Walter G. Sannita

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 Alzheimers 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. Alzheimers 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 Alzheimers disease and is consistent with electrophysiological observations. However, it is unclear to what extent the dysfunction of the visual system observable in Alzheimers 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.

Scalp-recorded oscillatory potentials evoked by transient pattern-reversal visual stimulation in man

Replicable oscillatory potentials, time-locked to pattern stimuli (9.0 degrees central; counterphase reversal at 2.13 Hz) were dissociated from conventional, broad-band VEPs recorded in healthy volunteers at occipital scalp locations by high-pass digital filtering at 17.0-20.0 Hz. Nine consecutive wavelets were identified with a 56.4 +/- 8.4 msec mean latency of the first replicable wavelet and mean peak-to-peak amplitude varying between 0.9 and 2.0 muV. The first 2 wavelets had significantly shorter latencies than wave N70 of unfiltered VEP, whereas the last 2 wavelets had longer latencies than N145. Latency and amplitude values varied as a function of contrast and spatial frequency of the stimulus, with shorter latencies and larger amplitudes at 60-90% contrast level and tuning of amplitude at 5.0 c/deg. All wavelets were correlated with wave P100 of unfiltered VEP, while a correlation with N70 of VEP was observed only for those wavelets with latencies in the range of wave P100. Two patients with documented brain lesions involving the visual system are described as examples of oscillatory responses occurring irrespective of filter bandpass and instead of the expected conventional VEP when the generation of these is interfered with by brain pathology. A substantial cortical contribution to the origin of the oscillatory response is conceivable. It is suggested that the oscillatory response to pattern-reversal stimulation reflects events in the visual system that are parallel to, and partly independent of, the conventional VEP, with potential application in research or for clinical purposes.

Visual pursuit: within-day variability in the severe disorder of consciousness.

Visual pursuit marks substantial recuperation from a vegetative state and evolution into a minimally-conscious state, but its incidence in different studies suggests some unreliability in contrast with its established prognostic relevance. Subjects in vegetative (n=9) or minimally-conscious (n=13) states were tested for visual pursuit 6 times/day (9:30, 10:30, and 11:30 am, and 2:00, 3:00, and 4.00 pm, for a total of 132 determinations). Visual pursuit was observed at all testing times in 8 minimally-conscious patients, and never in 5 subjects in a vegetative state. Its incidence per subject ranged from 50-100% of testing times in the minimally-conscious state (83±23%), and 0-33% in a vegetative state (7%±12), with spontaneous fluctuations during the day and maximal levels at 10.30 am and 3.00 pm, and was never observed at the post-prandial time point (2:00 pm). The overall chance of observing visual tracking at least once during the day was ∼33% in the vegetative state, whereas that of not observing it in the minimally-conscious state was ∼38%. These percentages are congruent with the reported misdiagnosis rate between the two conditions, and document spontaneous variability possibly related to circadian rhythms.

Eye light flashes on the mir space station

The phenomenon of light flashes (LF) in eyes for people in space has been investigated onboard Mir. Data on particles hitting the eye have been collected with the SilEye detectors, and correlated with human observations. It is found that a nucleus in the radiation environment of Mir has roughly a 1% probability to cause an LF, whereas the proton probability is almost three orders of magnitude less. As a function of LET, the LF probability increases above 10 keV/micrometer, reaching about 5% at around 50 keV/micrometer.

Human flash-VEP and quantitative EEG are independently affected by acute scopolamine

Scopolamine in acute intramuscular doses of 0.25-0.75 mg reduced the P2-N3 flash-VEP amplitude and, in the quantitative EEG, the 8.5-12.0 Hz power and total power in 8 healthy young male volunteers. The effects on flash-VEP and EEG total power were dose dependent and were evident 30 min and 90 min respectively after drug administration, regardless of dose. The reduction in 8.5-12.0 Hz power was limited to the 0.50 and 0.75 mg doses. No systematic effects on the pattern-VEP were observed. Possible interferences with flash- or pattern-VEP amplitude of the scopolamine-induced EEG changes were identified and removed by regression analysis and computation of VEP residuals from the regression function. The P2-N3 flash-VEP residuals proved EEG independent and showed relationships with dose and time after drug administration that were superimposable on those of the original data, with comparable significance levels at the drug/placebo and pre/postdrug statistical comparisons. The results indicate that VEP estimates of drug effects which are independent from EEG changes can be identified in human studies and allow some inference on the cholinergic specificity of the systems affecting late flash-VEP components. The statistical approach used in this study is suitable for application in VEP studies when effects of interacting factors are to be expected.

