Coma recovery scale-r: variability in the disorder of consciousness.

BACKGROUND: Despite evidence from neuroimaging research, diagnosis and early prognosis in the vegetative (VS/UWS) and minimally conscious (MCS) states still depend on the observation of clinical signs of responsiveness. Multiple testing has documented a systematic variability during the day in the incidence of established signs of responsiveness. Spontaneous fluctuations of the Coma Recovery Scale-revised (CRS-r) scores are conceivable. METHODS: We retrospectively analyzed the CRS-r repeatedly administered to 7 VS/UWS and 12 MCS subjects undergoing systematic observation during a conventional 13 weeks. rehabilitation plan. RESULTS: The CRS-r global, visual and auditory scores were found higher in the morning than at the afternoon administration in both VS/UWS and MCS subgroups over the entire period of observation. The probability for a VS/UWS subject of being classified as MCS at the morning testing at least once during the 13 weeks. observation was as high as 30%, i.e., compatible with the reported misdiagnosis rate between the two clinical conditions. CONCLUSIONS: Multiple CRS-r testing is advisable to minimize the risk of misclassification; estimates of spontaneous variability could be used to characterize with greater accuracy patients with disorder of consciousness and possibly help optimize the rehabilitation plan.

A study of the reliability of the Nociception Coma Scale.

OBJECTIVE: In this study, we investigated the reliability of the Nociception Coma Scale which has recently been developed to assess nociception in non-communicative, severely brain-injured patients. DESIGN: Prospective cross-sequential study. SETTING: Semi-intensive care unit and long-term brain injury care. SUBJECTS: Forty-four patients diagnosed as being in a vegetative state (n=26) or in a minimally conscious state (n=18). INTERVENTIONS: Patients were assessed by two experts (rater A and rater B) on two consecutive weeks to measure inter-rater agreement and test-retest reliability. MAIN MEASURES: Total scores and subscores of the Nociception Coma Scale. RESULTS: We performed a total of 176 assessments. The inter-rater agreement was moderate for the total scores (k = 0.57) and fair to substantial for the subscores (0.33 ≤ k ≤ 0.62) on week 2. The test-retest reliability was substantial for the total scores (k = 0.66) and moderate to almost perfect for the subscores (0.53 ≤ k ≤ 0.96) for rater A. The inter-rater agreement was weaker on week 1, whereas the test-retest reliability was lower for the least experienced rater (rater B). CONCLUSIONS: This study provides further evidence of the psychometric qualities of the Nociception Coma Scale. Future studies should assess the impact of practical experience and background on administration and scoring of the scale.

Quantitative EEG and neurochemical aspects of memory and learning.

Different, established or putative animal models of learning were studied by electrophysiological (EEG) and neurochemical methodologies. The training of rats to new behavioral patterns proved to result in the stimulation of total RNA synthesis rate in specific brain structures, as well as in modifications of the EEG organization of hippocampus. This two-fold approach to the assessment of modifications in learning-involved brain structures was extended to the study of mirror focus and kindling, to verify the suitability of these phenomena as experimental models of learning. Reduced (3H) uridine incorporation and proportion of poly (A)-associated RNA were found in mirror focus in comparison with control regions. These variations seem related to brain damage rather than be congruent with learning-related modifications. Further studies are necessary to verify whether the kindling phenomena are to be equated to learning models.

Valproate acute administration, EEG epileptic abnormalities, and ammonemia.

Acute, oral administration of 14.3 to 37.5 mg/kg magnesium valproate (peak serum concentrations, 65 to 139 micrograms/ml) increases spike-wave frequency at 2, 3, 4, and 5 hours postdrug, in the absence of hyperammonemia or significant correlations with ammonemia fluctuations. This observation suggests a direct role of valproate on neural activity.

Ammonia-independent modifications of the background EEG signal and paradoxical enhancement of epileptic abnormalities in EEG after acute administration of valproate to epileptic patients.

The effects on the background quantitative EEG (power spectral analysis) and concentration of valproate in plasma were studied after single-dose (14.3-33.3 mg/kg) oral administration in 12 epileptic patients with generalized nonconvulsive or partial seizures. An increase of the amplitude of the background EEG (diffuse and preponderant on anterior scalp areas) and a decrease of the 12.5-32.0 Hz relative power (limited to the posterior electrode deviations) were observed; the increase in the EEG total power was paralleled by a definite increment in incidence of epileptic phenomena in the EEG. Both effects proved unrelated to shifts in vigilance or changes in the concentration of ammonia or serum glucose in plasma and confirm previous observations from superimposable study designs. These findings are qualitatively opposite to those observed during long-term treatment at comparable doses and are suggested to reflect a direct CNS action of acute administration of valproate.

