Neuroimmune activation is associated with neurological outcome in anoxic and traumatic coma.

The pathophysiological underpinnings of critically disrupted brain connectomes resulting in coma are poorly understood. Inflammation is potentially an important but still undervalued factor. Here, we present a first-in-human prospective study using the 18-kDa translocator protein (TSPO) radioligand 18F-DPA714 for PET imaging to allow in vivo neuroimmune activation quantification in patients with coma (n = 17) following either anoxia or traumatic brain injuries in comparison with age- and sex-matched controls. Our findings yielded novel evidence of an early inflammatory component predominantly located within key cortical and subcortical brain structures that are putatively implicated in consciousness emergence and maintenance after severe brain injury (i.e. mesocircuit and frontoparietal networks). We observed that traumatic and anoxic patients with coma have distinct neuroimmune activation profiles, both in terms of intensity and spatial distribution. Finally, we demonstrated that both the total amount and specific distribution of PET-measurable neuroinflammation within the brain mesocircuit were associated with the patient's recovery potential. We suggest that our results can be developed for use both as a new neuroprognostication tool and as a promising biometric to guide future clinical trials targeting glial activity very early after severe brain injury.

Presynaptic dopamine deficit in minimally conscious state patients following traumatic brain injury.

Dopaminergic stimulation has been proposed as a treatment strategy for post-traumatic brain injured patients in minimally conscious state based on a clinical trial using amantadine, a weak dopamine transporter blocker. However, a specific contribution of dopaminergic neuromodulation in minimally conscious state is undemonstrated. In a phase 0 clinical trial, we evaluated 13 normal volunteers and seven post-traumatic minimally conscious state patients using 11C-raclopride PET to estimate dopamine 2-like receptors occupancy in the striatum and central thalamus before and after dopamine transporter blockade with dextroamphetamine. If a presynaptic deficit was observed, a third and a fourth 11C-raclopride PET were acquired to evaluate changes in dopamine release induced by l-DOPA and l-DOPA+dextroamphetamine. Permutation analysis showed a significant reduction of dopamine release in patients, demonstrating a presynaptic deficit in the striatum and central thalamus that could not be reversed by blocking the dopamine transporter. However, administration of the dopamine precursor l-DOPA reversed the presynaptic deficit by restoring the biosynthesis of dopamine from both ventral tegmentum and substantia nigra. The advantages of alternative pharmacodynamic approaches in post-traumatic minimally conscious state patients should be tested in clinical trials, as patients currently refractory to amantadine might benefit from them.

Regional cerebral metabolic patterns demonstrate the role of anterior forebrain mesocircuit dysfunction in the severely injured brain.

Although disorders of consciousness (DOCs) demonstrate widely varying clinical presentations and patterns of structural injury, global down-regulation and bilateral reductions in metabolism of the thalamus and frontoparietal network are consistent findings. We test the hypothesis that global reductions of background synaptic activity in DOCs will associate with changes in the pattern of metabolic activity in the central thalamus and globus pallidus. We compared 32 [(18)F]fluorodeoxyglucose PETs obtained from severely brain-injured patients (BIs) and 10 normal volunteers (NVs). We defined components of the anterior forebrain mesocircuit on high-resolution T1-MRI (ventral, associative, and sensorimotor striatum; globus pallidus; central thalamus and noncentral thalamus). Metabolic profiles for BI and NV demonstrated distinct changes in the pattern of uptake: ventral and association striatum (but not sensorimotor) were significantly reduced relative to global mean uptake after BI; a relative increase in globus pallidus metabolism was evident in BI subjects who also showed a relative reduction of metabolism in the central thalamus. The reversal of globus pallidus and central thalamus profiles across BIs and NVs supports the mesocircuit hypothesis that broad functional (or anatomic) deafferentation may combine to reduce central thalamus activity and release globus pallidus activity in DOCs. In addition, BI subjects showed broad frontoparietal metabolic down-regulation consistent with prior studies supporting the link between central thalamic/pallidal metabolism and down-regulation of the frontoparietal network. Recovery of left hemisphere frontoparietal metabolic activity was further associated with command following.