Magnetically recorded oscillatory responses to luminance stimulation in man

Fast-frequency (ca. 100-110 Hz) oscillatory potentials superimposed on waves N2 and P2 of conventional broad-band VEP were magnetically recorded in man from occipital locations in response to monocular transient flash stimulation with full-field flashes (3.5 cd.s.m-2 intensity) and in spots (1, 1.5, or 2.0 cm in diameter). These oscillations proved replicable between- and within-subject and were phase-locked to retinal oscillatory potentials, with maximum correlation at approximately 35 ms and mean delay (as measured between the first measurable peaks) of 27.4 +/- 1.6 ms. When stimuli were in spots at increasing eccentricity (5, 15, or 25 degrees) from foveal fixation, broad-band VEP were recorded regardless of diameter and eccentricity of spot, whereas oscillatory responses were not detectable at eccentricity of, or greater than, 15 degrees. This observation suggests that broad-band VEP and the oscillatory response are generated by (partly) distinct neuronal populations and/or functional arrangements and that there is some functional connection between cortical oscillatory responses and stimulus-related events triggered in central retina.

Study of cosmic rays and light flashes on board Space Station MIR: The SilEye experiment

The SilEye experiment aims to study the cause and processes related to the anomalous Light Flashes (LF) perceived by astronauts in orbit and their relation with Cosmic Rays. These observations will be also useful in the study of the long duration manned space flight environment. Two PC-driven silicon detector telescopes have been built and placed aboard Space Station MIR. SilEye-1 was launched in 1995 and provided particles track and LF information; the data gathered indicate a linear dependence of FLF(Hz) ( 4 2) 10(3) 5.3 1.7 10(4) Fpart(Hz) if South Atlantic Anomaly fluxes are not included. Even though higher statistic is required, this is an indication that heavy ion interactions with the eye are the main LF cause. To improve quality and quantity of measurements, a second apparatus, SilEye-2, was placed on MIR in 1997, and started work from August 1998. This instrument provides energetic information, which allows nuclear identification in selected energy ranges; we present preliminary measurements of the radiation field inside MIR performed with SilEye-2 detector in June 1998.

Quantitative EEG Effects and Plasma Concentration of Sodium Valproate: Acute and Long-Term Administration to Epileptic Patients

The quantitative background EEG effects (power spectral analysis) and plasma concentration of sodium valproate were studied after acute single-dose administration and during long-term single-drug treatment, in 10 previously untreated epileptic patients with generalized nonconvulsive seizures. A transient decrease of the signal amplitude (preponderant on anterior scalp areas) and of the 12.5 to 45.0-Hz relative power (limited to the posterior electrode derivations) was observed during the first weeks of chronic treatment. These EEG effects were not correlated with the drug plasma concentration levels or with the occurrence of behavioral side effects (e.g. drowsiness), while being concomitant with the reduction of specific epileptic EEG phenomena. Opposite trends of variation were observed after single-dose acute administration, though with limited statistical significance across subjects.

Quantitative EEG Effects and Drug Plasma Concentration of Phenobarbital, 50 and 100 mg Single-Dose Oral Administration to Healthy Volunteers: Evidence of Early CNS Bioavailability

Single, 50- and 100-mg oral doses of phenobarbital and a matching placebo were administered double-blind to 8 young, healthy male subjects. Multilead electroencephalographic (EEG) samples were recorded prior to, and at regular intervals within the 2 h following administration. The EEG signal was processed by power spectral analysis; the drug plasma concentration was assessed concomitantly. Plasma peaks after the 50- and 100-mg dose were, respectively, 3.38 +/- 1.29 and 4.09 +/- 1.24 micrograms/ml. Despite the low drug plasma concentration, a systematic power increment of the EEG fast frequency spectral segments occurred at either dose on the anterior scalp areas from the 30- or 60-min postdrug control onward, and was preponderant on central electrodes; a significant correlation (Kendals coefficient for ranked data) with the drug plasma concentration was observed limitedly to the anterior scalp areas. No correlation with plasma levels was observed for unsystematic EEG variations.

Residual Brain Processing in the Vegetative State

Vegetative state (VS) is a clinical condition in the severely brain damaged, characterized by wakefulness but unaccompanied by any evidence of awareness of self or environment, voluntary or purposeful behavioral responses to external stimuli, and communication. A metabolic dysfunction of the frontal-parietal network is thought to be responsible for the “functional disconnection” underlying it. Most subjects recover with or without residual disabilities depending on the extent of brain damage. However, VS persists for over 1 year in about 15% of all cases, with exceptional later recovery; prolonged observation has thus become possible and our perspectives have expanded substantially. In recent years, brain activation in response to painful or emotional stimuli (e.g., the mother’s voice or presence) or under stimulus conditions implying processing at varying levels of functional complexity (including learning and semantic functions) has been documented in unambiguously diagnosed VS subjects by advanced elec...