Psychophysiological correlates of coping and quality of life in patients with ALS.

OBJECTIVE: Self-regulation models of coping suggest that patients with chronic diseases reporting low quality of life (QoL), an indicator of failed coping efforts, should show facilitated access to disease related words. Here we investigated whether a reduced N400 amplitude within an incongruent, i.e. unpredictable disease-related context would be a correlate of this facilitated access. METHODS: ERPs were recorded in N=18 patients with amyotrophic lateral sclerosis (ALS) and N=20 age-matched healthy controls during reading of sentences, ending either with congruent or incongruent words. Incongruent and congruent words were disease related or disease unrelated. Mean N400 amplitudes were analyzed with mixed models. RESULTS: Generally, incongruent words elicited a more negative N400 amplitude than congruent words in all groups and conditions, i.e. an N400 effect. In patients with high QoL this N400 effect did not differ between disease related and unrelated words. In patients with low QoL, however, the N400 effect was significantly smaller for disease related than for disease unrelated words. In healthy controls N400 amplitudes showed no such interaction between congruence, disease relatedness and QoL. Results remained stable when controlling for disease severity, duration and depression. CONCLUSION: The N400 indicates increased accessibility to disease related information in ALS patients with low QoL. The increased access may imply a constantly activated disease related context which is linked to low QoL. SIGNIFICANCE: N400 modulation by disease related information may serve as a psychophysiological correlate of coping and the patient's QoL.

Towards a more precise neurophysiological assessment of cognitive functions in patients with disorders of consciousness.

PURPOSE: To analyze the principles that guide inference of covert cognitive functions and consciousness in patients with extremely severe brain damage on the basis of neurophysiological test results. METHODS: (1) A quantitative analysis of a range of possible inferences based on neurophysiological findings in low- and non-responsive patients; (2) a logical analysis of the various possible orders of application of neurophysiological tests in such patients. RESULTS: Surprisingly, improvement of neurophysiological test qualities contributes to the improvement of diagnostic results less than some other factors, such as the structure of the patient population, the quality of the previous clinical diagnosis, and the variability of the methods used. CONCLUSIONS: A sequential decision procedure is suggested. Different test paradigms should be combined most effectively to arrive at a reliable evaluation of cognitive functions in this patient population.

Effects of rizatriptan on the contingent negative variation in healthy women.

The effect of the antimigraine drug rizatriptan on the amplitude and habituation of the contingent negative variation (CNV) in healthy women was examined in a randomized, double-blind, placebo-controlled trial. The test persons were assigned either to a drug (n = 20) or a placebo group (n = 20). The CNV was recorded three times: before, directly after, and 24 h after drug or placebo intake. The CNV paradigm was presented in a standard, a cued and a choice version. Rizatriptan led to an increase of CNV amplitude that depended on the level of difficulty of the task. Whereas there was no drug effect in the standard version, an amplitude increase was obtained mainly in the choice task. The results are in line with the ceiling theory of migraine, which assumes a rise of CNV amplitude if the serotonin level is lowered.

Cognitive function in patients with late stage amyotrophic lateral sclerosis.

BACKGROUND: Subtle cognitive deficits have been found in a substantial percentage of patients with early stage amyotrophic lateral sclerosis (ALS). Cognitive function in later stages of the disease remain to be investigated because the neuropsychological tests that are usually employed, such as written or verbal fluency tests, cannot be performed by those patients because of motor or speech impairment, or both. METHODS: In the present study, 11 patients with late stage ALS who were severely physically impaired and matched controls underwent a neuropsychological test battery to explore their cognitive function with respect to disease related functional status. Testing was restricted to tasks that used a binary (yes/no) signal and did not require verbalisation or measures of reaction time to index performance. RESULTS: Although some patients displayed deficits in aspects of executive function, learning and memory, overall test results indicated normal cognitive function. A statistically highly significant negative correlation was found between the performance on two learning and memory tasks and the functional status of the patients. CONCLUSION: The results of this study indicate a superior performance on learning and memory tasks of patients whose disease had further progressed. This may have important implications for our view on cognitive function in relation to the course of the disease.

Predicting coma and other low responsive patients outcome using event-related brain potentials: a meta-analysis.

