Auditory steady-state response to chirp-modulated tones: A pilot study in patients with disorders of consciousness.

OBJECTIVE: Due to the problems with behavioral diagnosis of patients with prolonged DOC (disorders of consciousness), complementary approaches based on objective measurement of neural function are necessary. In this pilot study, we assessed the sensitivity of auditory chirp-evoked responses to the state of patients with severe brain injury as measured with CRS-R (Coma Recovery Scale - Revised). METHODS: A convenience sample of fifteen DOC patients was included in the study. Auditory stimuli, chirp-modulated at 1-120 Hz were used to evoke auditory steady-state response (ASSR). Phase-locking index (PLI) estimates within low gamma and high gamma windows were evaluated. RESULTS: The PLI estimates within a narrow low gamma 38-42 Hz window positively correlated with the CRS-R total score and with the scores of the Auditory and Visual Function subscales. In the same low gamma window, significant difference in the PLIs was found between minimally conscious (MCS) and vegetative state (VS) patients. We did not observe any between-group differences nor any significant correlations with CRS-R scores in the high gamma window (80-110 Hz). CONCLUSIONS: Our results support the notion that the activity around 40 Hz may serve as a possible marker of the integrity of thalamocortical networks in prolonged DOC patients. SIGNIFICANCE: Auditory steady-state responses at gamma-band frequencies highlight the role of upper parts of auditory system in evaluation of the level of consciousness in DOC patients.

Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.

The new severe acute respiratory syndrome- coronavirus 2 is reported to affect the nervous system. Among the reports of the various neurological manifestations, there are a few documented specific processes to explain the neurological signs. We report a para-infectious encephalitis patient with clinical, laboratory, and imaging findings during evolution and convalescence phase of coronavirus infection. This comprehensive overview can illuminate the natural history of similar cases. As the two previously reported cases of encephalitis associated with this virus were not widely discussed regarding the treatment, we share our successful approach and add some recommendations about this new and scarce entity.

Peri-personal space encoding in patients with disorders of consciousness and cognitive-motor dissociation.

Behavioral assessments of consciousness based on overt command following cannot differentiate patients with disorders of consciousness (DOC) from those who demonstrate a dissociation between intent/awareness and motor capacity: cognitive motor dissociation (CMD). We argue that delineation of peri-personal space (PPS) - the multisensory-motor space immediately surrounding the body - may differentiate these patients due to its central role in mediating human-environment interactions, and putatively in scaffolding a minimal form of selfhood. In Experiment 1, we determined a normative physiological index of PPS by recording electrophysiological (EEG) responses to tactile, auditory, or audio-tactile stimulation at different distances (5 vs. 75 cm) in healthy volunteers (N = 19). Contrasts between paired (AT) and summed (A + T) responses demonstrated multisensory supra-additivity when AT stimuli were presented near, i.e., within the PPS, and highlighted somatosensory-motor sensors as electrodes of interest. In Experiment 2, we recorded EEG in patients behaviorally diagnosed as DOC or putative CMD (N = 17, 30 sessions). The PPS-measure developed in Experiment 1 was analyzed in relation with both standard clinical diagnosis (i.e., Coma Recovery Scale; CRS-R) and a measure of neural complexity associated with consciousness. Results demonstrated a significant correlation between the PPS measure and neural complexity, but not with the CRS-R, highlighting the added value of the physiological recordings. Further, multisensory processing in PPS was preserved in putative CMD but not in DOC patients. Together, the findings suggest that indexing PPS allows differentiating between groups of patients whom both show overt motor impairments (DOC and CMD) but putatively distinct levels of awareness or motor intent.

Spatially Overlapping Regions Show Abnormal Thalamo-frontal Circuit and Abnormal Precuneus in Disorders of Consciousness.

Understanding the neural mechanisms of disorders of consciousness (DOC) is essential for estimating the conscious level and diagnosing DOC patients. Although previous studies reported brain functional connectivity (FC) and spontaneous neural activity patterns associated with consciousness, the relationship between them remains unclear. In this study, we identified the abnormal brain regions in DOC patients by performing voxel-wise FC strength (FCS) and fractional amplitude of low-frequency fluctuations (fALFF) analyses on resting-state functional magnetic resonance imaging data of 15 DOC patients and 24 healthy controls. Furthermore, we detected spatial intersections between two measures and estimated the correlations between either the FCS or the fALFF and the subscales of the Coma Recovery Scale-Revised (CRS-R). We found that the right superior frontal gyrus, left thalamus and right precuneus in which the DOC patients had a lower local FCS and fALFF than healthy controls, are coincident with regions of the mesocircuit model. In the right precuneus, the local FCS/fALFF was significantly positively correlated with the oromotor and motor scores/motor score of the CRS-R. Our findings may indicate that the co-occurrent pattern of spontaneous neural activity and functional connectivity in the thalamo-frontal circuit and the precuneus are associated with motor function in DOC patients.

