Assessment of Event-Related EEG Power After Single-Pulse TMS in Unresponsive Wakefulness Syndrome and Minimally Conscious State Patients.

In patients without a behavioral response, non-invasive techniques and new methods of data analysis can complement existing diagnostic tools by providing a method for detecting covert signs of residual cognitive function and awareness. The aim of this study was to investigate the brain oscillatory activities synchronized by single-pulse transcranial magnetic stimulation (TMS) delivered over the primary motor area in the time-frequency domain in patients with the unresponsive wakefulness syndrome or in a minimally conscious state as compared to healthy controls. A time-frequency analysis based on the wavelet transform was used to characterize rapid modifications of oscillatory EEG rhythms induced by TMS in patients as compared to healthy controls. The pattern of EEG changes in the patients differed from that of healthy controls. In the controls there was an early synchronization of slow waves immediately followed by a desynchronization of alpha and beta frequency bands over the frontal and centro-parietal electrodes, whereas an opposite early synchronization, particularly over motor areas for alpha and beta and over the frontal and parietal electrodes for beta power, was seen in the patients. In addition, no relevant modification in slow rhythms (delta and theta) after TMS was noted in patients. The clinical impact of these findings could be relevant in neurorehabilitation settings for increasing the awareness of these patients and defining new treatment procedures.

Coherence and Consciousness: Study of Fronto-Parietal Gamma Synchrony in Patients with Disorders of Consciousness.

Evaluation of consciousness needs to be supported by the evidence of brain activation during external stimulation in patients with unresponsive wakefulness syndrome (UWS). Assessment of patients should include techniques that do not depend on overt motor responses and allow an objective investigation of the spontaneous patterns of brain activity. In particular, electroencephalography (EEG) coherence allows to easily measure functional relationships between pairs of neocortical regions and seems to be closely correlated with cognitive or behavioral measures. Here, we show the contribution of higher order associative cortices of patients with disorder of consciousness (N = 26) in response to simple sensory stimuli, such as visual, auditory and noxious stimulation. In all stimulus modalities an increase of short-range parietal and long-range fronto-parietal coherences in gamma frequencies were seen in the controls and minimally conscious patients. By contrast, UWS patients showed no significant modifications in the EEG patterns after stimulation. Our results suggest that UWS patients can not activate associative cortical networks, suggesting a lack of information integration. In fact, fronto-parietal circuits result to be connectively disrupted, conversely to patients that exhibit some form of consciousness. In the light of this, EEG coherence can be considered a powerful tool to quantify the involvement of cognitive processing giving information about the integrity of fronto-parietal network. This measure can represent a new neurophysiological marker of unconsciousness and help in determining an accurate diagnosis and rehabilitative intervention in each patient.

Autonomic dysfunction in the early stage of ALS with bulbar involvement.

Our objective was to assess the autonomic function of ALS patients with and without bulbar signs to characterize dysautonomia in ALS disease. Standard autonomic tests and spectral analysis of heart rate variability (HRV), reflecting changes in the sympathovagal balance, were examined in 33 ALS patients (14 with bulbar signs) and 30 controls. Results showed that in the supine position, ALS patients had significantly lower total power and absolute values of high-frequency power indicating a depressed sinus arrhythmia. Patients with bulbar signs showed more marked autonomic alterations at rest. Tilting did not induce the expected increase in low-frequency and decrease in high-frequency power of HRV in all patients. No correlation was found between autonomic tests and clinical parameters. Our findings suggest an early subclinical involvement of the autonomic system in ALS, particularly affecting parasympathetic cardiac control. Patients with prominent bulbar signs show a more severe autonomic dysfunction under resting conditions.

EEG to Identify Attempted Movement in Unresponsive Wakefulness Syndrome.