Preservation of electroencephalographic organization in patients with impaired consciousness and imaging-based evidence of command-following.

OBJECTIVE: Standard clinical characterization of patients with disorders of consciousness (DOC) relies on observation of motor output and may therefore lead to the misdiagnosis of vegetative state or minimally conscious state in patients with preserved cognition. We used conventional electroencephalographic (EEG) measures to assess a cohort of DOC patients with and without functional magnetic resonance imaging (fMRI)-based evidence of command-following, and correlated the findings with standard clinical behavioral evaluation and brain metabolic activity. METHODS: We enrolled 44 patients with severe brain injury. Behavioral diagnosis was established using standardized clinical assessments. Long-term EEG recordings were analyzed to determine wakeful background organization and presence of elements of sleep architecture. A subset of patients had fMRI testing of command-following using motor imagery paradigms (26 patients) and resting brain metabolism measurement using (18) fluorodeoxyglucose positron emission tomography (31 patients). RESULTS: All 4 patients with fMRI evidence of covert command-following consistently demonstrated well-organized EEG background during wakefulness, spindling activity during sleep, and relative preservation of cortical metabolic activity. In the entire cohort, EEG organization and overall brain metabolism showed no significant association with bedside behavioral testing, except in a few cases when EEG was severely abnormal. INTERPRETATION: These findings suggest that conventional EEG is a simple strategy that complements behavioral and imaging characterization of DOC patients. Preservation of specific EEG features may be used to assess the likelihood of unrecognized cognitive abilities in severely brain-injured patients with very limited or no motor responses.

Organizing a Rational Approach to Treatments of Disorders of Consciousness Using the Anterior Forebrain Mesocircuit Model.

SUMMARY: Organizing a rational treatment strategy for patients with multifocal structural brain injuries and disorders of consciousness (DOC) is an important and challenging clinical goal. Among potential clinical end points, restoring elements of communication to DOC patients can support improved patient care, caregiver satisfaction, and patients' quality of life. Over the past decade, several studies have considered the use of the anterior forebrain mesocircuit model to approach this problem because this model proposes a supervening circuit-level impairment arising across DOC of varying etiologies. We review both the conceptual foundation of the mesocircuit model and studies of mechanisms underlying DOC that test predictions of this model. We consider how this model can guide therapeutic interventions and discuss a proposed treatment algorithm based on these ideas. Although the approach reviewed originates in the evaluation of patients with chronic DOC, we consider some emerging implications for patients in acute and subacute settings.

Kinematic improvement following Botulinum Toxin-A injection in upper-limb spasticity due to stroke.

Background Focal spasticity is a significant motor disorder following stroke, and Botulinum Toxin Type-A (BoNT-A) is a useful treatment for this. The authors evaluated kinematic modifications induced by spasticity, and whether or not there is any improvement following injection of BoNT-A. Methods Eight patients with stroke with upper-limb spasticity, showing a flexor pattern, were evaluated using kinematics before and after focal treatment with BoNT-A. A group of sex- and age-matched normal volunteers acted as a control group. Results Repeated-measures ANOVA showed that patients with stroke performed more slowly than the control group. Following treatment with BoNT-A, there was a significant improvement in kinematics in patients with stroke, while in the control group, performance remained unchanged. Conclusions Focal treatment of spasticity with BoNT-A leads to an adaptive change in the upper limb of patients with spastic stroke.

Continuous subcutaneous apomorphine for severe disorders of consciousness after traumatic brain injury.