Synchronized approximately 15.0-35.0 Hz oscillatory response to spatially modulated visual patterns in man.

When suitably stimulated, neurons in the striate visual cortex of cats fire in bursts at 20-60 Hz and the membrane potential oscillates rhythmically in the same frequency range and in phase. These oscillations reflect intrinsic properties of mammalian neurons, occur in coherent spatial patterns that depend on the segregation and stimulus selectivity of stimulated cells, and mediate in long-range synchronization across columns and over large cortical areas of cells responding to the same stimulus property/properties. The pool of activated neurons may be adequate in size to drive cellular oscillations into local fields and mass responses. Accordingly, stimulus-dependent oscillatory activity in the same frequency range was described in man after contrast stimulation. Our results describe oscillatory potentials at approximately 15.0-35.0 Hz that in man are (partly) independent from, and anticipate the occurrence of, the conventional low-frequency visual response evoked by transient, foveal stimulation with spatially-modulated patterns.

Cutaneous antihistaminic action of cetirizine and dose-related EEG concomitants of sedation in man.

The cutaneous antihistaminic action (prick test; 1:100, 1:200 and 1:1000) and neuropsychological and electroencephalographic (EEG) concomitants of sedation following the histamine H1 receptor antagonist cetirizine (10- and 20-mg acute oral doses) and chlorpheniramine, 4 mg, were investigated in a cross-over, placebo-controlled study in healthy male volunteers (age 23-29 years). With an average Cmax of cetirizine of 697.0 ng/ml (10 mg) and 1000.2 ng/ml (20 mg), the diameter of histamine-induced skin weals was reduced by 24.0-74.9% depending on histamine concentration and with no dose dependence for cetirizine. Placebo and chlorpheniramine were ineffective. Behavioral or neuropsychological signs of sedation were never observed. An increase of the 6.5-14.5 Hz EEG power, with anterior scalp preponderance, was observed after chlorpheniramine or cetirizine 20 mg. This effect of cetirizine was accounted for by a substantial increase of power in the 6.5-8.0 Hz frequency subsegment and is regarded, for these experimental conditions, as an established early EEG indication of mild sedation (vigilance 'state A'). No EEG effects were observed after placebo or cetirizine at the 10 mg dose. The existence of some histaminergic (H1) specificity of the mechanisms modulating vigilance and of a threshold dose of cetirizine for sedative action is suggested.

Stimulus-specific oscillatory responses of the brain: a time/frequency-related coding process.

OBJECTIVES: To review the coherent, rhythmic oscillations above approximately 20 Hz that occur in response to sensory inputs in the firing rate and membrane or local field potentials of distributed neuron aggregates of CNS layered structures. RESULTS: Oscillatory activity at approximately 20-80 Hz occurs in response to either olfactory, auditory and visual (contrast) stimuli; oscillations at frequencies centered on 100-120 Hz or 600 Hz are recorded, respectively, from the visual system (luminance stimulation) and from the somatosensory cortex. Experimental evidence suggests sources/mechanisms of generation that depend on inhibitory interneurons and pyramidal cells and are partially independent from those of conventional (broadband) evoked responses. In the olfactory and visual systems, the oscillatory responses reflect the global stimulus properties. A time/phase correlation between firing rate, spiking coincidence and oscillatory field responses has been documented. The oscillatory responses are postsynaptic both in cortex and in precortical structures (e.g. retina; LGN). Evidence indicates intracortical and thalamocortical interacting mechanisms of regulation as well as GABAergic and cholinergic modulation. In the visual cortex the oscillatory responses are driven by oscillations in the synaptic input. Oscillatory potentials are dependent on resonance phenomena and produce narrow-band synchronization of activated neurons. They may have a role in the 'binding' of separate neuronal aggregates into sensory units. CONCLUSIONS: Oscillatory responses contribute as a time/frequency coding mechanism to pacing neurons selectively for the physical properties of stimulus and are involved in sensory information processing.

Factor structure and ammonia-related modulation of the human retinal oscillatory potentials.

