Biomedical subjects
Publications and source records attributed to K Reinikainen.
The present study shows that an infrequent vowel ('deviant') presented among frequent vowels ('standard') elicits in sleeping human newborns a negativity in the auditory event-related potential (ERP) resembling the mismatch negativity (MMN) recorded in adults. Thus, the MMN appears to provide means to investigate brain mechanisms of vowel perception in infants.
Mismatch negativity (MMN) is an event-related potential (ERP) component elicited by any discernible change in a repetitive sound even in the absence of attention. Previous studies have established that MMN is generated by change detection in a process comparing the deviant sensory input with the neural memory trace encoding the physical features of the repetitive sound. In the present study, we recorded MMNs to tonal frequency changes directly from the human temporal cortex of patients with electrodes implanted in the brain for diagnosis and therapy. The intracranially recorded MMN was found to be attention independent and modality specific. It was confined to a rather small area in temporal cortex, which was different from the structures where attention-dependent N2 and P3 responses to the frequency change could be recorded.
Auditory event-related potentials (ERP) were recorded from 10 healthy older subjects and 9 patients with Alzheimer's disease (AD) to investigate whether auditory sensory memory is impaired in AD. Standard (85%) and deviant (15%) tones were presented in random order with interstimulus intervals (ISI) of 1 s or 3 s in separate blocks. Deviant tones elicited a specific ERP component called mismatch negativity (MMN) which reflects automatic stimulus change detection and thus presumably, the neural basis of sensory memory in audition. The MMN amplitude decreased as a function of the ISI more in the AD group than in the control group. This suggests that the memory trace decays faster in the AD patients than in age-matched healthy controls.
Being able to detect unusual, possibly dangerous events in the environment is a fundamental ability that helps ensure the survival of biological organisms. Novelty detection requires a memory system that models (builds neural representations of) events in the environment, so that changes are detected because they violate the predictions of the model. The earliest physiologically measurable brain response to novel auditory stimuli is the mismatch negativity, MMN, a component of the event-related potential. It is elicited when a predictable series of unvarying stimuli is unexpectedly followed by a deviating stimulus. As the occurrence of MMN is not usually affected by the direction of attention, MMN reflects the operation of automatic sensory (echoic) memory, the earliest memory system that builds traces of the acoustic environment against which new stimuli can be compared. The dependence of attentive novelty detection on earlier, pre-attentive processes, however, has remained elusive. Previous, related studies seem to suggest a relationship between MMN and attentive processes, although no conclusive evidence has so far been shown. Here we address novelty detection in humans both on a physiological and behavioural level, and show how attentive novelty detection is governed by a pre-attentive sensory memory mechanism.
The Mismatch Negativity (MMN) component of the auditory event-related potential (AERP) is elicited by infrequent, physically "deviant" stimuli in a sequence of frequent homogeneous stimuli ("standard"), for instance, by a change in frequency, intensity or duration etc. When the inter-stimulus interval (ISI) of tone pips was occasionally shortened either to 300, 150, 75, 60 and 52 ms from regular ISI 600 ms, which resulted in the elicitation of MMN. The amplitude of MMN elicited by occasional shorter ISI was not reduced as a function of ISI shortening. This indicates that the MMN is not just due to activation of new afferent elements by deviant stimulus. Thus, by no means the elicitation of the MMN can be explained on the basis of the refractoriness.
Auditory event-related potentials (ERPs) were recorded from reading subjects while they were presented with 50 ms tone pips intervened by regular silent intervals of 550 ms. This interval was occasionally shortened either to 250, 100, 25, 10, or 2 ms, which resulted in the elicitation of the mismatch-negativity (MMN), a change-specific ERP component not elicited by tones appearing after the regular, longer intervals. This indicates that the MMN is not just due to new afferent elements activated by deviant but not standard stimuli. In addition, the present results suggest that the temporal parameters of acoustic stimulation are also encoded in memory traces which therefore are representations of auditory events rather than only of static stimulus aspects.
