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BACKGROUND: Programmed cell death protein 1 (PD-1) inhibitors prolong survival versus chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC), which often expresses cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death-ligand 1 (PD-L1), providing a rationale for combined PD-(L)1 and CTLA-4 blockade. We report a phase I, open-label study of the PD-L1 inhibitor durvalumab plus the CTLA-4 inhibitor tremelimumab (NCT02262741). METHODS: In dose exploration, two cohorts of previously treated patients received durvalumab 10 mg/kg plus tremelimumab 3 mg/kg, or durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, for up to 12 months. Dose expansion comprised two cohorts of previously untreated patients with R/M HNSCC having baseline PD-L1 tumor cell (TC) expression ≥25% and <25% and one cohort of immunotherapy-pretreated patients with any PD-L1 level. All received durvalumab 20 mg/kg plus tremelimumab 1 mg/kg, then durvalumab 10 mg/kg, for up to 12 months. The primary endpoint was safety. The secondary endpoints were objective response rate (ORR) by RECIST version 1.1, pharmacokinetics, pharmacodynamics, and immunogenicity. RESULTS: A total of 71 patients were treated. The median duration of exposure was 13.6 weeks for durvalumab and 13.1 weeks for tremelimumab. In dose exploration, no dose-limiting toxicities occurred. No maximum tolerated dose was identified. Treatment-related adverse events (TRAEs) occurred in 69.0% of patients; grade 3/4 and serious TRAEs occurred in 31.0% and 18.3%, respectively. TRAEs led to discontinuation in 9.9%. There were no treatment-related deaths. The ORR was 5.6% (95% confidence interval 1.6-13.8), including one complete response and three partial responses, all patients were in dose expansion with PD-L1 TC ≥25% and no prior immunotherapy exposure; three had ongoing responses ≥12 months. The median overall survival in the total population was 8.6 months. Soluble PD-L1 suppression was almost complete in all cohorts, suggesting target engagement. CD4+Ki67+ T cells were significantly elevated in all dose-expansion cohorts. CONCLUSIONS: Treatment was well tolerated. However, response rates were low despite target engagement, no drug-drug interactions, and no drug-neutralizing antibodies to durvalumab.
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BACKGROUND: Pembrolizumab previously demonstrated robust antitumor activity and manageable safety in a phase Ib study of patients with heavily pretreated, programmed death ligand 1 (PD-L1)-positive, recurrent or metastatic nasopharyngeal carcinoma (NPC). The phase III KEYNOTE-122 study was conducted to further evaluate pembrolizumab versus chemotherapy in patients with platinum-pretreated, recurrent and/or metastatic NPC. Final analysis results are presented. PATIENTS AND METHODS: KEYNOTE-122 was an open-label, randomized study conducted at 29 sites, globally. Participants with platinum-pretreated recurrent and/or metastatic NPC were randomly assigned (1 : 1) to pembrolizumab or chemotherapy with capecitabine, gemcitabine, or docetaxel. Randomization was stratified by liver metastasis (present versus absent). The primary endpoint was overall survival (OS), analyzed in the intention-to-treat population using the stratified log-rank test (superiority threshold, one-sided P = 0.0187). Safety was assessed in the as-treated population. RESULTS: Between 5 May 2016 and 28 May 2018, 233 participants were randomly assigned to treatment (pembrolizumab, n = 117; chemotherapy, n = 116); Most participants (86.7%) received study treatment in the second-line or later setting. Median time from randomization to data cut-off (30 November 2020) was 45.1 months (interquartile range, 39.0-48.8 months). Median OS was 17.2 months [95% confidence interval (CI) 11.7-22.9 months] with pembrolizumab and 15.3 months (95% CI 10.9-18.1 months) with chemotherapy [hazard ratio, 0.90 (95% CI 0.67-1.19; P = 0.2262)]. Grade 3-5 treatment-related adverse events occurred in 12 of 116 participants (10.3%) with pembrolizumab and 49 of 112 participants (43.8%) with chemotherapy. Three treatment-related deaths occurred: 1 participant (0.9%) with pembrolizumab (pneumonitis) and 2 (1.8%) with chemotherapy (pneumonia, intracranial hemorrhage). CONCLUSION: Pembrolizumab did not significantly improve OS compared with chemotherapy in participants with platinum-pretreated recurrent and/or metastatic NPC but did have manageable safety and a lower incidence of treatment-related adverse events.