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.

Single unit activities recorded in the thalamus and the overlying parietal cortex of subjects affected by disorders of consciousness.

The lack of direct neurophysiological recordings from the thalamus and the cortex hampers our understanding of vegetative state/unresponsive wakefulness syndrome and minimally conscious state in humans. We obtained microelectrode recordings from the thalami and the homolateral parietal cortex of two vegetative state/unresponsive wakefulness syndrome and one minimally conscious state patients during surgery for implantation of electrodes in both thalami for chronic deep brain stimulation. We found that activity of the thalamo-cortical networks differed among the two conditions. There were half the number of active neurons in the thalami of patients in vegetative state/unresponsive wakefulness syndrome than in minimally conscious state. Coupling of thalamic neuron discharge with EEG phases also differed in the two conditions and thalamo-cortical cross-frequency coupling was limited to the minimally conscious state patient. When consciousness is physiologically or pharmacologically reversibly suspended there is a significant increase in bursting activity of the thalamic neurons. By contrast, in the thalami of our patients in both conditions fewer than 17% of the recorded neurons showed bursting activity. This indicates that these conditions differ from physiological suspension of consciousness and that increased thalamic inhibition is not prominent. Our findings, albeit obtained in a limited number of patients, unveil the neurophysiology of these conditions at single unit resolution and might be relevant for inspiring novel therapeutic options.

Disentangling disorders of consciousness: Insights from diffusion tensor imaging and machine learning.

Previous studies have suggested that disorders of consciousness (DOC) after severe brain injury may result from disconnections of the thalamo-cortical system. However, thalamo-cortical connectivity differences between vegetative state (VS), minimally conscious state minus (MCS-, i.e., low-level behavior such as visual pursuit), and minimally conscious state plus (MCS+, i.e., high-level behavior such as language processing) remain unclear. Probabilistic tractography in a sample of 25 DOC patients was employed to assess whether structural connectivity in various thalamo-cortical circuits could differentiate between VS, MCS-, and MCS+ patients. First, the thalamus was individually segmented into seven clusters based on patterns of cortical connectivity and tested for univariate differences across groups. Second, reconstructed whole-brain thalamic tracks were used as features in a multivariate searchlight analysis to identify regions along the tracks that were most informative in distinguishing among groups. At the univariate level, it was found that VS patients displayed reduced connectivity in most thalamo-cortical circuits of interest, including frontal, temporal, and sensorimotor connections, as compared with MCS+, but showed more pulvinar-occipital connections when compared with MCS-. Moreover, MCS- exhibited significantly less thalamo-premotor and thalamo-temporal connectivity than MCS+. At the multivariate level, it was found that thalamic tracks reaching frontal, parietal, and sensorimotor regions, could discriminate, up to 100% accuracy, across each pairwise group comparison. Together, these findings highlight the role of thalamo-cortical connections in patients' behavioral profile and level of consciousness. Diffusion tensor imaging combined with machine learning algorithms could thus potentially facilitate diagnostic distinctions in DOC and shed light on the neural correlates of consciousness. Hum Brain Mapp 38:431-443, 2017. © 2016 Wiley Periodicals, Inc.

The neural correlates of lexical processing in disorders of consciousness.

There is a growing interest in the use of functional imaging to assess brain activity in the absence of behavioural responses in patients with disorders of consciousness (DOC). In the present study, we applied a hierarchical auditory stimulation paradigm to functional magnetic resonance (fMRI) in a group of long-term DOC adult patients. Brain response to pairs of pseudowords, of unrelated words and of semantically related words, i.e. stimuli differing in lexical status (words vs. pseudowords) and semantic relatedness (related vs. unrelated) was assessed. The former contrast was considered to reflect the automatic brain response to the passive presentation of meaningful real words, while the latter aimed to assess the response to meaning relationships. The results of the study indicate that automatic lexical processing can be observed in minimally conscious state (MCS), but also in vegetative state/unresponsive wakefulness syndrome (VS/UWS) patients, as indicated by increase in blood oxygenation level dependent (BOLD) activity in the linguistic networks. DOC patients, for some task conditions, recruited additional areas in comparison to healthy participants. Furthermore this study provides additional evidence of the potential role of fMRI in the assessment of residual cognitive processing in some of these patients, which may not be evident at the clinical level.

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.

Brain-computer interfaces for patients with disorders of consciousness.

The disorders of consciousness refer to clinical conditions that follow a severe head injury. Patients diagnosed as in a vegetative state lack awareness, while patients diagnosed as in a minimally conscious state retain fluctuating awareness. However, it is a challenge to accurately diagnose these disorders with clinical assessments of behavior. To improve diagnostic accuracy, neuroimaging-based approaches have been developed to detect the presence or absence of awareness in patients who lack overt responsiveness. For the small subset of patients who retain awareness, brain-computer interfaces could serve as tools for communication and environmental control. Here we review the existing literature concerning the sensory and cognitive abilities of patients with disorders of consciousness with respect to existing brain-computer interface designs. We highlight the challenges of device development for this special population and address some of the most promising approaches for future investigations.