BACKGROUND: The prognosis of long-term severe disorders of consciousness due to traumatic brain injury is discouraging. There is little definitive evidence of the underlying mechanisms, but a deficiency of the dopaminergic system may be involved. METHODS: In a prospective open-labelled clinical study, the feasibility, relative efficacy and safety of continuous subcutaneous (s.c.) administration of apomorphine in Vegetative State (VS) or Minimally Conscious State (MCS) patients due to severe traumatic brain injury (TBI) was tested. Apomorphine was administered to eight patients. Outcome measures were the Coma Near-Coma Scale (CNCS) and Disability Rating Scale (DRS). RESULTS: Drug management was implemented without any problems. There was improvement in the primary outcomes for all patients. Awakening was seen as rapidly as within the first 24 hours of drug administration and as late as 4 weeks. Seven of the patients had completely recovered consciousness. All improvements were sustained for at least 1 year, even after apomorphine was discontinued. Drug-related adverse events were all anticipated and resolved after the dose was reduced. CONCLUSION: Based on this open-label pilot study, continuous s.c. apomorphine infusion appears to be feasible, safe and potentially effective in improving consciousness in patients in VS and MCS due to severe TBI.

Fast awakening from minimally conscious state with apomorphine.

BACKGROUND: Traumatic brain injury (TBI) can induce long-term severe disorders of consciousness. Evidence suggests an underlying dopaminergic deficit. Dopamine agonists may therefore play an important role in recovery of consciousness. OBJECTIVE: To explore the response to continuous subcutaneous administration of apomorphine in a patient who had remained in minimally conscious state for 104 days and to evaluate the anatomical substrate of the effect. DESIGN: A prospective, open-label, daily treatment, dose-escalation single case clinical study, with retrospective diffusion tensor image (DTI) evaluation. RESULTS: On the fist day of treatment, the patient was able to move his limbs on command and answer yes/no questions which had not been the case prior to apomorphine administration. Subsequently there was a full recovery of consciousness and substantial functional recovery that was sustained even after apomorphine discontinuation. At the highest dose, mild dyskinesias were observed. These resolved with a lowering of the dose. DTI demonstrated a decrease of thalamocortical and corticothalamic projections in this MCS patient compared to normal volunteers. CONCLUSION: Although this is an open-label single-patient case report, the data are consistent with the theory that a dopaminergic deficit underlies MCS and that it may be overcome with apomorphine administration.

The neural substrate of gesture recognition.

Previous studies have linked action recognition with a particular pool of neurons located in the ventral premotor cortex, the posterior parietal cortex and the superior temporal sulcus (the mirror neuron system). However, it is still unclear if transitive and intransitive gestures share the same neural substrates during action-recognition processes. In the present study, we used event-related functional magnetic resonance imaging (fMRI) to assess the cortical areas active during recognition of pantomimed transitive actions, intransitive gestures, and meaningless control actions. Perception of all types of gestures engaged the right pre-supplementary motor area (pre-SMA), and bilaterally in the posterior superior temporal cortex, the posterior parietal cortex, occipitotemporal regions and visual cortices. Activation of the posterior superior temporal sulcus/superior temporal gyrus region was found in both hemispheres during recognition of transitive and intransitive gestures, and in the right hemisphere during the control condition; the middle temporal gyrus showed activation in the left hemisphere when subjects recognized transitive and intransitive gestures; activation of the left inferior parietal lobe and intraparietal sulcus (IPS) was mainly observed in the left hemisphere during recognition of the three conditions. The most striking finding was the greater activation of the left inferior frontal gyrus (IFG) during recognition of intransitive actions. Results show that a similar neural substrate, albeit, with a distinct engagement underlies the cognitive processing of transitive and intransitive gestures recognition. These findings suggest that selective disruptions in these circuits may lead to distinct clinical deficits.

Cortico-cortical networks in patients with ideomotor apraxia as revealed by EEG coherence analysis.

We sought to determine whether coherent networks which circumvent lesioned cortex are seen in patients with ideomotor apraxia (IMA) while performing tool-use pantomimes. Five normal subjects and five patients with IMA (three patients with corticobasal degeneration and two with left hemisphere stroke) underwent 64-channel EEG recording while performing three tool-use pantomimes with their left hand in a self-paced manner. Beta band (20-22 Hz) coherence indicates that normal subjects have a dominant left hemisphere network responsible for praxis preparation, which was absent in patients. Corticobasal degeneration patients showed significant coherence increase between left parietal-right premotor areas. Left hemisphere stroke patients showed significant coherence increases in a right parietofrontal network. The right hemisphere appears to store useable praxis representations in IMA patients with left hemisphere damage.