Assessment of consciousness following severe brain-injury is challenging. Our hypothesis is that electroencephalography (EEG) can provide information on awareness, in terms of oscillatory activity and network task-related modifications, in people with disorders of consciousness. Similar results were obtained with neuroimaging techniques; we aim at demonstrating the use of EEG, which is low cost and routinely implemented, to the same goal. Nineteen-channel EEG was recorded in 7 persons with unresponsive wakefulness syndrome (UWS) and in 10 healthy subjects during the execution of active (attempted movement) and passive motor tasks as well as 2 mental imagery tasks. Event-related synchronization/desynchronization (ERS/ERD), coherence and network parameters were calculated in delta (1-4 Hz), theta (4-8 Hz), alpha1 (8-10 Hz), alpha2 (10-12 Hz), and beta (13-30 Hz) ranges. In UWS subjects, passive movement induced a weak alpha2 ERD over contralateral sensorimotor area. During motor imagery, ERD was detected over the frontal and motor contralateral brain areas; during spatial imagery, ERS in lower alpha band over the right temporo-parietal regions was missing. In UWS, functional connectivity provided evidence of network disruption and isolation of the motor areas, which cannot dialog with adjacent network nodes, likely suggesting a diffuse structural alteration. Our findings suggest that people with a clinical diagnosis of UWS were able to modulate their brain activity when prompted to perform movement tasks and thus suggest EEG as a potential tool to support diagnosis of disorders of consciousness.

Post-acute P300 predicts recovery of consciousness from traumatic vegetative state.

BACKGROUND: Evoked potentials allow one to assess functional integrity of sensory pathways projecting to primary sensory cortices and event-related potentials assess higher order cortical functions associated with stimulus detection and decision-making. Evoked and event-related potentials have been used to predict emergence from coma. This study aimed to determine whether they can help prediction of consciousness recovery in post-traumatic vegetative state (VS). METHODS: Thirty-four patients in post-traumatic VS were assessed clinically and neurophysiologically at 2-3 months after injury and followed up to 1 year. Patients were assessed with the Disability Rating Scale (DRS) and with electroencephalogram (EEG), brainstem auditory (BAEP) and somatosensory evoked potentials (SEP) and P300. Demographic, clinical and neurophysiological measures were analysed by descriptive and logistic regression techniques. RESULTS: At 1 year from injury, 26 patients (76%) had recovered consciousness and eight patients (24%) had not. In univariate analyses, a detectable P300, a reactive EEG and lower DRS scores were found at entry assessment more frequently (p < 0.05) in patients who later recovered consciousness than in those who did not. Logistic regression analysis revealed that P300 was the only factor contributing to prediction of conscious recovery with an area under the ROC curve of 0.94 (95% CI, 0.80-0.99). CONCLUSIONS: P300 is a strong predictor of conscious recovery in VS.

Behavioural and electrophysiological effects of tDCS to prefrontal cortex in patients with disorders of consciousness.

OBJECTIVES: Left dorsolateral prefrontal cortex anodal transcranial direct current stimulation (tDCS) was applied in a group of patients with disorders of consciousness to determine the effects of modulation of spontaneous oscillatory brain activity. METHODS: 12 patients in an unresponsive wakefulness syndrome (UWS) and 12 in a minimally conscious state (MCS) underwent 2-weeks active and 2-weeks sham tDCS. Neurophysiological assessment was performed with EEG power spectra and coherence analysis directly before and after each session. RESULTS: An increase of power and coherence of the frontal and parietal alpha and beta frequency bands and significant clinical improvements were seen after the active tDCS in MCS patients. In contrast, UWS patients showed some local frontal changes in the slow frequencies. No treatment effect was observed after sham. CONCLUSIONS: tDCS could induce changes in cortical EEG oscillations, modulating the travel of alpha and beta waves between anterior and posterior brain areas when some cognitive functions were preserved. This plays an important role in consciousness by integrating cognitive-emotional processing with the state of arousal. In unresponsive people, brain integration seems to be lost. SIGNIFICANCE: Our results further support the critical role of long-range fronto-parietal connections in consciousness and show the potential therapeutic utility of tDCS.

Effects of combined endurance and resistance training in Amyotrophic Lateral Sclerosis: A pilot, randomized, controlled study.

Based on available evidence, muscle strengthening and cardiovascular exercises can help maintain function and not adversely affect the progression of disease in patients with ALS. However, this evidence is not sufficiently detailed to recommend a specific exercise prescription. The purpose of this project was to assess clinical outcomes of a combined exercise programme to increase knowledge of rehabilitation in ALS patients. 38 ALS patients were assigned randomly to two groups: one group underwent a specific exercise programme (ALS-EP) based on a moderate aerobic workout and isometric contractions, and the second group followed a standard neuromotor rehabilitation treatment. Objective evaluation consisted of cardiovascular measures, muscle strength and fatigue. Some positive effects of physical activity on ALS patients were found. Among the benefits, an overall improvement of functional independence in all patients, independently of the type of exercise conducted was seen. In addition, improvements in muscle power, oxygen consumption and fatigue were specifically observed in the ALS-EP group, all hallmarks of a training effect for the specific exercises. In conclusion, moderate intensity exercise is beneficial in ALS, helping in avoiding deconditioning and muscle atrophy resulting from progressive inactivity.