Studies of human auditory and somatosensory modalities have shown that there is an oscillatory response in the gamma-band (at about 40 Hz) frequency which is elicited by either steady state or transient stimulation. The auditory 40-Hz response is generated at least partially in the auditory cortex as a result of thalamocortical interaction and may serve perceptual integration and conscious perception. A connection to selective attention has been implied in human and animal studies, although the evidence is inconclusive. Moreover, fundamental differences between the human and animal 40-Hz responses prohibit generalization. Furthermore, most experiments have used steady-state stimulation during which the brain does not regain its resting state between stimuli as it does when transient stimulation is used. Here we study the effect of selective attention on the auditory gamma-band (40-Hz) transient response using subjects listening to tone pips presented in one ear while ignoring a concurrent sequence of tone pips in the other ear. The 40-Hz response was larger when subjects paid attention to stimuli rather than ignored them. This attention effect was most pronounced over the frontal and central scalp areas. Our results demonstrate a physiological correlate of selective attention in the 40-Hz transient response in humans.
The effect of tetrahydroaminoacridine (THA) on the cerebrospinal fluid (CSF) monoamine metabolites was studied in 22 patients with Alzheimer's disease in an open treatment trial. The CSF monoamine metabolites were assayed at baseline and after 4 weeks' active THA treatment with 100 mg/d. A statistically significant increase in the CSF homovanillic acid (HVA) and in 5-hydroxyindoleacetic acid (5-HIAA) content was found. The increase of the CSF 5-HIAA level correlated significantly with improvement in cognitive tests and in the Instrumental Activities of Daily Living Scale. We conclude that besides its anticholinesterase activity THA enhances also the monoaminergic neurotransmission in the brain and that the clinical improvement during THA treatment may be partly mediated through the monoaminergic system.
The attention effect on the auditory event-related potential (ERP) in dichotic conditions was studied as a function of the interstimulus interval (ISI). Subjects attended to stimuli delivered to a designated ear and responded to infrequent pitch deviants in this input. The mean ISI was either 80, 160, 480, or 800 ms. Negative difference waves (Nds) were computed by subtracting ERPs to unattended standards from ERPs to the same stimuli when attended. The exogenous N1, as estimated from unattended standard ERPs, was larger contralaterally to the stimulus and inverted in polarity at mastoids. With decreasing ISIs, N1 diminished in amplitude much faster than did the Nd. In addition, N1 latency remained stable, whereas Nd peaked markedly earlier with shorter ISIs, almost perfectly coinciding with the exogenous N1. However, this temporal coincidence found in grand averages proved to be illusory in single subjects. The early Nd showed no contralateral asymmetry at its peak, but asymmetry was apparent during the ascending slope. These lateral asymmetries resembled those of the exogenous N1 but occurred later. The early Nd peak was, at least mainly, caused by an endogenous attention effect, the processing negativity (PN), even with very short ISIs, but an effect on the exogenous N1 could not be excluded.
A rapid dosimetric method with controlled tidal breathing for histamine challenge was evaluated by assessment of its repeatability, by comparing to a present nondosimetric standard method, and by application to adult patients with recent asthma (n = 31), chronic asthma (n = 33), chronic cough (n = 71) or chronic rhinitis (n = 41) and to healthy controls (n = 31). An automatic inhalation-synchronized dosimetric jet nebulizer with a known lung deposition of the aerosol was used to administer histamine and to control breathing. The non-cumulative doses of histamine diphosphate were 0.025, 0.1, 0.4 and 1.6 mg, administered during 0.4 s following tidal inspiration of 100 ml of air. The test procedure required 1 inhalation of histamine 4 mg/ml and followed by 1, 4 and 16 inhalations of histamine 16 mg/ml from the device, and its duration was about 30 minutes. The intraindividual correlation coefficient of the histamine dose causing a reduction of 15 percent in FEV1 (PD15FEV1) on 2 consecutive days in 14 asthmatic subjects was 0.937; the standard error of the single determination was 13 percent of the mean PD15 FEV1. A PD15FEV1 value below 0.4 mg was found only in asthmatic subjects; in chronic asthma, below 0.5 mg; in recent asthma, between 0.1 mg and 1.6 mg or more. In patients with chronic cough and chronic rhinitis, 20 and 32 percent, respectively, the PD15FEV1 values between 0.4 and 1.6 mg, the other patients in these groups were non-responsive. In all healthy control subjects, the PD15FEV1 was over 1.0 mg, 80 percent of them were nonresponsive to the maximum 1.6 mg dose. This new test allows rapid, accurate, and quantitative assessment of bronchial responsiveness to histamine.