Cortical Response to the Natural Speech Envelope Correlates with Neuroimaging Evidence of Cognition in Severe Brain Injury.

Recent studies identify severely brain-injured patients with limited or no behavioral responses who successfully perform functional magnetic resonance imaging (fMRI) or electroencephalogram (EEG) mental imagery tasks [1-5]. Such tasks are cognitively demanding [1]; accordingly, recent studies support that fMRI command following in brain-injured patients associates with preserved cerebral metabolism and preserved sleep-wake EEG [5, 6]. We investigated the use of an EEG response that tracks the natural speech envelope (NSE) of spoken language [7-22] in healthy controls and brain-injured patients (vegetative state to emergence from minimally conscious state). As audition is typically preserved after brain injury, auditory paradigms may be preferred in searching for covert cognitive function [23-25]. NSE measures are obtained by cross-correlating EEG with the NSE. We compared NSE latencies and amplitudes with and without consideration of fMRI assessments. NSE latencies showed significant and progressive delay across diagnostic categories. Patients who could carry out fMRI-based mental imagery tasks showed no statistically significant difference in NSE latencies relative to healthy controls; this subgroup included patients without behavioral command following. The NSE may stratify patients with severe brain injuries and identify those patients demonstrating "cognitive motor dissociation" (CMD) [26] who show only covert evidence of command following utilizing neuroimaging or electrophysiological methods that demand high levels of cognitive function. Thus, the NSE is a passive measure that may provide a useful screening tool to improve detection of covert cognition with fMRI or other methods and improve stratification of patients with disorders of consciousness in research studies.

Isolation Syndrome after Cardiac Arrest and Therapeutic Hypothermia.

Here, we present the first description of an isolation syndrome in a patient who suffered prolonged cardiac arrest and underwent a standard therapeutic hypothermia protocol. Two years after the arrest, the patient demonstrated no motor responses to commands, communication capabilities, or visual tracking at the bedside. However, resting neuronal metabolism and electrical activity across the entire anterior forebrain was found to be normal despite severe structural injuries to primary motor, parietal, and occipital cortices. In addition, using quantitative electroencephalography, the patient showed evidence for willful modulation of brain activity in response to auditory commands revealing covert conscious awareness. A possible explanation for this striking dissociation in this patient is that altered neuronal recovery patterns following therapeutic hypothermia may lead to a disproportionate preservation of anterior forebrain cortico-thalamic circuits even in the setting of severe hypoxic injury to other brain areas. Compared to recent reports of other severely brain-injured subjects with such dissociation of clinically observable (overt) and covert behaviors, we propose that this case represents a potentially generalizable mechanism producing an isolation syndrome of blindness, motor paralysis, and retained cognition as a sequela of cardiac arrest and therapeutic hypothermia. Our findings further support that highly-preserved anterior cortico-thalamic integrity is associated with the presence of conscious awareness independent from the degree of injury to other brain areas.

Local changes in network structure contribute to late communication recovery after severe brain injury.

Spontaneous recovery of brain function after severe brain injury may evolve over a long time period and is likely to involve both structural and functional reorganization of brain networks. We longitudinally tracked the recovery of communication in a patient with severe brain injury using multimodal brain imaging techniques and quantitative behavioral assessments measured at the bedside over a period of 2 years and 9 months (21 months after initial injury). Structural diffusion tensor imaging revealed changes in brain structure across interhemispheric connections and in local brain regions that support language and visuomotor function. These findings correlated with functional brain imaging using functional magnetic resonance imaging and positron emission tomography, which demonstrated increased language network recruitment in response to natural speech stimuli, graded increases in interhemispheric interactions of language-related frontal cortices, and increased cerebral metabolic activity in the language-dominant hemisphere. In addition, electrophysiological studies showed recovery of synchronization of sleep spindling activity. The observed changes suggest a specific mechanism for late recovery of communication after severe brain injury and provide support for the potential of activity-dependent structural and functional remodeling over long time periods.