Magnetoencephalography in Stroke Recovery and Rehabilitation.

Magnetoencephalography (MEG) is a non-invasive neurophysiological technique used to study the cerebral cortex. Currently, MEG is mainly used clinically to localize epileptic foci and eloquent brain areas in order to avoid damage during neurosurgery. MEG might, however, also be of help in monitoring stroke recovery and rehabilitation. This review focuses on experimental use of MEG in neurorehabilitation. MEG has been employed to detect early modifications in neuroplasticity and connectivity, but there is insufficient evidence as to whether these methods are sensitive enough to be used as a clinical diagnostic test. MEG has also been exploited to derive the relationship between brain activity and movement kinematics for a motor-based brain-computer interface. In the current body of experimental research, MEG appears to be a powerful tool in neurorehabilitation, but it is necessary to produce new data to confirm its clinical utility.

Dopaminergic Medication Modulates Learning from Feedback and Error-Related Negativity in Parkinson's Disease: A Pilot Study.

Dopamine systems mediate key aspects of reward learning. Parkinson's disease (PD) represents a valuable model to study reward mechanisms because both the disease process and the anti-Parkinson medications influence dopamine neurotransmission. The aim of this pilot study was to investigate whether the level of levodopa differently modulates learning from positive and negative feedback and its electrophysiological correlate, the error related negativity (ERN), in PD. Ten PD patients and ten healthy participants performed a two-stage reinforcement learning task. In the Learning Phase, they had to learn the correct stimulus within a stimulus pair on the basis of a probabilistic positive or negative feedback. Three sets of stimulus pairs were used. In the Testing Phase, the participants were tested with novel combinations of the stimuli previously experienced to evaluate whether they learned more from positive or negative feedback. PD patients performed the task both ON- and OFF-levodopa in two separate sessions while they remained on stable therapy with dopamine agonists. The electroencephalogram (EEG) was recorded during the task. PD patients were less accurate in negative than positive learning both OFF- and ON-levodopa. In the OFF-levodopa state they were less accurate than controls in negative learning. PD patients had a smaller ERN amplitude OFF- than ON-levodopa only in negative learning. In the OFF-levodopa state they had a smaller ERN amplitude than controls in negative learning. We hypothesize that high tonic dopaminergic stimulation due to the dopamine agonist medication, combined to the low level of phasic dopamine due to the OFF-levodopa state, could prevent phasic "dopamine dips" indicated by the ERN needed for learning from negative feedback.

Selective attention impairment in amyotrophic lateral sclerosis.

Objective of this study was to evaluate attentional control mechanisms in amyotrophic lateral sclerosis (ALS) using an auditory event-related potentials (ERPs) paradigm. Fifteen mild to moderate ALS patients and 15 healthy controls were administered a brief neuropsychological test battery and an ERPs paradigm assessing selective attention. Four types of auditory stimuli were presented in random order: short standard (200 Hz, 200 ms), long standard (200 Hz, 500 ms), short deviant (1000 Hz, 200 ms) and long deviant (1000 Hz, 500 ms). Participants had to respond to the long deviant stimuli only. During the task the electroencephalogram (EEG) was recorded. The N200, P300 and re-orienting negativity (RON) ERP components were analysed. Compared to controls ALS patients showed reduced amplitudes and delayed latencies of N200, P300 and RON. These results could be attributable to both an alteration in change detection resulting in a reduction of the allocation and re-orientation of attentional resources or a general slowing or reduction of neural processing efficiency in the same system. The ERPs results support the hypothesis that ALS involves extramotor cognitive functions including auditory attentional processing at all processing stages, early (200 ms) and late (300-600 ms). These data prove the usefulness and sensitivity of the auditory ERPs in detection of cognitive functions in ALS patients.

Amyotrophic lateral sclerosis progression and stability of brain-computer interface communication.

Our objective was to investigate the relationship between brain-computer interface (BCI) communication skill and disease progression in amyotrophic lateral sclerosis (ALS). We sought also to assess stability of BCI communication performance over time and whether it is related to the progression of neurological impairment before entering the locked-in state. A three years follow-up, BCI evaluation in a group of ALS patients (n = 24) was conducted. For a variety of reasons only three patients completed the three years follow-up. BCI communication skill and disability level, using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised, were assessed at admission and at each of the three follow-ups. Multiple non-parametric statistical methods were used to ensure reliability of the dependent variables: correlations, paired test and factor analysis of variance. Results demonstrated no significant relationship between BCI communication skill (BCI-CS) and disease evolution. The patients who performed the follow-up evaluations preserved their BCI-CS over time. Patients' age at admission correlated positively with the ability to achieve control over a BCI. In conclusion, disease evolution in ALS does not affect the ability to control a BCI for communication. BCI performance can be maintained in the different stages of the illness.