In sequences of identical auditory stimuli, infrequent deviant stimuli elicit an event-related brain potential component called mismatch negativity (MMN). MMN is presumed to reflect the existence of a memory trace of the frequent stimulus at the moment of presentation of the infrequent stimulus. This hypothesis was tested by applying the recognition-masking paradigm of cognitive psychology. In this paradigm, a masking sound presented shortly before or after a test stimulus diminishes the recognition memory of this stimulus, the more so the shorter the interval between the test and masking stimuli. This interval was varied in the present study. It was found that the MMN amplitude strongly correlated with the subject's ability to discriminate between frequent and infrequent stimuli. This result strongly suggests that MMN provides a measure for a trace of sensory memory, and further, that with MMN, this memory can be studied without performance-related distortions.
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The thalamus is involved in the regulation of the neocortical rhythmicity reflected in EEG as the alpha rhythm. Recent evidence suggests that the thalamus is affected in Alzheimer's disease (AD). We studied the relationship between the dominant occipital rhythm of the lifetime EEG and the choline acetyltransferase activity (ChAT) and monoamine concentrations in the postmortem thalamus of 20 histologically verified AD patients. The AD patients were divided into 3 groups (5-6 Hz, 7 Hz and 8-9 Hz) according to the frequency of the dominant occipital rhythm (FOC). Noradrenaline (NA) concentrations were significantly lower for the 5-6 Hz and 7 Hz subgroups as compared to the 8-9 Hz subgroup. The NA content of the thalamus correlated significantly with the FOC (r = 0.46, P = 0.04). The ChAT activity or concentrations of dopamine or serotonin did not correlate with the FOC or differ across the AD subgroups. The results suggests that the noradrenergic deficit of the thalamus may contribute to slowing of the dominant occipital rhythm in AD.
The major intent of this study was to compare the role of stimulus repetition and change in the elicitation of the MMN, an ERP component specific to stimulus change, and N2b, usually partially overlapping the MMN when stimuli are attended. Event-related potentials were recorded in one set of conditions where subjects ignored the stimuli and read a book, and in another set of conditions where subjects counted stimuli designated as targets. Stimuli were delivered in 4 ways, the common feature between all these conditions being the occurrence of infrequent events at a probability of 0.20: (1) an oddball paradigm with 1 deviant, (2) an oddball paradigm with 2 deviants, each with a probability of 0.10, (3) a regular alternation of tones of 2 pitches where either of the 2 tones infrequently repeated (P = 0.20), and (4) a random presentation of tones of 5 different pitches, where any of the 5 tones infrequently repeated (P = 0.20). In the count conditions, the infrequent events were designated as targets. It was found that the MMN was elicited by stimulus change and not stimulus repetition in the ignore and count conditions, whereas the N2b was elicited by both stimulus changes and repetitions in the count conditions. It was also possible, in the count conditions, to disentangle the part of the late positive complex which is related to stimulus deviation and the part which is related to stimulus significance (target).