OBJECTIVE: A meta-analysis was performed to estimate the predictive power (odd ratio, OR) for awakening of auditory event-related potential (ERP) components in low responsive patients with stroke or hemorrhage, trauma, anoxic, post-operative, and metabolic encephalopathy etiologies. METHODS: We reviewed MEDLINE and analyzed citations for retrieved articles. Logistic regressions were applied on patient samples (Glasgow Coma Scale <12) across and for separate etiologies. RESULTS: For stroke and hemorrhage the ORs with 95% confidence intervals were: 2.05 [1.12-3.75] (N100), 4.47 [1.92-10.44] (MMN), 10.29 [2.00-52.79] (P300), for trauma: 1.63 [0.70-3.80] (N100), 4.72 [1.35-16.44] (MMN), 12.89 [4.82-34.43] (P300), anoxic: 8.03 [2.83-22.75] (N100), 15.50 [4.27-56.26] (MMN), 5.93 [2.38-14.77] (P300), post-operative: 10.66 [1.98-57.50] (N100), metabolic encephalopathy: 2.12 [0.34-13.13] (N100), 3.60 [0.28-46.36] (MMN), 7.71 [0.75-79.77] (P300), and all etiologies: 2.85 [1.91-4.27] (N100), 6.53 [3.55-12.01] (MMN), and 8.79 [4.88-15.83] (P300). Based on six N100 studies (N=548 patients), five MMN studies (N=470), and six P300 studies (N=313), the N100, MMN, or P300, when present, significantly predicted awakening, P300 and MMN being significantly better predictors than N100. CONCLUSIONS: The MMN and P300 appear to be reliable predictors of awakening. SIGNIFICANCE: The prognostic assessment of low responsive patients with auditory ERP should take into account both MMN and P300.

Information processing in severe disorders of consciousness: vegetative state and minimally conscious state.

OBJECTIVE: To study the presence of electrophysiological indicators of remaining cortical functions in patients with persistent vegetative state (PVS) and minimally conscious state (MCS). Previous electrophysiological and PET data indicated that some PVS patients have partially intact cortical processing functions. However, it remains unclear whether the reported patients were representative for PVS population or just some exceptional cases. METHODS: Event-related brain responses to stimuli of different complexity levels, recorded in 98 patients with extremely severe diffuse brain injuries, 50 of which in PVS. Four main indicators of cortical functions were: (i) N1-P2 complex as an index of simple, undifferentiated cortical processing; (ii) mismatch negativity as an index of pre-attentive, probably unconscious, cortical orientation; (iii) P3 wave as an index of deep cortical analysis of physical stimuli, and (iv) brain responses to semantic stimuli. RESULTS: Cortical responses were found in all PVS patients with a background EEG activity > 4 Hz. All responses investigated, including those to semantic stimuli that indicated comprehension of meaning, occurred significantly above chance, though less frequently than in patients with severe brain injuries who were conscious. CONCLUSIONS: Cortical responses were lacking in most patients with severe EEG slowing (< 4 Hz). Follow-up data revealed that the presence of a mismatch negativity, a short disease duration, and the traumatic etiology were related to a better outcome. SIGNIFICANCE: The data show that in a subpopulation of PVS patients with preserved thalamocortical feedback connections, remaining cortical information processing is a consistent finding and may even involve semantic levels of processing.

Stimulus complexity enhances auditory discrimination in patients with extremely severe brain injuries.

There is controversy as to what extent the processing of spectrally rich sounds in the human auditory cortex is related to the processing of singular frequencies. An informative index of the function of the auditory cortex, particularly important in neurological patients, is the mismatch negativity (MMN), a component of auditory event-related potentials. In the present study the MMN was recorded in 79 patients with extremely severe diffuse brain injuries, most of them in persistent vegetative state or minimal consciousness state. Both sinusoidal ('pure') and complex musical tones were used. Different statistical approaches converged in that musical tones elicited an MMN significantly more frequently, and of a larger amplitude, than simple sine tones. This implies that using simple stimuli in clinical populations may lead to a severe underestimation of the functional state of a patient's auditory system. The findings are also in line with behavioral and physiological data indicating independent processing of complex sounds in the auditory cortex.

Cognitive processing in completely paralyzed patients with amyotrophic lateral sclerosis.

