Spatial characteristics of spontaneous and stimulus-induced individual functional connectivity networks in severe disorders of consciousness.

BACKGROUND: Functional connectivity (fcMRI) analyses of resting state functional magnetic resonance imaging (fMRI) data revealed substantial differences between states of consciousness. The underlying cause-effect linkage, however, remains unknown to the present day. The aim of this study was to examine the relationship between fcMRI measures and Disorders of Consciousness (DOC) in resting state and under adequate stimulation. METHODS AND FINDINGS: fMRI data from thirteen patients with unresponsive wakefulness syndrome, eight patients in minimally conscious state, and eleven healthy controls were acquired in rest and during the application of nociceptive and emotional acoustic stimuli. We compared spatial characteristics and anatomical topography of seed-based fcMRI networks on group and individual levels. The anatomical topography of fcMRI networks of patients was altered in all three conditions as compared with healthy controls. Spread and distribution of individual fcMRI networks, however, differed significantly between patients and healthy controls in stimulation conditions only. The exploration of individual metric values identified two patients whose spatial metrics did not deviate from metric distributions of healthy controls in a statistically meaningful manner. CONCLUSIONS: These findings suggest that the disturbance of consciousness in DOC is related to deficits in global topographical network organization rather than a principal inability to establish long-distance connections. In addition, the results question the claim that task-free measurements are particularly valuable as a tool for individual diagnostics in severe neurological disorders. Further studies comparing connectivity indices with outcome of DOC patients are needed to determine the clinical relevance of spatial metrics and stimulation paradigms for individual diagnosis, prognosis and treatment in DOC.

Information processing in patients in vegetative and minimally conscious states.

OBJECTIVE: Evaluation of a short two-tone oddball paradigm to discriminate between the vegetative state (VS) and minimal consciousness state (MCS) in a sample of patients with severe disorders of consciousness (DOC). METHOD: EEG was recorded from 45 DOC patients and 14 healthy participants while listening to an auditory oddball paradigm presented in a passive - just listen - and an active - count the odd tones - condition. In patients, the experiment was repeated after a minimum of one week. RESULTS: Prevalence of the P300 was higher in healthy participants (71%) than in patients, but did not discriminate between VS (T1: ∼10%; T2: ∼11%) and MCS (T1: ∼13%; T2: 25%) patients. CONCLUSION: Results cast doubt on whether this simple auditory stimulation paradigm, which requires cognitive action from the listener, is sensitive enough to discriminate between patients with DOC. SIGNIFICANCE: The sensitivity of the P300 ERP obtained in a short two-tone oddball paradigm presented in a passive and an active condition appears to be too low for routine application in a clinical setting aiming at distinguishing between VS and MCS patients.

Functional electrical stimulation-assisted active cycling--therapeutic effects in patients with hemiparesis from 7 days to 6 months after stroke: a randomized controlled pilot study.

OBJECTIVE: To determine whether functional electrical stimulation (FES)-assisted active cycling is more effective than active cycling without FES concerning walking and balance. Specifically, walking ability was classified as to the amount of personal assistance needed to be able to walk and balance was evaluated for static and dynamic balance tasks. DESIGN: Monocentric, randomized, single-blinded, controlled trial. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Patients with severe hemiparesis due to stroke (N=40). INTERVENTIONS: Twenty minutes of active leg cycling with or without FES applied to the paretic vastus medialis and rectus femoris of quadriceps and to the biceps femoris and semitendinosus muscles, 3 times/wk for 4 weeks. MAIN OUTCOME MEASURES: Functional ambulation classification (FAC) and performance-oriented mobility assessment (POMA) were the primary outcome measures. The leg subscale of the motricity index (MI) and the modified Ashworth scale were the secondary outcome measures. Evaluation was done before and after the intervention period and after an additional 2 weeks. RESULTS: After the intervention, the FAC, POMA, and the MI (P<.016) for both intervention groups improved significantly. The FAC of the control group increased by a median of 1 category and that of the FES group by 2 categories. The median change in POMA was 2 and 4 points for the control group and the FES group, respectively. The Mann-Whitney U test between-group comparisons revealed that these gains were significantly better in the FES group for both the FAC (U=90; z=-2.58; P=.013; r=-.42) and the POMA (U=60; z=-3.43; P<.0004; r=-.56). Because of missing data and slightly decreased effect sizes during the follow-up phase (FAC, r=-.33; POMA, r=-.41), differences did not reach statistically significant P values. The MI leg subscale showed significant improvements in both groups. However, there were no significant differences between the groups at any time. No changes were observed on the modified Ashworth scale. CONCLUSIONS: FES-assisted active cycling seems to be a promising intervention during rehabilitation in patients with stroke.

