Athina Demertzi

Connectivity graph analysis of the auditory resting state network in tinnitus

Thirteen chronic tinnitus patients and fifteen age-matched healthy controls were studied on a 3T magnetic resonance imaging (MRI) scanner during resting condition (i.e. eyes closed, no task performance). The auditory resting-state component was selected using an automatic component selection approach. Functional connectivity (correlations/anti-correlations) in the extracted network was portrayed by integrating the independent component analysis (ICA) approach with a graph theory method. Tinnitus and control groups showed different graph connectivity patterns. In the control group, the connectivity graph was divided into two distinct anti-correlated networks. The first one encompassed the auditory cortices and the insula. The second one encompassed frontoparietal and anterior cingulate cortices, brainstem, amygdala, basal ganglia/nucleus accumbens and parahippocampal regions. In the tinnitus group, only one of the two previously described networks was observed, encompassing the auditory cortices and the insula. Direct group comparison showed, in the tinnitus group, an increased functional connectivity between auditory cortices and the left parahippocampal region surviving multiple comparisons. We investigated a possible correlation between four tinnitus relevant measures (tinnitus handicap inventory (THI) and tinnitus questionnaire (TQ) scores, tinnitus duration and tinnitus intensity during the scanning session) and the connectivity pattern in the tinnitus population. We observed a significant positive correlation between the beta values of the posterior cingulate/precuneus region and the THI score. Our results show a modified functional connectivity pattern in tinnitus sufferers and highlight the role of the parahippocampal region in tinnitus physiopathology. They also point out the importance of the activity and connectivity pattern of the posterior cingulate cortex/precuneus region to the development of the tinnitus associated distress. This article is part of a Special Issue entitled: Tinnitus Neuroscience.

METABOLIC ACTIVITY IN EXTERNAL AND INTERNAL AWARENESS NETWORKS IN SEVERELY BRAIN-DAMAGED PATIENTS

OBJECTIVE An extrinsic cerebral network (encompassing lateral frontoparietal cortices) related to external/sensory awareness and an intrinsic midline network related to internal/self-awareness have been identified recently. This study measured brain metabolism in both networks in patients with severe brain damage. DESIGN Prospective [18F]-fluorodeoxyglucose-positron emission tomography and Coma Recovery Scale-Revised assessments in a university hospital setting. SUBJECTS Healthy volunteers and patients in vegetative state/unresponsive wakefulness syndrome (VS/UWS), minimally conscious state (MCS), emergence from MCS (EMCS), and locked-in syndrome (LIS). RESULTS A total of 70 patients were included in the study: 24 VS/UWS, 28 MCS, 10 EMCS, 8 LIS and 39 age-matched controls. VS/UWS showed metabolic dysfunction in extrinsic and intrinsic networks and thalami. MCS showed dysfunction mostly in intrinsic network and thalami. EMCS showed impairment in posterior cingulate/retrosplenial cortices. LIS showed dysfunction only in infratentorial regions. Coma Recovery Scale-Revised total scores correlated with metabolic activity in both extrinsic and part of the intrinsic network and thalami. CONCLUSION Progressive recovery of extrinsic and intrinsic awareness network activity was observed in severely brain-damaged patients, ranging from VS/UWS, MCS, EMCS to LIS. The predominance of intrinsic network impairment in MCS could reflect altered internal/self-awareness in these patients, which is difficult to quantify at the bedside.

What about Pain in Disorders of Consciousness

The management and treatment of acute pain is very difficult in non-communicative patients with disorders of consciousness (i.e., vegetative state/unresponsive wakefulness syndrome (VS/UWS) and minimally conscious state), creating an ethical dilemma for caregivers and an emotional burden among both relatives and caregivers. In this review, we summarize recent findings about the neural substrates of nociception and pain in VS/UWS patients as well as recent behavioral assessment methods of nociception specifically designed for patients in altered states of consciousness. We will finally discuss implications for pain treatment in these patients.

A human brain network derived from coma-causing brainstem lesions

Objective: To characterize a brainstem location specific to coma-causing lesions, and its functional connectivity network. Methods: We compared 12 coma-causing brainstem lesions to 24 control brainstem lesions using voxel-based lesion-symptom mapping in a case-control design to identify a site significantly associated with coma. We next used resting-state functional connectivity from a healthy cohort to identify a network of regions functionally connected to this brainstem site. We further investigated the cortical regions of this network by comparing their spatial topography to that of known networks and by evaluating their functional connectivity in patients with disorders of consciousness. Results: A small region in the rostral dorsolateral pontine tegmentum was significantly associated with coma-causing lesions. In healthy adults, this brainstem site was functionally connected to the ventral anterior insula (AI) and pregenual anterior cingulate cortex (pACC). These cortical areas aligned poorly with previously defined resting-state networks, better matching the distribution of von Economo neurons. Finally, connectivity between the AI and pACC was disrupted in patients with disorders of consciousness, and to a greater degree than other brain networks. Conclusions: Injury to a small region in the pontine tegmentum is significantly associated with coma. This brainstem site is functionally connected to 2 cortical regions, the AI and pACC, which become disconnected in disorders of consciousness. This network of brain regions may have a role in the maintenance of human consciousness.

Burnout in healthcare workers managing chronic patients with disorders of consciousness.

