Biomedical subjects

I Winkler

Publications and source records attributed to I Winkler.

At least 37 records · Page 2Linked to original sources

PubMed1999

Neuronal populations in the human brain extracting invariant relationships from acoustic variance.

The ability to extract invariant relationships from physically varying stimulation is critical for example to categorical perception of complex auditory information such as speech and music. Human subjects were presented with tone pairs randomly varying over a wide frequency range, there being no physically constant tone pair at all. Instead, the invariant feature was either the direction of the tone pairs (ascending: the second tone was higher in frequency than the first tone) or the frequency ratio (musical interval) of the two tones. The subjects ignored the tone pairs, and instead attended a silent video. Occasional deviant pairs (either descending in direction or having a different frequency ratio) elicited the mismatch negativity (MMN) of the event-related potential, demonstrating the existence of neuronal populations which automatically (independently of attention) extract invariant relationships from acoustical variance.

Acoustic Stimulation↗

PubMed1999

Temporal integration of auditory stimulus deviance as reflected by the mismatch negativity.

We recorded event-related brain potentials (ERPs) to two different infrequent deviant tones presented successively within the repetitive sequence of a standard tone. A separate mismatch negativity (MMN) component was elicited by each of the two deviants when the interval separating their onsets was 300 ms. However, only a single MMN component was elicited when the temporal separation between the onsets of the two deviants was 150 ms. Previous studies obtained similar results using two temporally separated deviations carried by a single sound. Taken together, these results support the notion of a general temporal integration mechanism in the formation of auditory events with ca. 200 ms long window.

Acoustic Stimulation↗

PubMed1999

Pre-attentive detection of vowel contrasts utilizes both phonetic and auditory memory representations.

Event-related brain potentials (ERP) were recorded to infrequent changes of a synthesized vowel (standard) to another vowel (deviant) in speakers of Hungarian and Finnish language, which are remotely related to each other with rather similar vowel systems. Both language groups were presented with identical stimuli. One standard-deviant pair represented an across-vowel category contrast in Hungarian, but a within-category contrast in Finnish, with the other pair having the reversed role in the two languages. Both within- and across-category contrasts elicited the mismatch negativity (MMN) ERP component in the native speakers of either language. The MMN amplitude was larger in across- than within-category contrasts in both language groups. These results suggest that the pre-attentive change-detection process generating the MMN utilized both auditory (sensory) and phonetic (categorical) representations of the test vowels.

Acoustic Stimulation↗

PubMed1999

The concept of auditory stimulus representation in cognitive neuroscience.

The sequence of neurophysiological processes elicited in the auditory system by a sound is analyzed in search of the stage at which the processes carrying sensory information cross the borderline beyond which they directly underlie sound perception. Neurophysiological data suggest that this transition occurs when the sensory input is mapped onto the physiological basis of sensory memory in the auditory cortex. At this point, the sensory information carried by the stimulus-elicited process corresponds, for the first time, to that contained by the actual sound percept. Before this stage, the sensory stimulus code is fragmentary, lacks the time dimension, cannot enter conscious perception, and is not accessible to top-down processes (voluntary mental operations). On these grounds, 2 distinct stages of auditory sensory processing, prerepresentational and representational, can be distinguished.

Auditory Cortex↗

PubMed1999

Antiviral activity of the human immunodeficiency virus type 1-specific nonnucleoside reverse transcriptase inhibitor HBY 097 alone and in combination with zidovudine in a phase II study. HBY 097/2001 Study Group.