OBJECTIVE: To investigate in man the factor structure of retinal oscillatory potentials (OPs) to full-field luminance stimulation (0.9-9.5 cd.s.m(-2)) and the correlation with the spontaneous fluctuations of plasma ammonia. METHODS: Six male healthy volunteers were studied. Five OP recordings and ammonia determinations (GLDH method) were obtained for each subject at 2 h interval during an 8 h experimental session. A standard factor analysis was applied on the OP latency (time from stimulus to peak) and amplitudes values. RESULTS: Two consecutive factors on latencies and two factors on amplitudes were identified, consistent with reported differences between the earlier and later OP waves. The model explained a large portion of the OP variance. Both factors on latencies and factor 1 on amplitudes were directly correlated to the stimulus intensity and the ammonia plasma concentration in the 15.8-39.5 micromol/l range. Factors 1 and 2 on latencies decreased and factor 1 on amplitude increased at increasing stimulus intensities. The latency factors decreased and the amplitude factor increased with increasing ammonia concentration. Factor 2 on amplitudes did not correlate with the stimulus intensity or ammonia concentration. CONCLUSIONS: The factor structure further supports the evidence of functional differences between early and late OP waves. The observed correlation conceivably reflects a role of ammonia in the modulation of retinal electrophysiology in physiological conditions and potentially accounts for spontaneous variability in otherwise controlled electrophysiological studies.

Time dynamics of stimulus- and event-related gamma band activity: contrast-VEPs and the visual P300 in man.

OBJECTIVES: To investigate the time dynamics and phase relationship with the stimulus of the onset/offset visual evoked potentials (VEPs), P300 and gamma band oscillatory responses to visual (contrast) stimulation. Gamma band oscillatory activity mediates in sensory and cognitive operations, with a role in stimulus-related cortical synchronization, but is reportedly reduced in the time window of the P300 response. METHODS: Ten healthy volunteers were studied. VEPs and P300 were obtained in a stimulus condition combining standard contrast stimulation and a visual odd-ball paradigm. Visual stimuli were gratings with a sinusoidal luminance profile (9.0 degrees central retina; 1.3 cycles/degree; 70% contrast) that were presented monocularly in onset/offset mode, with vertical orientation (frequent stimulus; 80%) or with a 15 degrees rotation to the right (infrequent, target stimulus). The total signal activity (temporal spectral evolution), the activity phase-locked to the stimulus onset (rectified integrated average), and the 'locking index' (ratio of the activity phase-locked to the stimulus to the total signal activity) were computed over time and across frequencies on the signals recorded at occipital (visual responses) and central locations (P300). RESULTS: Oscillatory activity centered around approximately 20.0-35.0 Hz and phase-locked to the stimulus was recorded at occipital locations with time dynamics anticipating the conventional VEPs. Phase-locking was higher after frequent than in response to target stimuli and after the stimulus offset compared to onset, while the phase-locking of the VEP frequency components was higher after the stimulus onset. The low frequency components of the P300 recorded at Cz (below approximately 8.0-10.0 Hz) were almost totally phase-locked to the stimulus, while the gamma band activity at the P300 location did not vary over time in amplitude or phase-locking and was mostly non-locked to the target stimulus. CONCLUSIONS: These observations add to the evidence of a role of the gamma band oscillatory responses (centered at approximately 20.0-35.0 Hz) in visual information processing and suggest that the increment in gamma band activity during cognitive operations also depends on task characteristics, vigilance or selective attention, and brain functional state. The visual P300 appears to reflect low frequency synchronization mechanisms.

Adrenocorticotropin-related modulation of the human EEG and individual variability.

During a 6-h period in resting conditions, the blood concentrations at rest of cortisol, glucose and the adrenocorticotropic hormone (ACTH) varied spontaneously within physiological ranges in eight healthy male volunteers (24.5+/-1.7 years), without pulsatile changes, correlation among variables, or indications of stress response. The power of the 6.5-14.0 Hz physiological 'alpha' rhythm of the electroencephalogram (EEG) proved inverted-U correlated with the ACTH concentration (with maximum power at 12-14 pmol/l ACTH) but was independent from the extent of ACTH change or from cortisol/glucose concentrations. Two subgroups of subjects with low/high EEG power values could be separated depending on ACTH concentration, with estimated cut-off at 7-8 pmol/l. A direct ACTH modulation of brain electrophysiology or common factors (e.g. the corticotropin-releasing hormone) pacing both ACTH and EEG are suggested and may account for individual EEG differences.

Cholinergic modulation, visual function and Alzheimer's dementia.