Effects of repetitive peripheral magnetic stimulation on upper-limb spasticity and impairment in patients with spastic hemiparesis: a randomized, double-blind, sham-controlled study.

OBJECTIVE: To investigate short-term and long-term effects of repetitive peripheral magnetic stimulation (rpMS) on spasticity and motor function. DESIGN: Monocentric, randomized, double-blind, sham-controlled trial. SETTING: Neurologic rehabilitation hospital. PARTICIPANTS: Patients (N=66) with severe hemiparesis and mild to moderate spasticity resulting from a stroke or a traumatic brain injury. The average time ± SD since injury for the intervention groups was 26 ± 71 weeks or 37 ± 82 weeks. INTERVENTIONS: rpMS for 20 minutes or sham stimulation with subsequent occupational therapy for 20 minutes, 2 times a day, over a 2-week period. MAIN OUTCOME MEASURES: Modified Tardieu Scale and Fugl-Meyer Assessment (arm score), assessed before therapy, at the end of the 2-week treatment period, and 2 weeks after study treatment. Additionally, the Tardieu Scale was assessed after the first and before the third therapy session to determine any short-term effects. RESULTS: Spasticity (Tardieu >0) was present in 83% of wrist flexors, 62% of elbow flexors, 44% of elbow extensors, and 10% of wrist extensors. Compared with the sham stimulation group, the rpMS group showed short-term effects on spasticity for wrist flexors (P=.048), and long-term effects for elbow extensors (P<.045). Arm motor function (rpMS group: median 5 [4-27]; sham group: median 4 [4-9]) did not significantly change over the study period in either group, whereas rpMS had a positive effect on sensory function. CONCLUSIONS: Therapy with rpMS increases sensory function in patients with severe limb paresis. The magnetic stimulation, however, has limited effect on spasticity and no effect on motor function.

Can mental imagery functional magnetic resonance imaging predict recovery in patients with disorders of consciousness?

OBJECTIVE: To determine the potential prognostic value of using functional magnetic resonance imaging (fMRI) to identify patients with disorders of consciousness, who show potential for recovery. DESIGN: Observational study. SETTING: Unit for acute rehabilitation care. PARTICIPANTS: Patients (N=22) in a vegetative state (VS; n=10) and minimally conscious state (MCS; n=12) during the first 200 days after the initial incident. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Further course on the Coma Recovery Scale-Revised. RESULTS: Participants performed a mental imagery fMRI paradigm. They were asked to alternately imagine playing tennis and navigating through their home. In 14 of the 22 examined patients (VS, n=5; MCS, n=9), a significant activation of the regions of interest (ROIs) of the mental imagery paradigm could be found. All 5 patients with activation of a significant blood oxygen level dependent signal, who were in a VS at the time of the fMRI examination, reached at least an MCS at the end of the observation period. In contrast, 5 participants in a VS who failed to show activation in ROIs, did not (sensitivity 100%, specificity 100%). Six of 9 patients in an MCS with activation in ROIs emerged from an MCS. Of 3 patients in an MCS who did not show activation, 2 patients stayed in an MCS and 1 patient emerged from the MCS (sensitivity 85%, specificity 40%). CONCLUSIONS: The fMRI paradigm mental imagery displays a high concordance with the further clinical course of patients in a VS. All 5 patients in a VS who showed significant activation of ROIs had a favorable further course until the end of the observation period. We therefore propose the term "functional minimally conscious state" for these patients. They may benefit from rehabilitation treatment. In cases where no significant activation was seen, the method has no prognostic value. Prediction of the clinical course of patients in an MCS by fMRI was considerably less accurate than in patients in a VS.

Patients with unresponsive wakefulness syndrome respond to the pain cries of other people.

OBJECTIVE: Recent publications show that using imagery instructions, brain activation patterns indicating consciousness can be found in approximately 10% of patients with unresponsive wakefulness syndrome (UWS; previously called vegetative state). It is possible, however, that patients who cannot follow instructions (because of limited memory/attention capacities, for example) are nevertheless conscious and retain emotional abilities to feel pain and pleasure. The aim of this study was to assess residual affective consciousness in a specific network of brain structures, the so-called pain matrix (PM) of the brain. METHODS: We examined 44 carefully diagnosed UWS patients at 2 imaging centers. fMRI was used to investigate the brain hemodynamic responses to (a) imagery instructions, and (b) pain cries as opposed to neutral human vocalizations. RESULTS: In line with the data of other groups, consistent responses to imagery instructions were obtained in 5 patients. In contrast, the PM was activated by pain cries in 24 patients. The PM consists of a sensory subsystem, which underlies pain sensation, and an affective subsystem, which underlies the characteristic aversive emotional tone of pain. The former was activated in 34% of patients, the latter in 30% of patients. CONCLUSION: Although there is debate about whether patients with UWS can perceive their own pain, our data indicate that many of them respond to the signals of pain in others. One can speculate that "affective consciousness" can remain even in patients with very severe brain damage who have no capacity for cognition.