The safety and antiviral activity of the second-generation nonnucleoside inhibitor HBY 097 was investigated in asymptomatic or mildly symptomatic human immunodeficiency virus (HIV)-1-infected patients in a randomized, double-blinded, dose-escalation study. Mean maximum virus load decreases ranged from -1.31 log10 copies/mL of plasma at week 1 in the group receiving HBY 097 monotherapy (250 mg three times daily) to -2.19 log10 copies/mL at week 4 in the group receiving zidovudine plus HBY 097 (750 mg three times daily). After 12 weeks, these patients had viral RNA copy numbers 1.05 log10 below baseline. Genotypic analysis of resistance development revealed reverse transcriptase K103N variants in most patients, which was associated with less durable efficacy of HBY 097 treatment. Fewer patients receiving combination therapy with high-dose HBY 097 developed the K103N variant (P<.01). HBY 097 caused pronounced acute suppression of HIV-1 replication both in combination with zidovudine and alone. Therefore, sustained antiviral activity can be expected from multiple combination therapy regimens including a quinoxaline derivative.

Adult↗

PubMed1999

Brain responses reveal the learning of foreign language phonemes.

Learning to speak a new language requires the formation of recognition patterns for the speech sounds specific to the newly acquired language. The present study demonstrates the dynamic nature of cortical memory representations for phonemes in adults by using the mismatch negativity (MMN) event-related potential. We studied Hungarian and Finnish subjects, dividing the Hungarians into a naive (no knowledge of Finnish) and a fluent (in Finnish) group. We found that the MMN for a contrast between two Finnish phonemes was elicited in the fluent Hungarians but not in the naive Hungarians. This result indicates that the fluent Hungarians developed cortical memory representations for the Finnish phoneme system that enabled them to preattentively categorize phonemes specific to this language.

Adult↗

PubMed1998

Mismatch negativity: deviance detection or the maintenance of the 'standard'.

Electric brain responses were measured to infrequent tones that broke the frequency alternation of two tones, deviated in duration or violated both regularities (alternation and constant duration). Mismatch negativity (MMN) was elicited by both simple deviants with the duration-related MMN peaking approximately 130 ms later than the alternation-related MMN. The double deviant elicited two successive MMNs. Thus violation of each regularity elicited a separate MMN, whereas previous studies showed that multiple temporally separate deviations from a single repetitive standard elicit one MMN only. These results suggest that the primary function of the MMN-generating process is more closely related to maintaining the representation of auditory regularities than to deviance detection per se.

Acoustic Stimulation↗

PubMed1998

Structures of Tyr188Leu mutant and wild-type HIV-1 reverse transcriptase complexed with the non-nucleoside inhibitor HBY 097: inhibitor flexibility is a useful design feature for reducing drug resistance.

The second generation Hoechst-Bayer non-nucleoside inhibitor, HBY 097 (S-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydroqui noxalin-2(1H)-thione), is an extremely potent inhibitor of HIV-1 reverse transcriptase (RT) and of HIV-1 infection in cell culture. HBY 097 selects for unusual drug-resistance mutations in HIV-1 RT (e.g. Gly190Glu) when compared with other non-nucleoside RT inhibitors (NNRTIs), such as nevirapine, alpha-APA and TIBO. We have determined the structure of HBY 097 complexed with wild-type HIV-1 RT at 3.1 A resolution. The HIV-1 RT/HBY 097 structure reveals an overall inhibitor geometry and binding mode differing significantly from RT/NNRTI structures reported earlier, in that HBY 097 does not adopt the usual butterfly-like shape. We have determined the structure of the Tyr188Leu HIV-1 RT drug-resistant mutant in complex with HBY 097 at 3.3 A resolution. HBY 097 binds to the mutant RT in a manner similar to that seen in the wild-type RT/HBY 097 complex, although there are some repositioning and conformational alterations of the inhibitor. Conformational changes of the structural elements forming the inhibitor-binding pocket, including the orientation of some side-chains, are observed. Reduction in the size of the 188 side-chain and repositioning of the Phe227 side-chain increases the volume of the binding cavity in the Tyr188Leu HIV-1 RT/HBY 097 complex. Loss of important protein-inhibitor interactions may account for the reduced potency of HBY 097 against the Tyr188Leu HIV-1 RT mutant. The loss of binding energy may be partially offset by additional contacts resulting from conformational changes of the inhibitor and nearby amino acid residues. This would suggest that inhibitor flexibility can help to minimize drug resistance.