Transcranial direct current stimulation (tDCS) of Broca's area in chronic aphasia: a controlled outcome study.

BACKGROUND: In the last decade transcranial direct current stimulation (tDCS) has been introduced in aphasia post-stroke recovery as a tool for modulating neuroplasticity. However, it is still unclear whether tDCS should be applied at rest (off-line) or combined with behavioral treatment strategies (on-line), therefore, this study investigates the effect of repeated sessions of off-line tDCS on language recovery in post-stroke chronic aphasic patients. METHODOLOGY: Eight post-stroke patients with different type and degree of chronic aphasia underwent two weeks of off-line anodal tDCS (2 mA intensity for 20 min a day) on Broca's area and two weeks of sham stimulation as a control condition. Language recovery was measured assessing object and action naming abilities with a computerized picture naming task. RESULTS: No significant difference between anodal tDCS and sham stimulation, both for object and action naming tasks, was found. Descriptive analysis of single cases showed that after tDCS only one patient improved substantially on action naming task. CONCLUSION: With the exception of one patient, the overall results suggest that in chronic aphasic patients the off-line tDCS protocol applied in this study is not effective in improving noun and verb naming abilities.

Effect of high-frequency repetitive transcranial magnetic stimulation on brain excitability in severely brain-injured patients in minimally conscious or vegetative state.

BACKGROUND: Repetitive transcranial magnetic stimulation (rTMS) induces prolonged functional changes in the cerebral cortex in normal conditions and in altered states of consciousness. Its therapeutic effects have been variously documented. OBJECTIVE: The aim of this study was to investigate the reactivity of electroencephalography (EEG) and the clinical response in six severely brain-injured patients in an altered state of consciousness (minimally conscious state [MCS] or vegetative state [VS]). EEG rhythm and brain excitability were measured before and after a protocol of high-frequency rTMS. METHODS: All six patients underwent clinical and neurophysiological evaluation before rTMS and immediately thereafter. EEG data in resting state were acquired at the beginning of the exam (T0), after rTMS (T1), and 38 min after rTMS (T2). From these data the power values were computed using Fast Fourier Transform. RESULTS: rTMS over the motor cortex induced long-lasting behavioral and neurophysiological modifications in only one patient in MCS. No significant clinical or EEG modifications were detected in any of the other patients, except for changes in motor threshold and motor evoked potential amplitude over the stimulated motor areas. CONCLUSIONS: The main finding of the study is the correlation between EEG reactivity and clinical response after rTMS. Reappearance of fast activity and an increase in slow activity were noted in the one patient with transitory arousal, whereas no significant reliable changes were observed in the other patients showing no clinical reactivity.

Kinematic and neurophysiological consequences of an assisted-force-feedback brain-machine interface training: a case study.

In a proof-of-principle prototypical demonstration we describe a new type of brain-machine interface (BMI) paradigm for upper limb motor-training. The proposed technique allows a fast contingent and proportionally modulated stimulation of afferent proprioceptive and motor output neural pathways using operant learning. Continuous and immediate assisted-feedback of force proportional to rolandic rhythm oscillations during actual movements was employed and illustrated with a single case experiment. One hemiplegic patient was trained for 2 weeks coupling somatosensory brain oscillations with force-field control during a robot-mediated center-out motor-task whose execution approaches movements of everyday life. The robot facilitated actual movements adding a modulated force directed to the target, thus providing a non-delayed proprioceptive feedback. Neuro-electric, kinematic, and motor-behavioral measures were recorded in pre- and post-assessments without force assistance. Patient's healthy arm was used as control since neither a placebo control was possible nor other control conditions. We observed a generalized and significant kinematic improvement in the affected arm and a spatial accuracy improvement in both arms, together with an increase and focalization of the somatosensory rhythm changes used to provide assisted-force-feedback. The interpretation of the neurophysiological and kinematic evidences reported here is strictly related to the repetition of the motor-task and the presence of the assisted-force-feedback. Results are described as systematic observations only, without firm conclusions about the effectiveness of the methodology. In this prototypical view, the design of appropriate control conditions is discussed. This study presents a novel operant-learning-based BMI-application for motor-training coupling brain oscillations and force feedback during an actual movement.