Electrophysiological evidence at a cellular level and in vivo macroelectrode recordings converge in indicating a degree of specificity of acetylcholine action in vision. Acetylcholine (ACh) function is also thought to play a significant role in memory, learning and other cognitive processes. In this respect, ACh action is suggested to serve in both sensory and cognitive processes. The pharmacological blocking of brain muscarinic transmission has been proposed as a model of geriatric memory impairment and Alzheimer's dementia. Visual electrophysiological testing is deemed of diagnostic specificity for this disease. ACh brain neurotransmission, however, mostly contributes to the modulation of nonspecific aspects of cognition, such as arousal or attention. Alzheimer's dementia results from complex neuron alterations [which also affect muscarinic receptors among other (sub)cellular structures] rather than simply reflecting ACh impoverishment. A substantial loss of retinal ganglion cells is documented in patients with Alzheimer's disease and is consistent with electrophysiological observations. However, it is unclear to what extent the dysfunction of the visual system observable in Alzheimer's dementia is qualitatively different from that occurring spontaneously during aging. The dissimilarities between the effect of acute muscarinic blocking (e.g. by scopolamine) and dementia outnumber the similarities. Accordingly, the conventional ACh agonist-antagonist model of dementia now appears questionable, and replacement treatment with compounds enhancing ACh function proved disappointing. It is suggested that (nonspecific) ACh action becomes function-specific, as determined by the architecture of local brain circuits in which it is involved.

Effects of physiological changes of serum glucose on the pattern-VEP of healthy volunteers.

The correlation between amplitude and latencies of the pattern-reversal VEP (1.7-3.6 50% contrast) and the serum glucose was studied in six healthy, male volunteers (21-26 yr.; mean: 23.2 +/- 1.6 yr.). Pattern-VEP and serum glucose were obtained at 2-h intervals during a 8-h experimental session. The effect of spatial frequency on VEP (increased latencies and amplitude with increasing spatial frequency) was removed statistically by computing the residuals from the nonlinear regression function vs. the spatial frequency. The residuals were then processed as stimulus-independent variables. At glucose serum concentrations within the physiological range of variability (55-103 mg/dl), the P100 latency increased (p < 0.04) with increasing serum glucose, with a 6.9% estimated latency difference between lower and higher glucose concentrations. This correlation depends mostly on the association of shorter and longer P100 latencies with glucose concentration values in the lower and upper portions of the normal concentration range respectively, but accounts for about 4% of the overall variance and may be accidental (therefore a potential bias in otherwise controlled VEP studies) or suggest functional relationships between glucose availability and vision.

Stimulus- and frequency-specific oscillatory mass responses to visual stimulation in man.

Oscillatory mass responses centered at about 20-35 Hz or 100-120 Hz occur (after contrast or luminance visual stimulation, respectively) in the retina and cortex of animals and man and are recorded by electrical or magnetic methods. These oscillatory events reflect stimulus-related uni/multicellular oscillations of the firing rate/membrane potential and result from synchronization of neuronal assemblies selectively responding to the stimulus characteristics. Methodological problems in the study of these events derive from the contiguity in frequency between the ERG or VEP and the oscillatory responses and from the need to reliably define oscillatory events in time and frequency. Two methods (time-frequency analysis by matching pursuit and locking index) have been implemented to approach this issue. Theory and application are reviewed.

Study of bioequivalence of magnesium and sodium valproates.

The in vivo bioavailability of magnesium valproate (500 and 1000 mg) enteric-coated tablets has been compared with that of sodium valproate (Depakine) (500 and 1000 mg) enteric-coated tablets. The two preparations were found to be bioequivalent; magnesium valproate appeared to be a drug without bioavailability problems and with reduced inter-subject variability, compared with that of sodium valproate. A reversed-phase HPLC method for the determination of valproates is described.

Pharmacokinetics and electroencephalographic effects of darodipine 50-200 mg modified release (MR) acute oral administration: dose-finding study in healthy volunteers.

Pharmacokinetics and electroencephalographic [EEG; power spectral analysis] effects of the acute oral Ca-antagonist darodipine (50 mg MR, 100 mg MR, and 200 mg MR) were investigated in a cross-over, placebo-controlled study on healthy male volunteers (age 23-28 yrs). No effects on heart rate, blood pressure or behaviour were observed with these doses at average Cmax levels ranging between 4.74 and 33.53 ng/ml and with a Tmax ranging from 2 to 6 h depending on the dose. No significant differences in drug kinetics were observed between the 100-mg and the 200-mg dose. A significant increase of EEG total power and a decrease of relative power in the 14.5-32.0 Hz frequency interval were observed at the 100-mg and 200-mg doses. These effects were greater and more consistent across subjects at 100 mg than at 200 mg, and were correlated with darodipine plasma concentrations, with indications of an active concentration threshold at approximately 4-5 ng/ml. The 50-mg dose proved ineffective on the EEG signal.