Antiviral Agents↗

PubMed1998

Retention of marked sensitivity to (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-di hydroquin oxaline-2(1H)-thione (HBY 097) by an azidothymidine (AZT)-resistant human immunodeficiency virus type 1 (HIV-1) strain subcultured in the combined presence of quinoxaline HBY 097 and 2',3'-dideoxy-3'-thiacytidine (lamivudine).

An azidothymidine (AZT)-resistant virus strain (HIV-1/AZT) (containing the 67 Asp --> Asn, 70 Lys --> Arg, 215 Thr --> Phe and 219 Lys --> Gln mutations into its reverse transcriptase) was grown in the combined presence of 2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) and the nonnucleoside reverse transcriptase inhibitor (S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3,4-dih ydroquinoxaine-2(1H)-thione (quinoxaline HBY 097). Replication of HIV-1/AZT was inhibited to a significantly greater extent by the combination of 3TC and quinoxaline HBY 097 than by either drug alone. Virus breakthrough was markedly delayed in the combined presence of 3TC and HBY 097 at drug concentrations as low as 0.05 microg/mL and 0.0025 microg/mL, respectively. The virus that was recovered after exposure to the compounds (3TC and HBY 097) individually had acquired, in the genetic AZT-resistance background of HIV-1/AZT, 103 Lys --> Glu and 106 Val --> Ala mutations. The 103 Lys --> Glu mutation had not been observed before. However, both virus mutants retained marked sensitivity to HBY 097. In all cases, the genotypic AZT-resistance mutations were maintained in the mutant virus RT genomes, and the viruses also remained phenotypically resistant to AZT. Given the exquisite potency of a concomitant combination of 3TC and HBY 097 in suppressing virus replication, this drug combination should be further pursued in clinical trials in HIV-1-infected individuals.

Anti-HIV Agents↗

PubMed1998

Temporal constraints of auditory event synthesis: evidence from ERPs.

The temporal constraints of auditory event synthesis were investigated using event-related potentials. Standard stimuli consisted of an initial constant-frequency segment followed by a frequency glide. Occasionally, stimuli deviating from this standard both in intensity and within the direction of the glide were presented in the otherwise repetitive sound sequence. Previous results suggested that such 'double' deviants elicit only a single mismatch negativity (MMN) if the two temporally separate deviant elements were integrated within a common unit. Two successive MMNs were elicited by double deviants when the initial constant-frequency segment of the sound was 250 ms long, but only one when this segment was 150 ms in duration. The results support the hypothesis that the auditory input is processed in approximately 200 ms long temporal integration windows.

Acoustic Stimulation↗

PubMed1998

Preattentive processing of auditory spatial information in humans.

Auditory event-related potentials were recorded from reading subjects to frequent and infrequent tones. Frequent tones presented by a loudspeaker in front of the subject were interspersed with infrequent tones delivered either by one of the symmetrically-placed lateral loudspeakers, or by both lateral loudspeakers simultaneously. This latter sound was perceived as originating from a spacious source in the direction of the central loudspeaker. A sizable mismatch negativity (MMN) and P3a were elicited by all three infrequent stimuli, suggesting that infrequent changes in the direction or perceived spaciousness of the sound source were preattentively detected. In addition, a dissociation between the MMN and P3a amplitudes was found: whereas lateral deviants elicited a larger P3a than the simultaneous left + right deviant, the MMN amplitude was approximately equal for all three deviants.

Acoustic Stimulation↗

PubMed1998

Combined mapping of human auditory EEG and MEG responses.