Synchronization of parietal and premotor areas during preparation and execution of praxis hand movements.

OBJECTIVE: We sought to determine temporal patterns of functional connectivity between the parietal, premotor, and motor cortices during preparation and execution of praxis hand movements. METHODS: Normal subjects were instructed to perform six transitive (tool use) and intransitive (communicative gesture) self-paced pantomimes with the right hand while recording 64-channel electroencephalography (EEG) and electromyography (EMG) from right thumb and forearm flexors. Focusing on corticocortical coherence, we explored the time-course of synchronously active parietal and premotor circuits involved in these motor tasks. Trials were marked for EMG onset and averaged across subjects to determine changes in coherence relative to baseline between parietal, premotor, and motor areas. RESULTS: Coherence of homologous electrode pairs was similar when comparing transitive and intransitive movements. During preparation, beta band (18-22 Hz) coherence was maximal between electrodes over the left parietal lobe and left premotor electrodes. Additionally during preparation, the premotor area showed high coherence to the motor hand area and the parietal cortex. Electrodes over the supplementary motor area also showed coherence to the motor and parietal, but not the premotor area. Before and during execution, a second peak of high coherence increase was present in each area that demonstrated coherence increases during preparation. There was no coherence increase between parietal and motor areas. Coherence rapidly diminished 1.5-2.0 s after movement onset. CONCLUSIONS: Patterns of increased corticocortical coupling within a parietal, premotor, and motor network are present during preparation and execution of praxis movements. SIGNIFICANCE: This study adds to evidence that parietofrontal networks may be critical for integrating preparatory and motor-related activity for praxis movements.

Neuromodulation of the conscious state following severe brain injuries.

Disorders of consciousness (DOC) following severe structural brain injuries globally affect the conscious state and the expression of goal-directed behaviors. In some subjects, neuromodulation with medications or electrical stimulation can markedly improve the impaired conscious state present in DOC. We briefly review recent studies and provide an organizing framework for considering the apparently widely disparate collection of medications and approaches that may modulate the conscious state in subjects with DOC. We focus on neuromodulation of the anterior forebrain mesocircuit in DOC and briefly compare mechanisms supporting recovery from structural brain injuries to those underlying facilitated emergence from unconsciousness produced by anesthesia. We derive some general principles for approaching the problem of restoration of consciousness after severe structural brain injuries, and suggest directions for future research.

The effect of the visual context in the recognition of symbolic gestures.

BACKGROUND: To investigate, by means of fMRI, the influence of the visual environment in the process of symbolic gesture recognition. Emblems are semiotic gestures that use movements or hand postures to symbolically encode and communicate meaning, independently of language. They often require contextual information to be correctly understood. Until now, observation of symbolic gestures was studied against a blank background where the meaning and intentionality of the gesture was not fulfilled. METHODOLOGY/PRINCIPAL FINDINGS: Normal subjects were scanned while observing short videos of an individual performing symbolic gesture with or without the corresponding visual context and the context scenes without gestures. The comparison between gestures regardless of the context demonstrated increased activity in the inferior frontal gyrus, the superior parietal cortex and the temporoparietal junction in the right hemisphere and the precuneus and posterior cingulate bilaterally, while the comparison between context and gestures alone did not recruit any of these regions. CONCLUSIONS/SIGNIFICANCE: These areas seem to be crucial for the inference of intentions in symbolic gestures observed in their natural context and represent an interrelated network formed by components of the putative human neuron mirror system as well as the mentalizing system.

Left parietal activation related to planning, executing and suppressing praxis hand movements.

