusion-encoding
directions. This limitation determines the capacity of a tensor to model properly multiple fiber tracts
in one voxel. For that reason we applied the fiber assignment by continuous tracking (FACT)
streamline tracking algorithm [22]. This algorithm is computationally inexpensive and has been
demonstrated to be able to robustly reproduce brain circuitry. Figure 2 illustrate the performance of
the tractography method and the high topological association between damaged tissue and fiber
disruption in both patients. Application of advanced tractographic algorithms with high angular
resolution can avoid limitations inherent to streamline tracking. However, they might not be
computationally feasible as diagnostic tools in a clinical environment.
Disrupted Axonal Fiber Connectivity As a Marker of Impaired Consciousness States
The main limitation to our study is that our findings are limited to two patients. However, large
scale trials from patients with severe brain damage present challenging complexities related with
acquisition, analysis and interpretation of neuroimaging data and inhomogeneities in lesion topology,
which are unique for each patient. Our results suggest that DTI-based network connectivity combined
with graph theory is useful to study the long range effect of confined injuries and the relationship with
the degree of consciousness impairment, underlying PVS and LIS. The feasibility and reliability in the
application of these techniques to characterize single cases have encouraging implications for use
them as diagnostic and prognostic techniques in DOC.
Our results suggest that DTI-based network connectivity combined with graph theory is useful to
study the long range effect of confined injuries and the relationship with the degree of consciousness
impairment, underlying PVS and LIS. This is the first approach to characterize the dissimilarities in
branching configuration underlying the clinical and behavioral differences between vegetative states
and locked-in syndrome. More detailed comparisons between normal and pathological ACS and ACD
maps combined with graphic theoretical tools could become a potential procedure to diagnose and
distinguish different disorders of consciousness related to white matter injury in the pathways from
brainstem to cerebral cortex.
RRR was partially supported by the “Abdus Salam” International Center for Theoretical Physics,
Trieste, Italy. Authors would like to thank Andy Stanert for the revision of the manuscript.
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Received: June 13 2013 Revised: June 18 2013 Accepted: June 23 2013.
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Diagnosis of patients with a disorder of consciousness is very challenging. Previous studies investigating resting state networks demonstrate that 2 main features of the so-called default mode network (DMN), metabolism and functional connectivity, are impaired in patients with a disorder of consciousness. However, task-induced deactivation--a third main feature of the DMN--has not been explored in a group of patients. Deactivation of the DMN is supposed to reflect interruptions of introspective processes. Seventeen patients with unresponsive wakefulness syndrome (UWS, former vegetative state), 8 patients in minimally conscious state (MCS), and 25 healthy controls were investigated with functional magnetic resonance imaging during a passive sentence listening task. Results show that deactivation in medial regions is reduced in MCS and absent in UWS patients compared to healthy controls. Moreover, behavioral scores assessing the level of consciousness correlate with deactivation in patients. On single-subject level, all control subjects but only 2 patients in MCS and 6 with UWS exposed deactivation. Interestingly, all patients who deactivated during speech processing (except for one) showed activation in left frontal regions which are associated with conscious processing. Our results indicate that deactivation of the DMN can be associated with the level of consciousness by selecting those who are able to interrupt ongoing introspective processes. In consequence, deactivation of the DMN may function as a marker of consciousness.
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This article reviews the contributions of the Cuban Neuroscience Center to the evolution of the statistical parametric mapping (SPM) of quantitative Multimodal Neuroimages (qMN), from its inception to more recent work. Attention is limited to methods that compare individual qMN to normative databases (n/qMN). This evolution is described in three successive stages: (a) the development of one variant of normative topographical quantitative EEG (n/qEEG-top) which carries out statistical comparison of individual EEG spectral topographies with regard to a normative database — as part of the now popular SPM of brain descriptive parameters; (b) the development of n/qEEG tomography (n/qEEG-TOM), which employs brain electrical tomography (BET) to calculate voxelwise SPM maps of source spectral features with respect to a norm; (c) the development of a more general n/qMN by substituting EEG parameters with other neuroimaging descriptive parameters to obtain SPM maps. The study also describes the creation of Cuban normative databases, starting with the Cuban EEG database obtained in the early 90s, and more recently, the Cuban Human Brain Mapping Project (CHBMP). This project has created a 240 subject database of the normal Cuban population, obtained from a population-based random sample, comprising clinical, neuropsychological, EEG, MRI and SPECT data for the same subjects. Examples of clinical studies using qMN are given and, more importantly, receiver operator characteristics (ROC) analyses of the different developments document a sustained effort to assess the clinical usefulness of the techniques.