Objectives: The aim of this study was to assess the presence of burnout among professional caregivers managing patients with severe brain injury recovering from coma and working in neurorehabilitation centres or nursing homes. Methods: The Maslach Burnout Inventory was sent to 40 centres involved in the Belgian federal network for the care of vegetative and minimally conscious patients. The following demographic data were also collected: age, gender, profession, expertise in the field, amount of time spent with patients and working place. Results: Out of 1068 questionnaires sent, 568 were collected (53% response rate). Forty-five were excluded due to missing data. From the 523 healthcare workers, 18% (n = 93) presented a burnout, 33% (n = 171) showed emotional exhaustion and 36% (n = 186) had a depersonalization. Profession (i.e. nurse/nursing assistants), working place (i.e. nursing home) and the amount of time spent with patients were associated with burnout. The logistic regression showed that profession was nevertheless the strongest variable linked to burnout. Conclusions: According to this study, a significant percentage of professional caregivers and particularly nurses taking care of patients in a vegetative state and in a minimally conscious state suffered from burnout. Prevention of burnout symptoms among caregivers is crucial and is expected to promote more efficient medical care of these challenging patients.

Changes in cerebral metabolism in patients with a minimally conscious state responding to zolpidem

Background: Zolpidem, a short-acting non-benzodiazepine GABA agonist hypnotic, has been shown to induce paradoxical responses in some patients with disorders of consciousness (DOC), leading to recovery of arousal and cognitive abilities. We here assessed zolpidem-induced changes in regional brain metabolism in three patients with known zolpidem response in chronic post-anoxic minimally conscious state (MCS). Methods: [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) and standardized clinical assessments using the Coma Recovery Scale-Revised were performed after administration of 10 mg zolpidem or placebo in a randomized double blind 2-day protocol. PET data preprocessing and comparison with a healthy age-matched control group were performed using statistical parametric mapping (SPM8). Results: Behaviorally, all patients recovered functional communication after administration of zolpidem (i.e., emergence from the MCS). FDG-PET showed increased metabolism in dorsolateral prefrontal and mesiofrontal cortices after zolpidem but not after placebo administration. Conclusion: Our data show a metabolic activation of prefrontal areas, corroborating the proposed mesocircuit hypothesis to explain the paradoxical effect of zolpidem observed in some patients with DOC. It also suggests the key role of the prefrontal cortices in the recovery of functional communication and object use in hypoxic patients with chronic MCS.

Disorders of consciousness: Moving from passive to resting state and active paradigms.

Following coma, some patients will recover wakefulness without signs of consciousness (i.e., vegetative state) or may show nonreflexive movements but with no ability for functional communication (i.e., minimally conscious state). Currently, there remains a high rate of misdiagnosis of the vegetative state. The increasing use of fMRI and EEG tools permits the clinical characterization of these patients to be improved. We first discuss “resting metabolism” and “passive activation” paradigms, used in neuroimaging and evoked potential studies, which merely identify neural activation reflecting “automatic” processing—that is, occurring without the patients willful intervention. Secondly, we present an alternative approach consisting of instructing subjects to imagine well-defined sensory-motor or cognitive-mental actions. This strategy reflects volitional neural activation and, hence, witnesses awareness. Finally, we present results on blood-oxgen-level-dependent “default mode network”/resting state studies that might be a promising tool in the diagnosis of these challenging patients.

Sedation of Patients With Disorders of Consciousness During Neuroimaging: Effects on Resting State Functional Brain Connectivity.

BACKGROUND: To reduce head movement during resting state functional magnetic resonance imaging, post-coma patients with disorders of consciousness (DOC) are frequently sedated with propofol. However, little is known about the effects of this sedation on the brain connectivity patterns in the damaged brain essential for differential diagnosis. In this study, we aimed to assess these effects. METHODS: Using resting state functional magnetic resonance imaging 3T data obtained over several years of scanning patients for diagnostic and research purposes, we employed a seed-based approach to examine resting state connectivity in higher-order (default mode, bilateral external control, and salience) and lower-order (auditory, sensorimotor, and visual) resting state networks and connectivity with the thalamus, in 20 healthy unsedated controls, 8 unsedated patients with DOC, and 8 patients with DOC sedated with propofol. The DOC groups were matched for age at onset, etiology, time spent in DOC, diagnosis, standardized behavioral assessment scores, movement intensities, and pattern of structural brain injury (as assessed with T1-based voxel-based morphometry). RESULTS: DOC were associated with severely impaired resting state network connectivity in all but the visual network. Thalamic connectivity to higher-order network regions was also reduced. Propofol administration to patients was associated with minor further decreases in thalamic and insular connectivity. CONCLUSIONS: Our findings indicate that connectivity decreases associated with propofol sedation, involving the thalamus and insula, are relatively small compared with those already caused by DOC-associated structural brain injury. Nonetheless, given the known importance of the thalamus in brain arousal, its disruption could well reflect the diminished movement obtained in these patients. However, more research is needed on this topic to fully address the research question.

Ethics in Disorders of Consciousness

The introduction of the mechanical ventilator in the 1950s and the development of intensive care in the 1960s permitted many patients to sustain their vegetative functions and survive severe injuries. Despite such advances, in many cases patients were found to suffer from altered states of consciousness which had never been encountered before as these patients would normally have died from apnea [1]. The imminent ethical impact of these profound states of unconsciousness was reflected in the composition of the first bioethical committees discussing the redefinition of life and the concept of therapeutic obstinacy. In 1968, the Ad Hoc Committee of Harvard Medical School published a milestone paper for the redefinition of death as irreversible coma and brain failure [2]. The committee was comprised of ten physicians, a theologian, a lawyer and a historian of science, betokening the medical, legal and societal debates that were to follow. We will here give a brief overview of some ethical issues related to the concept of consciousness and the medical management of patients with disorders of consciousness, such as comatose, vegetative and minimally conscious states that may be encountered in the intensive care setting. We will emphasize the problem of pain management and end-of life decision-making.

Brain-heart interactions reveal consciousness in non-communicating patients

We here aimed at characterizing heart–brain interactions in patients with disorders of consciousness. We tested how this information impacts data‐driven classification between unresponsive and minimally conscious patients.