Cholinergic function and dysfunction in the visual system.

Acetylcholine (ACh) function is thought not only to play a significant role in memory, learning and other cognitive processes, but studies at a cellular level and in vivo indicate an important role for ACh in vision as well, especially for visual information processing. A suitable experimental model of geriatric memory impairment and Alzheimer dementia that pharmacologically blocks the brain muscarinic transmission has been proposed. This model has been extensively used also as an attempt to test cholinergic drugs in the absence of detailed knowledge of sites and mechanisms of ACh action and as test condition in the investigation of the role of ACh in visual information processing. Alzheimer's dementia results from complex neuron alterations, rather than simply reflecting ACh impoverishment, also involving the visual system, with substantial loss of retinal ganglion cells and alterations in visual information processing. Viewing all these data as a whole, nonspecific ACh actions on cognition, such as arousal or attention, contribute in modulating the function-specific action of ACh in information processing, both at cognitive and visual level.

Stimulus- and event-related evoked potentials: from neuroscience to clinical neuropharmacology.

Synaptic neural (and neural system) functions are peculiarly sensitive to neuroactive compounds. Pharmacological interference/modulation is readily reflected by modifications in the organization of central nervous system (CNS), electrophysiologic signals occurring spontaneously in response to sensory stimulation (stimulus-related or evoked responses) or elicited in conjunction with sensory, motor or cognitive events (event-related potentials). Evoked responses reflect the basic physiology of sensory processes, while event-related potentials combine the time/space resolution of electrophysiologic signals with the specificity of eliciting neuropsychological conditions. The rationale for investigating drug effects on evoked and event-related potentials is manifold. Both are related to sensory and operant behavior and under suitable experimental conditions allow interpretation of drug-related changes in terms of CNS excitability. Some continuity between observations in man and in vivo or in vitro animal data is often possible. Proper handling of the stimulus physical properties or experimental/situational links may allow the responses to be related to sensory input or to neuropsychological manipulation of selectively activated CNS functions or functional subsystems and therefore to control spontaneous variability. This review summarizes today's knowledge of the application of electrophysiology to human neuropharmacology, with due reference to basic pharmacology and experimental evidence.

[Cigarette smoking. A pilot project of dehabituation and experimental research]. / Fumo di sigaretta. Un progetto pilota di disassuefazione e una ricerca sperimentale.

An interdisciplinary approach was adopted in a pilot programme research project as the most effective way to obtain concrete results in curing tobacco-addiction. The various stages and effects of the treatment are analysed as a means of identifying the most appropriate techniques. The early results are reported under separate headings according to treatment type (psychological, neurophysiological, dietary, clinical, chemical).

Effects of heavy ions on visual function and electrophysiology of rodents: the ALTEA-MICE project.

ALTEA-MICE will supplement the ALTEA project on astronauts and provide information on the functional visual impairment possibly induced by heavy ions during prolonged operations in microgravity. Goals of ALTEA-MICE are: (1) to investigate the effects of heavy ions on the visual system of normal and mutant mice with retinal defects; (2) to define reliable experimental conditions for space research; and (3) to develop animal models to study the physiological consequences of space travels on humans. Remotely controlled mouse setup, applied electrophysiological recording methods, remote particle monitoring, and experimental procedures were developed and tested. The project has proved feasible under laboratory-controlled conditions comparable in important aspects to those of astronauts' exposure to particle in space. Experiments are performed at the Brookhaven National Laboratories [BNL] (Upton, NY, USA) and the Gesellschaft für Schwerionenforschung mbH [GSI]/Biophysik (Darmstadt, FRG) to identify possible electrophysiological changes and/or activation of protective mechanisms in response to pulsed radiation. Offline data analyses are in progress and observations are still anecdotal. Electrophysiological changes after pulsed radiation are within the limits of spontaneous variability under anesthesia, with only indirect evidence of possible retinal/cortical responses. Immunostaining showed changes (e.g. increased expression of FGF2 protein in the outer nuclear layer) suggesting a retinal stress reaction to high-energy particles of potential relevance in space.