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Functional neuroimaging and electrophysiology studies are changing our understanding of patients with coma and related states. Some severely brain damaged patients may show residual cortical processing in the absence of behavioural signs of consciousness. Given these new findings, the diagnostic errors and their potential effects on treatment as well as concerns regarding the negative associations intrinsic to the term vegetative state, the European Task Force on Disorders of Consciousness has recently proposed the more neutral and descriptive term unresponsive wakefulness syndrome. When vegetative/unresponsive patients show minimal signs of consciousness but are unable to reliably communicate the term minimally responsive or minimally conscious state (MCS) is used. MCS was recently subcategorized based on the complexity of patients' behaviours: MCS+ describes high-level behavioural responses (i.e., command following, intelligible verbalizations or non-functional communication) and MCS- describes low-level behavioural responses (i.e., visual pursuit, localization of noxious stimulation or contingent behaviour such as appropriate smiling or crying to emotional stimuli). Finally, patients who show non-behavioural evidence of consciousness or communication only measurable via para-clinical testing (i.e., functional MRI, positron emission tomography, EEG or evoked potentials) can be considered to be in a functional locked-in syndrome. An improved assessment of brain function in coma and related states is not only changing nosology and medical care but also offers a better-documented diagnosis and prognosis and helps to further identify the neural correlates of human consciousness.
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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.
The ascending reticular activating system (ARAS) mediates arousal, an essential component of human consciousness. Lesions of the ARAS cause coma, the most severe disorder of consciousness. Because of current methodological limitations, including of postmortem tissue analysis, the neuroanatomic connectivity of the human ARAS is poorly understood. We applied the advanced imaging technique of high angular resolution diffusion imaging (HARDI) to elucidate the structural connectivity of the ARAS in 3 adult human brains, 2 of which were imaged postmortem. High angular resolution diffusion imaging tractography identified the ARAS connectivity previously described in animals and also revealed novel human pathways connecting the brainstem to the thalamus, the hypothalamus, and the basal forebrain. Each pathway contained different distributions of fiber tracts from known neurotransmitter-specific ARAS nuclei in the brainstem. The histologically guided tractography findings reported here provide initialevidence for human-specific pathways of the ARAS. The unique composition of neurotransmitter-specific fiber tracts within each ARAS pathway suggests structural specializations that subserve the different functional characteristics of human arousal. This ARAS connectivity analysis provides proof of principle that HARDI tractography may affect the study of human consciousness and its disorders, including in neuropathologic studies of patients dying in coma and the persistent vegetative state.
The demonstration by Monti et al. (2010) of willful modulation of brain activity in persistent vegetative state implies the exceptional condition of a "complete motor locked-in syndrome." As a consequence, the contradictory character of the diagnosis minimally conscious state should be recognized because behaviorally observed minimal cognitive responsiveness does not exclude a higher level of well-differentiated self-consciousness. Introduction of the descriptive entities "complete motor locked-in syndrome" and "minimal cognitive responsiveness" is therefore advocated in the service of diagnostic precision.
There is consistent evidence that brain volume changes in early and late life. Most longitudinal studies usually only span a few years and include a limited number of participants. In this review, we integrate findings from 56 longitudinal magnetic resonance imaging (MRI) studies on whole brain volume change in healthy individuals. The individual longitudinal MRI studies describe only the development in a limited age range. In total, 2,211 participants were included. Age at first measurement varied between 4 and 88 years of age. The studies included in this review were performed using a large range of methods (e.g., different scanner protocols and different acquisition parameters). We applied a weighted regression analysis to estimate the age dependency of the rate of relative annual brain volume change across studies. The results indicate that whole brain volume changes throughout the life span. A wave of growth occurs during childhood/adolescence, where around 9 years of age a 1% annual brain growth is found which levels off until at age 13 a gradual volume decrease sets in. During young adulthood, between ∼18 and 35 years of age, possibly another wave of growth occurs or at least a period of no brain tissue loss. After age 35 years, a steady volume loss is found of 0.2% per year, which accelerates gradually to an annual brain volume loss of 0.5% at age 60. The brains of people over 60 years of age show a steady volume loss of more than 0.5%. Understanding the mechanisms underlying these plastic brain changes may contribute to distinguishing progressive brain changes in psychiatric and neurological diseases from healthy aging processes. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.
Recent fMRI studies have shown that it is possible to reliably identify the default-mode network (DMN) in the absence of any task, by resting-state connectivity analyses in healthy volunteers. We here aimed to identify the DMN in the challenging patient population of disorders of consciousness encountered following coma. A spatial independent component analysis-based methodology permitted DMN assessment, decomposing connectivity in all its different sources either neuronal or artifactual. Three different selection criteria were introduced assessing anticorrelation-corrected connectivity with or without an automatic masking procedure and calculating connectivity scores encompassing both spatial and temporal properties. These three methods were validated on 10 healthy controls and applied to an independent group of 8 healthy controls and 11 severely brain-damaged patients [locked-in syndrome (n = 2), minimally conscious (n = 1), and vegetative state (n = 8)]. All vegetative patients showed fewer connections in the default-mode areas, when compared with controls, contrary to locked-in patients who showed near-normal connectivity. In the minimally conscious-state patient, only the two selection criteria considering both spatial and temporal properties were able to identify an intact right lateralized BOLD connectivity pattern, and metabolic PET data suggested its neuronal origin. When assessing resting-state connectivity in patients with disorders of consciousness, it is important to use a methodology excluding non-neuronal contributions caused by head motion, respiration, and heart rate artifacts encountered in all studied patients.