Cognitive functions have never been studied before in completely paralyzed patients, probably due to the lack of the appropriate method. In this study, three male patients in the last stage of amyotrophic lateral sclerosis (ALS) are examined. They were totally locked-in, i.e., incapable of any voluntary response including eye movements. Given this complete lack of motor expression, the method of event-related brain potentials (ERPs) was used. The ERP recording was carried out at the patients' bedside. In one patient indications of preserved cognitive abilities including adequate language comprehension were obtained. The data of the second patient also demonstrate a high degree of intactness of complex cognitive functions, but some ERP phenomena were consistently abnormal, which may be interpreted as a consequence of disease-related degenerative processes. In the third patient no electrocortical response which might indicate higher cortical processing was found. This first ERP study of totally paralyzed patients shows that some of them can possess high, perhaps even normal, information processing capacity after a long period of severe immobility and artificial ventilation.

Brain-computer communication: self-regulation of slow cortical potentials for verbal communication.

OBJECTIVE: To test a training procedure designed to enable severely paralyzed patients to communicate by means of self-regulation of slow cortical potentials. DESIGN: Application of the Thought Translation Device to evaluate the procedure in patients with late-stage amyotrophic lateral sclerosis (ALS). SETTING: Training sessions in the patients' homes. PARTICIPANTS: Two male patients with late-stage ALS. INTERVENTIONS: Patients learned voluntary control of their slow cortical potentials by means of an interface between the brain and a computer. Training was based on visual feedback of slow cortical potentials shifts and operant learning principles. The learning process was divided into small steps of increasing difficulty. MAIN OUTCOME MEASURES: Accuracy of self-control of slow cortical potentials (percentage of correct responses). Learning progress calculated as a function of training session. RESULTS: Within 3 to 8 weeks, both patients learned to self-regulate their slow cortical potentials and to use this skill to select letters or words in the Language Support Program. CONCLUSIONS: This training schedule is the first to enable severely paralyzed patients to communicate without any voluntary muscle control by using self-regulation of an electroencephalogram potential only. The protocol could be a model for training patients in other brain-computer interface techniques.

Event-related potentials in an auditory semantic oddball task in humans.

Whenever rare target stimuli are presented interspersed by frequent irrelevant stimuli (standards), the targets elicit a late parieto-central positive wave called P3. Usually standards and targets differ by a simple physical feature (e.g. tone pitch). Less consistent are the data obtained in semantic tasks, in which standards and targets are represented by different word classes. Given an equal number of words in the target and standard categories, each individual standard is more frequent than each target, that is, the frequency of the category is confounded with that of individual stimuli. In the present study participants were presented five semantic classes each being represented by 15 words. Words belonging to one particular class should be counted. Thus targets were rare (20%), although the frequencies of each word and of each semantic class were equal. A highly significant P3 was recorded. Its latency was longer, and the amplitude was smaller, than when standards and targets were two tones. These data indicate that brain waves recorded in semantic tasks are not necessarily manifestations of specific semantic processing.

Modification of slow cortical potentials in patients with refractory epilepsy: a controlled outcome study.

PURPOSE: To compare self-regulation of low-frequency EEG components (slow cortical potentials, SCPs) with other methods of seizure control for patients with drug-refractory partial epilepsy and to separate the real anticonvulsive effect from placebo effects. METHODS: Results of a treatment program of SCP self-regulation (experimental group) are compared with two groups of patients, one of which learned self-control of respiratory parameters (end-tidal CO2 and respiration rate: RES group); the other received medication with new anticonvulsive drugs (AEDs) in combination with psychosocial counseling (MED group). Clinical, cognitive, behavioral, and personality measures were assessed before and after treatment. In addition, to control for placebo responses, patients repeatedly estimated their beliefs in the efficiency of the respective treatment, their satisfaction and expectations, and the quality of the relationship with their therapists. RESULTS: SCP and MED groups showed a significant decrease of seizure frequency, but the RES group did not. Clear positive changes in the sociopsychological adjustment were obtained in all three groups, with the maximal improvement being attained in the RES group. CONCLUSIONS: All kinds of therapy result in considerable improvement of patients' emotional state, which may in part be due to potential placebo effects: however, this improvement is not related to the quality of the therapeutic effect proper (i.e., seizure reduction). Traditional double-blind control group designs are inappropriate for behavioral interventions or treatments with psychoactive pharmacologic drugs. Rather, specific tests can be developed to control the placebo effect and to separate it from the genuine therapeutic effects.

Brain-computer communication: unlocking the locked in.

With the increasing efficiency of life-support systems and better intensive care, more patients survive severe injuries of the brain and spinal cord. Many of these patients experience locked-in syndrome: The active mind is locked in a paralyzed body. Consequently, communication is extremely restricted or impossible. A muscle-independent communication channel overcomes this problem and is realized through a brain-computer interface, a direct connection between brain and computer. The number of technically elaborated brain-computer interfaces is in contrast with the number of systems used in the daily life of locked-in patients. It is hypothesized that a profound knowledge and consideration of psychological principles are necessary to make brain-computer interfaces feasible for locked-in patients.