The preventive effects of inhaled formoterol (a new beta 2-agonist) and salbutamol aerosols on histamine-induced bronchoconstriction were studied in 12 patients with mild or moderate asthma in a placebo-controlled, double-blind study. Three hours after the administration of 12 micrograms formoterol, 200 micrograms salbutamol (doses with equal bronchodilator effects) or placebo via aerosol, histamine challenge was undertaken, using a dosimetric jet nebulizer with controlled tidal breathing. The noncumulative dose of histamine diphosphate aerosol provoking a 15% fall in FEV1 (PD15) was calculated. The PD15 after inhalation of 12 micrograms formoterol was significantly higher than that after 200 micrograms salbutamol (median values 640 and 310 micrograms, respectively; p < 0.01). For both treatments, the PD15 was significantly higher than that after placebo (median 185 micrograms). The results indicate that the preventive effect against histamine-induced bronchoconstriction at 3 h after drug is significantly better with formoterol than with salbutamol when using inhaled doses with an equal acute bronchodilator effect.
We studied the effect of tetrahydroaminoacridine (THA) on cerebrospinal fluid somatostatin-like immunoreactivity (CSF-SLI) in probable Alzheimer disease (AD) patients (n = 20) who took part in an open THA treatment trial. The maintenance dose (100 mg/day) was continued for 4 weeks. Samples of CSF were obtained before treatment and at the end of the treatment period. The CSF-SLI increased significantly (P = 0.01) in the responders for the treatment (increase of the Mini-Mental State Examination score greater than or equal to 3; n = 11), while the non-responders (n = 9) showed a significant decrease of CSF-SLI (P = 0.003). The change of CSF-SLI had also a significant correlation (P = 0.001) with neuropsychological performance. We conclude that the effects of of THA on the CSF-SLI may be due to presynaptic cholinergic or direct somatostatinergic stimulation.
BACKGROUND: The presence of airway inflammation even in mild asthma points to the potential value of antiinflammatory therapy. We compared the effect of an inhaled corticosteroid, budesonide, with that of an inhaled beta 2-agonist, terbutaline, in the long-term treatment of newly detected asthma. METHODS: We studied 103 patients (29 male and 74 female patients 15 to 64 years old) in whom asthma had appeared within the previous year. The patients were randomly assigned in blinded fashion to two treatment groups: one to receive 600 micrograms of inhaled budesonide twice a day, and the other to receive 375 micrograms of inhaled terbutaline twice a day. The study period was two years. RESULTS: After six weeks of treatment, the patients treated with budesonide tolerated inhaled histamine better than the patients treated with terbutaline (a difference of one doubling dose step, P less than 0.001), and the difference was sustained. Patients' diaries kept during the first three months of the study and during the last month of the first and second years showed budesonide to be more effective than terbutaline in improving peak expiratory flow in the morning (average increase from the pretreatment value, 32.8 liters per minute for budesonide vs. 4.8 liters per minute for terbutaline; P less than 0.001) and in the evening (P less than 0.01). Budesonide was also more effective in reducing the symptoms of asthma (P less than 0.01) and the use of supplemental beta 2-agonist medication (P less than 0.01). Ten patients were withdrawn from the terbutaline group because treatment was insufficiently effective, whereas only one dropped out of the budesonide group. The adverse reactions to both treatments were few and mild. CONCLUSIONS: Antiinflammatory therapy with inhaled budesonide is an effective first-line treatment for patients with newly detected, mild asthma, and it is superior to the use of terbutaline in such patients.
We report the results of our study suggesting that a single dose pharmaco-EEG may predict treatment response to tetrahydroaminoacridine (THA) in Alzheimer's disease (AD). 14 AD patients and 7 age-matched neurologically healthy controls were selected for the study. AD patients had 7 weeks' THA treatment. 6 patients were regarded as responders and 8 patients as nonresponders, respectively. AD patients as well as controls had a baseline EEG recording and next day another recording 90 minutes after a peroral single dose of 50 mg THA. The relative change from the baseline in the alpha-theta ratio was the most sensitive discriminator of responders and nonresponders (P = 0.004, ANOVA).