OBJECTIVE: We sought to investigate the activity of bilateral parietal and premotor areas during a Go/No Go paradigm involving praxis movements of the dominant hand. METHODS: A sentence was presented which instructed subjects on what movement to make (S1; for example, "Show me how to use a hammer."). After an 8-s delay, "Go" or "No Go" (S2) was presented. If Go, they were instructed to make the movement described in the S1 instruction sentence as quickly as possible, and continuously until the "Rest" cue was presented 3 s later. If No Go, subjects were to simply relax until the next instruction sentence. Event-related potentials (ERP) and event-related desynchronization (ERD) in the beta band (18-22 Hz) were evaluated for three time bins: after S1, after S2, and from -2.5 to -1.5 s before the S2 period. RESULTS: Bilateral premotor ERP was greater than bilateral parietal ERP after the S2 Go compared with the No Go. Additionally, left premotor ERP was greater than that from the right premotor area. There was predominant left parietal ERD immediately after S1 for both Go and No Go, which was sustained for the duration of the interval between S1 and S2. For both S2 stimuli, predominant left parietal ERD was again seen when compared to that from the left premotor or right parietal area. However, the left parietal ERD was greater for Go than No Go. CONCLUSION: The results suggest a dominant role in the left parietal cortex for planning, executing, and suppressing praxis movements. The ERP and ERD show different patterns of activation and may reflect distinct neural movement-related activities. SIGNIFICANCE: The data can guide further studies to determine the neurophysiological changes occurring in apraxia patients and help explain the unique error profiles seen in patients with left parietal damage.

The role of the dorsal stream for gesture production.

Skilled gestures require the integrity of the neural networks involved in storage, retrieval, and execution of motor programs. Premotor cortex and/or parietal cortex lesions frequently produce deficits during performance of gestures, transitive more than intransitive. The dorsal stream links object information with object action, suggesting that mechanical knowledge of tool use is stored focally in the brain. Using event-related fMRI, we explored activity during instructed-delay transitive and intransitive hand gestures. The comparison between planning-preparation and execution of gestures demonstrated a temporal rostral to caudal gradient of activation in the ventral premotor cortex (PMv) and inferior to superior gradient of activation in the posterior parietal cortex (PPc). Comparison between transitive and intransitive gestures established a functional specificity within the dorsal stream for mechanical knowledge. Results demonstrate that not only PPc but also the PMv acts in the processing of sensorimotor information during gestures. This might be the substrate underlying selective deficits in ideomotor apraxia patients.

Reorganization of the human ipsilesional premotor cortex after stroke.

The substrates that mediate recovery of motor function after stroke are incompletely understood. Several primate and human studies proposed the involvement of the premotor cortex of the lesioned hemisphere. Here, we studied four chronic stroke patients with focal subcortical lesions affecting the corticospinal outflow originating in the primary motor cortex (M1) and good motor recovery. We tested the hypothesis that, in these patients, disruption of activity in the premotor cortex of the lesioned hemisphere by transcranial magnetic stimulation (TMS) would result in degraded behaviour in the paretic hand. TMS was applied to the primary motor cortex, dorsal premotor cortex (PMd) and ventral premotor cortex (PMv) of the affected (M1AH, PMdAH, PMvAH) and intact (M1IH, PMdIH, PMvIH) hemispheres of patients and healthy controls in the setting of a simple reaction time (SRT) paradigm performed with the hand contralateral to the stimulated hemisphere. TMS applied to M1 led to substantial contralateral SRT delays in both groups. TMS applied to PMdAH of patients elicited clear delays in contralateral SRT in the paretic hand, whereas TMS applied to PMdIH of patients or healthy volunteers did not. Motor evoked potentials after stimulation of PMdAH were, on average, larger and had, on average, shorter latency than after stimulation of M1AH. These results indicate that PMdAH participates as a substrate mediating functional recovery of executive motor function in patients with focal lesions of corticospinal outflow originating in M1 and good motor recovery. Our results are consistent with the hypothesis that the dorsal premotor cortex of the affected hemisphere can reorganize to control basic parameters of movement usually assigned to M1 function.