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Neoplasias Nasofaríngeas , Platina , Humanos , Neoplasias Nasofaríngeas/tratamento farmacológico , Anticorpos Monoclonais Humanizados , Docetaxel , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: Interleukin 12 (IL-12) is a pivotal regulator of innate and adaptive immunity. We conducted a prospective open-label, phase II clinical trial of electroporated plasmid IL-12 in advanced melanoma patients (NCT01502293). PATIENTS AND METHODS: Patients with stage III/IV melanoma were treated intratumorally with plasmid encoding IL-12 (tavokinogene telseplasmid; tavo), 0.5 mg/ml followed by electroporation (six pulses, 1500 V/cm) on days 1, 5, and 8 every 90 days in the main study and additional patients were treated in two alternative schedule exploration cohorts. Correlative analyses for programmed death-ligand 1 (PD-L1), flow cytometry to assess changes in immune cell subsets, and analysis of immune-related gene expression were carried out on pre- and post-treatment samples from study patients, as well as from additional patients treated during exploration of additional dosing schedules beyond the pre-specified protocol dosing schedule. Response was measured by study-specific criteria to maximize detection of latent and potentially transient immune responses in patients with multiple skin lesions and toxicities were graded by the Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0). RESULTS: The objective overall response rate was 35.7% in the main study (29.8% in all cohorts), with a complete response rate of 17.9% (10.6% in all cohorts). The median progression-free survival in the main study was 3.7 months while the median overall survival was not reached at a median follow up of 29.7 months. A total of 46% of patients in all cohorts with uninjected lesions experienced regression of at least one of these lesions and 25% had a net regression of all untreated lesions. Transcriptomic and immunohistochemistry analysis showed that immune activation and co-stimulatory transcripts were up-regulated but there was also increased adaptive immune resistance. CONCLUSIONS: Intratumoral Tavo was well tolerated and led to systemic immune responses in advanced melanoma patients. While tumor regression and increased immune infiltration were observed in treated as well as untreated/distal lesions, adaptive immune resistance limited the response.
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Interleucina-12 , Melanoma , Neoplasias Cutâneas , Eletroporação , Humanos , Imunidade , Interleucina-12/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/genética , Plasmídeos , Estudos Prospectivos , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
BACKGROUND: Simultaneous chemotherapy with vascular endothelial growth factor (VEGF) inhibition has not shown additional benefit over chemotherapy alone in advanced melanoma. We tested administration of the potent VEGF inhibitor axitinib followed by paclitaxel/carboplatin to determine whether enhanced tumour proliferation during axitinib withdrawal leads to sustained chemosensitivity. METHODS: We conducted a prospective phase II trial in metastatic melanoma patients with ECOG performance status 0-1 and normal organ function. Axitinib 5 mg PO b.i.d. was taken on days 1-14 of each 21-day treatment cycle, and carboplatin (AUC=5) with paclitaxel (175 mg m(-2)) was administered on day 1 starting with cycle 2. 3'-Deoxy-3'-(18)F-fluorothymidine ((18)F-FLT)-PET scans were performed in five patients to assess tumour proliferation on days 1, 14, 17, and 20 of cycle 1. Molecular profiling for BRAF was performed for all patients with cutaneous, acral, or mucosal melanoma. RESULTS: The treatment was well tolerated. The most common grade 3 AEs were hypertension, neutropenia, and anaemia. Grade 4 non-haematologic AEs were not observed. Four of five patients completing (18)F-FLT-PET scans showed increases (23-92%) in SUV values during the axitinib holiday. Of 36 evaluable patients, there were 8 confirmed PRs by Response Evaluation Criteria in Solid Tumors. Overall, 20 patients had SD and 8 had PD as the best response. The median PFS was 8.7 months and the median overall survival was 14.0 months. Five BRAF(V600E/K) patients had significantly worse PFS than patients without these mutations. CONCLUSIONS: Axitinib followed by carboplatin and paclitaxel was well tolerated and effective in BRAF wild-type metastatic melanoma. 3'-Deoxy-3'-(18)F-fluorothymidine-PET scans showed increased proliferation during axitinib withdrawal.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Imidazóis/administração & dosagem , Indazóis/administração & dosagem , Melanoma/tratamento farmacológico , Inibidores de Proteínas Quinases/administração & dosagem , Proteínas Proto-Oncogênicas B-raf/genética , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Axitinibe , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Didesoxinucleosídeos , Feminino , Humanos , Imidazóis/efeitos adversos , Indazóis/efeitos adversos , Masculino , Melanoma/diagnóstico por imagem , Melanoma/genética , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Tomografia por Emissão de Pósitrons/métodos , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Radiografia , Resultado do TratamentoRESUMO
Basal cell carcinoma (BCC), the most common cancer in the U.S.A., is treated primarily with local excision. In some cases, lesion size, location or extent prevent complete resection. Locally advanced BCC responds to systemic therapy with the Hedgehog pathway inhibitor vismodegib, but withdrawal of treatment may result in disease relapse. Here we present a case of locally advanced auricular BCC treated with induction vismodegib and radiation, resulting in durable local control and an acceptable level of acute toxicity.