Auditory electric and magnetic P50(m), N1(m) and MMN(m) responses to standard, deviant and novel sounds were studied by recording brain electrical activity with 25 EEG electrodes simultaneously with the corresponding magnetic signals measured with 122 MEG gradiometer coils. The sources of these responses were located on the basis of the MEG responses; all were found to be in the supratemporal plane. The goal of the present paper was to investigate to what degree the source locations and orientations determined from the magnetic data account for the measured EEG signals. It was found that the electric P50, N1 and MMN responses can to a considerable degree be explained by the sources of the corresponding magnetic responses. In addition, source-current components not detectable by MEG were shown to contribute to the measured EEG signals.

Acoustic Stimulation↗

PubMed1998

Neural mechanisms of involuntary attention to acoustic novelty and change.

Behavioral and event-related brain potential (ERP) measures were used to elucidate the neural mechanisms of involuntary engagement of attention by novelty and change in the acoustic environment. The behavioral measures consisted of the reaction time (RT) and performance accuracy (hit rate) in a forced-choice visual RT task where subjects were to discriminate between odd and even numbers. Each visual stimulus was preceded by an irrelevant auditory stimulus, which was randomly either a "standard" tone (80%), a slightly higher "deviant" tone (10%), or a natural, "novel" sound (10%). Novel sounds prolonged the RT to successive visual stimuli by 17 msec as compared with the RT to visual stimuli that followed standard tones. Deviant tones, in turn, decreased the hit rate but did not significantly affect the RT. In the ERPs to deviant tones, the mismatch negativity (MMN), peaking at 150 msec, and a second negativity, peaking at 400 msec, could be observed. Novel sounds elicited an enhanced N1, with a probable overlap by the MMN, and a large positive P3a response with two different subcomponents: an early centrally dominant P3a, peaking at 230 msec, and a late P3a, peaking at 315 msec with a right-frontal scalp maximum. The present results suggest the involvement of two different neural mechanisms in triggering involuntary attention to acoustic novelty and change: a transient-detector mechanism activated by novel sounds and reflected in the N1 and a stimulus-change detector mechanism activated by deviant tones and novel sounds and reflected in the MMN. The observed differential distracting effects by slightly deviant tones and widely deviant novel sounds support the notion of two separate mechanisms of involuntary attention.

Acoustic Stimulation↗

PubMed1998

Processing of novel sounds and frequency changes in the human auditory cortex: magnetoencephalographic recordings.

Whole-head magnetoencephalographic (MEG) responses to repeating standard tones and to infrequent slightly higher deviant tones and complex novel sounds were recorded together with event-related brain potentials (ERPs). Deviant tones and novel sounds elicited the mismatch negativity (MMN) component of the ERP and its MEG counterpart (MMNm) both when the auditory stimuli were attended to and when they were ignored. MMNm generators were located bilateral to the superior planes of the temporal lobes where preattentive auditory discrimination appears to occur. A subsequent positive P3a component was elicited by deviant tones and with a larger amplitude by novel sounds even when the sounds were to be ignored. Source localization for the MEG counterpart of P3a (P3am) suggested that the auditory cortex in the superior temporal plane is involved in the neural network of involuntary attention switching to changes in the acoustic environment.

Acoustic Stimulation↗

PubMed1997

Pre-attentive categorization of sounds by timbre as revealed by event-related potentials.

Infrequent (10%) pure tones were randomly presented among nine different missing-fundamental tones having the same pitch (10% each) to subjects playing a computer game. MMN (an index of pre-attentive change detection) was elicited by timbre-deviant pure tones with 150 and 500 ms stimulus duration. This suggests that the spectral component of timbre is pre-attentively determined from relatively short (150 ms) acoustic samples. Previous research established that resolving the pitch of the same missing-fundamental tones requires longer (> 150 ms) sounds. Consequently, timbre and pitch are probably determined by separate neural processes. The present results also demonstrate pre-attentive categorization of sounds based on timbre as MMN could only be elicited by the pure tones if their timbre was contrasted with the combined group of the nine standard sounds of qualitatively similar rich timbre.