Preservation of auditory P300-like potentials in cortical deafness.

The phenomenon of blindsight has been largely studied and refers to residual abilities of blind patients without an acknowledged visual awareness. Similarly, "deaf hearing" might represent a further example of dissociation between detection and perception of sounds. Here we report the rare case of a patient with a persistent and complete cortical deafness caused by damage to the bilateral temporo-parietal lobes who occasionally showed unexpected reactions to environmental sounds despite she denied hearing. We applied for the first time electrophysiological techniques to better understand auditory processing and perceptual awareness of the patient. While auditory brainstem responses were within normal limits, no middle- and long-latency waveforms could be identified. However, event-related potentials showed conflicting results. While the Mismatch Negativity could not be evoked, robust P3-like waveforms were surprisingly found in the latency range of 600-700 ms. The generation of P3-like potentials, despite extensive destruction of the auditory cortex, might imply the integrity of independent circuits necessary to process auditory stimuli even in the absence of consciousness of sound. Our results support the reverse hierarchy theory that asserts that the higher levels of the hierarchy are immediately available for perception, while low-level information requires more specific conditions. The accurate characterization in terms of anatomy and neurophysiology of the auditory lesions might facilitate understanding of the neural substrates involved in deaf-hearing.

Persistent cortical deafness: a voxel-based morphometry and tractography study.

OBJECTIVE: In cortical deafness, no auditory signals can be perceived by the cortex despite normal peripheral hearing. Cortical deafness rarely persists, but generally evolves into other cortical auditory syndromes. In this report, we describe a patient showing a stable and persisting pattern of cortical deafness 16 months after two major ischemic strokes. METHODS: Voxel based morphometric evidence from high resolution three-dimensional MRI and data from tractography are reported for the first time, to our knowledge, in this syndrome in addition to behavioral and electrophysiological findings. RESULTS: The most remarkable findings came from the tractography data, where an asymmetric pattern was found showing severe damage of connections within the anterior right hemisphere, in regions subserving self-awareness. Frontal asymmetry, although detectable by the morphometric analysis, was less informative than that detected in the tractography data. CONCLUSION: The evidence from this case study suggests that damage to the neural systems involved in awareness may play an important role in the emergence of cortical deafness and its persistence.

Behavioral and neurophysiological effects of repetitive transcranial magnetic stimulation on the minimally conscious state: a case study.

BACKGROUND: In 2007, Schiff et al reported a patient in a minimally conscious state (MCS) who responded to deep brain stimulation (DBS), but clinicians cannot predict which patients might respond prior to the implantation of electrodes. METHODS: A patient in a MCS for 5 years participated in an ABA design alternating between repetitive transcranial magnetic stimulation (rTMS) and peripheral nerve stimulation. rTMS (condition A) involved the delivery of 10 trains of 100 stimuli at 20 Hz using a stimulator with a 70-mm figure-of-eight coil to elicit a contraction of the abductor pollicis brevis. Condition B used median nerve electrical stimulation. RESULTS: After peripheral stimulation, the patient did not exhibit clinical, behavioral, or electroencephalographic (EEG) changes. The frequency of specific and meaningful behaviors increased after rTMS, along with the absolute and relative power of the EEG δ, ß, and α bands. CONCLUSION: These results suggest that rTMS may improve awareness and arousal in MCS. If these results are reproducible, rTMS may identify subgroups of MCS patients who might benefit from DBS.

Brain-computer interface in stroke: a review of progress.

Brain-computer interface (BCI) technology has been used for rehabilitation after stroke and there are a number of reports involving stroke patients in BCI-feedback training. Most publications have demonstrated the efficacy of BCI technology in post-stroke rehabilitation using output devices such as Functional Electrical Stimulation, robot, and orthosis. The aim of this review is to focus on the progress of BCI-based rehabilitation strategies and to underline future challenges. A brief history of clinical BCI-approaches is presented focusing on stroke motor rehabilitation. A context for three approaches of a BCI-based motor rehabilitation program is outlined: the substitutive strategy, classical conditioning and operant conditioning. Furthermore, we include an overview of a pilot study concerning a new neuro-forcefeedback strategy. This pilot study involved healthy participants. Finally we address some challenges for future BCI-based rehabilitation.