Alteration of regional cerebral blood flow to thyrotropin-releasing hormone therapy in acute encephalitis and encephalopathy during childhood.

BACKGROUND: Thyrotropin-releasing hormone (TRH) is now used as a therapeutic agent for various neurological disorders. Animal study has shown that TRH was attributable to increased cerebral blood flow (CBF). AIMS: There have been occasional reports that TRH therapy was effective for improving symptoms of persistent disturbance of consciousness after acute encephalitis or encephalopathy during childhood. To determine whether TRH has an effect on increasing CBF to patients who have consciousness disturbance caused by acute encephalitis or encephalopathy, and to determine the optimal method of administration. METHODS: Sixteen patients aged 0.7-10.9 years (mean age, 3.2+/-3.1 years) who presented with persistent disturbance of consciousness resulting from acute encephalitis or encephalopathy and were treated with TRH. Regional CBF (rCBF) was measured by single photon emission computed tomography before and after TRH therapy. The alteration rates of rCBF were compared between the divided two groups concerning the dose levels, dosing periods, and treatment lags. RESULTS: The alteration rates of rCBF of the high dose group were higher than those of the low dose group. Differences in the dosing periods and treatment lags did not cause any significant difference of the alteration rates of rCBF. CONCLUSION: The study showed that higher alteration rates of the CBF were observed in the higher dosing group, and TRH have the potency of increasing CBF. TRH therapy would have the potential for effective treatment of persistent consciousness disturbance caused by childhood acute encephalitis or encephalopathy.

Pathophysiology of altered consciousness during seizures: Subtraction SPECT study.

BACKGROUND: The mechanisms underlying altered consciousness during seizures are poorly understood. Previous clinicopathologic studies suggest a role for the thalamus and upper brainstem in consciousness mechanisms. OBJECTIVE: To examine blood flow changes associated with altered consciousness during seizures. METHODS: Seventy-one patients with epilepsy who underwent video-EEG monitoring and ictal/interictal SPECT were studied. Patients were divided into three groups depending on their conscious state during seizures: 1) complete impairment of consciousness (CI), 2) no impairment of consciousness (NI), or 3) uncertain impairment of consciousness (UI). The distribution of blood flow changes during these seizures was assessed by subtraction (ictal - interictal) SPECT co-registered to MRI. Conscious state was assessed in relation to secondary ictal hyperperfusion in subcortical regions (i.e., thalamus and upper brainstem). RESULTS: Impairment of consciousness showed a strong association with secondary hyperperfusion in the thalamic/upper brainstem region (p = 0.01), occurring in 92% (45/49) of CI, 69% (9/13) of UI, and 11% (1/9) of NI. CONCLUSIONS: These findings are consistent with a role for the thalamus and upper brainstem in consciousness mechanisms. The authors suggest that the spread of epileptic discharges or a trans-synaptic activation (diaschisis) of these structures is an important mechanism in the alteration of consciousness during seizures. Variance in the results may be due to differences in timing of radioisotope injection, sensitivity of the subtraction SPECT technique, and the ability to clinically assess the conscious state.

Sonographic lenticulostriate vasculopathy in infants: some associations and a hypothesis.

PURPOSE: To describe the causes of infantile lenticulostriate vasculopathy (LSV) as demonstrated by sonography and propose the pathogenesis of these findings. METHODS: Five hundred eighty-six infants were examined via echoencephalography because of seizures, psychomotor retardation, dysmorphism, congenital malformation, microcephaly, macrocephaly, bulging of anterior fontanel, consciousness disturbance, or prematurity. We directed our attention on the sonographic study to the basal ganglionic and thalamic areas. Twenty-eight of the 586 patients underwent color Doppler studies. RESULTS: In 34 infants with gray-scale neurosonographic findings of LSV, 16 were associated with various causes that have been reported before. In 8 patients entities not previously associated with LSV were found: neonatal lupus, neonatal hypoglycemia, uncomplicated prematurity, encephalitis, and head injury. In the remaining 10 cases, a specific cause could not be found. The LSV was found in 16 (40%), 5 (14%), and 13 (3%) patients with perinatal, acquired, and nonspecific causes, respectively. Generally, this is an uncommon finding because it was observed in only 34 (5.8%) of the study infants; 24 of these 34 had a documented cause of the vasculopathy. With LSV associated with perinatal causes there was a greater chance of sonographic LSV's developing than with that of acquired causes. CONCLUSIONS: We suggest that sonographic LSV is a nonspecific marker of a previous insult to the developing brain, and the special hemodynamics of the fetal brain plays an important role in its pathogenesis.