Acoustic Stimulation↗

PubMed1997

In vitro selection for different mutational patterns in the HIV-1 reverse transcriptase using high and low selective pressure of the nonnucleoside reverse transcriptase inhibitor HBY 097.

In vitro resistance of HIV-1 against high levels of HBY 097 ((S)-4-isopropoxycarbonyl-6-methoxy-3-(methylthiomethyl)-3, 4-dihydro-quinoxaline-2(1H)-thione) and other quinoxaline nonnucleoside reverse transcriptase inhibitors (NNRTIs) is characterized by a specific amino acid substitution in the reverse transcriptase (RT), Gly 190Glu. This change results in decreased RT polymerase activity and in reduced growth properties of the corresponding viral variant. Here we show that the appearance of the crippling mutation at codon 190 can be prevented by lowering the selective pressure exerted by HBY 097. Under low selective pressure an accumulation of other NNRTI-specific mutations is observed. Up to five NNRTI-specific substitutions were detected in some of these virus lineages. In addition, we report novel RT amino acid changes which were not observed previously, including Val106lle, Val106Leu, and Gly190Thr. HBY 097 selects for different mutational patterns under high and low selective pressure conditions, respectively. Thus, the type of mutations which appear in HIV-infected patients undergoing therapy may be determined by the levels of the selecting drug.

Antiviral Agents↗

PubMed1997

Zidovudine-resistant human immunodeficiency virus type 1 strains subcultured in the presence of both lamivudine and quinoxaline HBY 097 retain marked sensitivity to HBY 097 but not to lamivudine.

Replication of zidovudine-resistant human immunodeficiency virus type 1 (HIV-1) strains (containing the 41 Met-->Leu and 215 Thr-->Tyr mutations in reverse transcriptase [RT]) was inhibited to a significantly greater extent by the combination of lamivudine and quinoxaline HBY 097 than by either drug alone or even fully suppressed by concomitant HBY 097 and lamivudine administration at relatively low concentrations. The virus recovered after exposure to the drug combinations individually had acquired the 103 Lys-->Arg, 138 Glu-->Lys, 184 Met-->Ile, and 189 Val-->Ile mutations in the genetic zidovudine-resistance background of zidovudine-resistant HIV-1. These mutants retained marked sensitivity to HBY 097. The genotypic zidovudine-resistance mutations were maintained in the mutant virus RT genomes, and the viruses also remained phenotypically resistant to zidovudine. Given the exquisite potency of the combination of lamivudine and HBY 097 in suppressing viral replication, this combination should be further pursued in clinical trials examining treatment of HIV-1-infected persons.

Anti-HIV Agents↗

PubMed1997

Two separate codes for missing-fundamental pitch in the human auditory cortex.

Two auditory event-related potential components, the supratemporal N1 and the mismatch negativity (MMN), index traces encoding the missing-fundamental pitch. The present results suggest that these two codes derive from separate pitch extraction processes. Frequent 300-Hz and infrequent 600-Hz missing-fundamental tones were presented, in some stimulus blocks with short (150 ms), in others, with long (500 ms) stimulus durations. MMN, reflecting a preattentive change detection process, was elicited by infrequent missing-fundamental tones only in the long-duration condition. Correspondingly, subjects were able to detect these high-pitch missing-fundamental tones amongst similar low-pitch ones only when the stimulus duration was long. In addition, the MMN response peaked ca. 120 ms later for missing-fundamental tones than for pure tones of the fundamental frequency suggesting that missing-fundamental pitch resolving took substantially longer than extracting the spectral pitch. In contrast, a differential N1 response to the missing-fundamental pitch was found for both stimulus durations, with no substantial difference in peak latency between the pure and missing-fundamental tones. The contrasting features found for the two auditory cortical missing-fundamental pitch codes support the notion of two separate missing-fundamental pitch resolving mechanisms.

Adolescent↗