Brain potentials in human patients with extremely severe diffuse brain damage.

To test higher cortical functions of neurological patients, oddball tasks are often used in which a frequent and a rare stimulus are randomly presented and a P3 brain wave is recorded to the rare stimulus. We examined 33 patients with extremely severe brain injury. Three oddball conditions were used: with two sine tones (ST), with two complex tones (CT) and with vowels 'o' and 'i'. Across all patients, CT elicited P3 more often than ST, and the occurrence of the P3 after vowels was intermediate. However, among patients who showed a distinct P3 wave, its amplitude in the subgroup with traumatic brain injury was larger to vowels than to CT. In patients with non-traumatic etiology, CT and vowels elicited a P3 of a nearly equal amplitude. Stimuli of sufficient complexity should be used when the P3 technique is applied for assessment of cortical functions in severely impaired patients.

Self-initiation of EEG-based communication in paralyzed patients.

OBJECTIVES: Severely paralyzed patients could learn to voluntarily generate slow cortical potential (SCP) shifts in their electroencephalogram and to use these signals to operate a communication device. To enhance the patients' autonomy, the present study describes the development of a permanently available communication system that can be turned on and off by locked-in patients without external assistance. A skill necessary for turning the system on is the ability to regulate one's slow potentials in the absence of continuous feedback. METHODS: A stepwise learning approach was employed to train two paralyzed patients to regulate their SCPs without continuous feedback. Elements of the original communication system were gradually removed and elements of the new stand-by mode were introduced. RESULTS: At the end of the learning procedure, both patients achieved correct response rates of above 84% in training sessions without continuous feedback. This skill enabled them to turn the communication device on and off without assistance from others. CONCLUSIONS: These findings suggest that severely paralyzed individuals can learn to operate an EEG-based communication device autonomously.

Learning effects on event-related brain potentials.

This study investigates whether learning can manifest itself in EEG changes without explicit awareness of the acquired knowledge and without any motor requirement (to rule out acquisition of motor skills). Subjects passively heard particular stimulus combinations interspersed with random combinations. Immediately after this, stimulus combinations were presented which contained violations of the previously learned regular sequences. These violations elicited two frontally distributed negative waves peaked at about 250 ms and 500 ms, respectively. None of the participants could detect any regularity of the stimulation. No significant difference between regular vs random stimulus combinations was found during acquisition. These findings indicate that learning without explicit knowledge does not require motor activity (i.e. is independent of learning response sequences) and does not depend on stimulus probabilities.

The thought translation device (TTD) for completely paralyzed patients.

The thought translation device trains locked-in patients to self-regulate slow cortical potentials (SCP's) of their electroencephalogram (EEG). After operant learning of SCP self-control, patients select letters, words or pictograms in a computerized language support program. Results of five respirated, locked-in-patients are described, demonstrating the usefulness of the thought translation device as an alternative communication channel in motivated totally paralyzed patients with amyotrophic lateral sclerosis.

Learning and self-regulation of slow cortical potentials in older adults.

Two groups of subjects, aged 20-28 and 50-64, respectively, matched for health status and verbal abilities, learned to control their slow cortical potentials (SCP) in a feedback paradigm by producing, on command, SCP shifts in either positive or negative direction. Both groups were able to differentiate significantly between the positivity task and the negativity task, with the differentiation score being only slightly (and not significantly) lower in older than in younger subjects. In all conditions, however, significantly more negative brain responses were obtained in older than in younger subjects. This effect was larger in the positivity task versus negativity task, and larger in trials without continuous SCP feedback versus trials with feedback. Additionally four learning tasks were carried out with all subjects. The older group demonstrated substantial performance deficits in two tasks with explicit learning (verbal and visual). In contrast, implicit learning (perceptual learning and skill acquisition) was not impaired with age. The results are at odds with the idea of general age-related learning deficit and concur with the hypothesis that only explicit, but not implicit, learning processes are compromised in older subjects. The pattern of consistently more negative SCP shifts produced by elderly subjects may indicate their impaired cortical inhibition. Another interpretation, which does not exclude the inhibitory deficit hypothesis but seems to better agree with other psychophysiological data, may be that older subjects have disturbance in the system controlling arousal and effort.