Global functional connectivity reveals highly significant differences between the vegetative and the minimally conscious state.

A major challenge in the diagnosis of disorders of consciousness is the differential diagnosis between the vegetative state (VS) and the minimally conscious state (MCS). Clinically, VS is defined by complete unawareness, whereas MCS is defined by the presence of inconsistent but clearly discernible behavioural signs of consciousness. In healthy individuals, pain cries have been reported to elicit functional activation within the pain matrix of the brain, which may be interpreted as empathic reaction. In this study, pain cries were presented to six VS patients, six MCS patients, and 17 age-matched healthy controls. Conventional task-related functional magnetic resonance imaging (fMRI) showed no significant differences in functional activation between the VS and MCS groups. In contrast to this negative finding, the application of a novel data-driven technique for the analysis of the brain's global functional connectivity yielded a positive result. The weighted global connectivity (WGC) was significantly greater in the MCS group compared to the VS group (p < 0.05, family-wise error corrected). Using areas of significant WGC differences as 'seed regions' in a secondary connectivity analysis revealed extended functional networks in both MCS and healthy groups, whereas no such long-range functional connections were observed in the VS group. These results demonstrate the potential of functional connectivity MRI (fcMRI) as a clinical tool for differential diagnosis in disorders of consciousness.

Semiautomatic landmark-based two-dimensional-three-dimensional image fusion in living mice: correlation of near-infrared fluorescence imaging of Cy5.5-labeled antibodies with flat-panel volume computed tomography.

Connecting fluorescence signals with anatomic structures enhances our ability to monitor biologic processes in mice. Here, we present a semiautomated approach to correlate two-dimensional (2D) noninvasive near-infrared fluorescence (NIRF) imaging with three-dimensional (3D), high-resolution, flat-panel volume computed tomography (fpVCT). We developed an algorithm to colocalize fluorescence signals of NIRF-labeled antibodies directed against matriptase and urokinase plasminogen activator receptor (uPAR) to orthotopic carcinomas in mice visualized by fpVCT. For this purpose, mice were anesthetized and fixed on a multimodality animal bed containing fiducial markers filled with iodine-containing contrast agent and fluorescent dye. After intravenous administration of contrast agent and Cy5.5-labeled antibodies, NIRF and fpVCT images were obtained, without repositioning the mice. Binding of Cy5.5-labeled matriptase-specific antibody to pancreatic tumors and Cy5.5-labeled uPAR-specific antibody to mammary carcinomas was assessed by time-domain NIRF imaging measuring the location of fluorescence intensity and its lifetime. In summary, we developed a novel 2D-3D registration technique for image fusion with NIRF imaging and fpVCT to provide complementary information in tumor models on the in vivo association of functional information with anatomic structures. The combination of fpVCT with NIRF imaging will now allow targeted and effective monitoring of preclinical tumor therapies.

The influence of acoustic and tactile stimulation on vegetative parameters and EEG in persistent vegetative state.

In the present study, we investigated whether different kinds of stimulation in the persistent vegetative state (PVS) lead to specific patterns of physiological reactions. In addition, a possible effect of stimulating drugs was explored by comparing recordings with and without pharmacological stimulation. Eighteen patients in the PVS were submitted to tactile or acoustic stimulation. The latter consisted of white noise and of the voices of close relatives delivered via a digital voice recorder. Additionally, half of the patients were pharmacologically stimulated with amantadine, L-dopa or amphetamine. The effect of stimulation was assessed by recording the electroencephalogram (EEG), electromyogram (EMG), skin conductance response (SCR) and heart rate (HR). Tactile stimulation was associated with statistically significant increases in EEG and EMG parameters, SCR and HR. White noise stimulation led to significant increases in SCR and EMG parameters. The physiological responses to relatives? voices did not differ from baseline activity. Pharmacological stimulation increased the baseline level of activation, but showed no interaction with sensory stimulation. The data presented indicate that the level of arousal in patients in the PVS can be adequately monitored by measuring SCR, HR and EMG parameters.