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Carcinoma Basocelular/radioterapia , Neoplasias da Orelha/radioterapia , Proteínas Hedgehog/antagonistas & inibidores , Neoplasias Cutâneas/radioterapia , Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Basocelular/tratamento farmacológico , Terapia Combinada , Neoplasias da Orelha/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Piridinas/uso terapêutico , Neoplasias Cutâneas/tratamento farmacológicoRESUMO
BACKGROUND: Src inhibitors sensitise melanoma cells to chemotherapy in preclinical models. The combination of dasatinib and dacarbazine was tested in a phase I trial in melanoma. METHODS: Patients had ECOG performance status 0-2 and normal organ function. Dacarbazine was administered on day 1 and dasatinib on day 2 through 19 of each 21-day cycle. Both were escalated from 50 mg b.i.d. of dasatinib and 800 mg m(-2) of dacarbazine. Available pre-treatment biopsies were sequenced for BRAF, NRAS, and C-Kit mutations. RESULTS: Dose-limiting toxicity was reached at dasatinib 70 mg b.i.d./dacarbazine 1000 mg m(-2), and was predominantly haematological. In 29 patients receiving dasatinib 70 mg b.i.d., the objective response rate (ORR) was 13.8%, the clinical benefit rate (ORR+SD) was 72.4%, the 6-month progression-free survival (PFS) was 20.7%, and the 12-month overall survival (OS) was 34.5%. Two out of three patients who were wild type for BRAF, NRAS, and c-KIT mutations had confirmed partial responses, and one had a minor response. CONCLUSION: The recommended phase II dose is dasatinib 70 mg b.i.d with dacarbazine 800 mg m(-2). PFS and OS data for dasatinib at 70 mg b.i.d. with dacarbazine compared favourably with historical controls. Preliminary data support evaluating tumour mutation status further as a biomarker of response.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Melanoma/tratamento farmacológico , Metástase Neoplásica , Quinases da Família src/antagonistas & inibidores , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Dacarbazina/efeitos adversos , Dasatinibe , Feminino , Humanos , Masculino , Melanoma/patologia , Pessoa de Meia-Idade , Pirimidinas/efeitos adversos , Análise de Sobrevida , Tiazóis/efeitos adversos , Resultado do TratamentoRESUMO
BACKGROUND: Sagopilone is a novel fully synthetic epothilone with promising preclinical activity and a favourable toxicity profile in phase I testing. METHODS: A phase II pharmacokinetic and efficacy trial was conducted in patients with metastatic melanoma. Patients had measurable disease, Eastern Cooperative Oncology Group performance status 0-2, adequate haematological, and organ function, with up to 2 previous chemotherapy and any previous immunotherapy regimens. Sagopilone, 16 mg m⻲, was administered intravenously over 3 h every 21 days until progression or unacceptable toxicity. RESULTS: Thirty-five patients were treated. Sagopilone showed multi-exponential kinetics with a mean terminal half-life of 64 h and a volume of distribution of 4361 l m⻲ indicating extensive tissue/tubulin binding. Only grade 2 or lower toxicity was observed: these included sensory neuropathy (66%), leukopenia (46%), fatigue (34%), and neutropenia (31%). The objective response rate was 11.4% (one confirmed complete response, two confirmed partial responses, and one unconfirmed partial response). Stable disease for at least 12 weeks was seen in an additional eight patients (clinical benefit rate 36.4%). CONCLUSION: Sagopilone was well tolerated with mild haematological toxicity and sensory neuropathy. Unlike other epothilones, it shows activity against melanoma even in pretreated patients. Further clinical testing is warranted.
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Benzotiazóis/toxicidade , Benzotiazóis/uso terapêutico , Epotilonas/toxicidade , Epotilonas/uso terapêutico , Melanoma/tratamento farmacológico , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/toxicidade , Benzotiazóis/farmacocinética , Progressão da Doença , Epotilonas/farmacocinética , Feminino , Meia-Vida , Humanos , Masculino , Melanoma/patologia , Melanoma/radioterapia , Melanoma/cirurgia , Metástase Neoplásica , Estadiamento de Neoplasias , Estudos Prospectivos , Medição de Risco , Resultado do Tratamento , Moduladores de Tubulina/uso terapêutico , Moduladores de Tubulina/toxicidadeRESUMO
Event-related brain potentials to non-attended auditory stimuli were recorded from patients with dorsolateral prefrontal cortex (DPFCx) lesions and from age-matched control subjects as they performed a visual reaction time task. Auditory stimuli consisted of monaural sequences of repetitive standard tones (1000 Hz) and occasional deviant tones of a higher frequency (1300 Hz). In comparison with control subjects, DPFCx patients showed enhanced P1 amplitudes (mean peak latency 50 msec), consistent with reduced frontally mediated gating of sensory input to the auditory cortex. The mismatch negativity (MMN) elicited by deviant tones was reduced in DPFCx patients over a broad latency range (130-210 msec), especially over the lesioned hemisphere and for tones delivered to the ear ipsilateral to the lesion. The results suggest that DPFCx and DPFCx-temporal projections play a critical role in involuntary orienting to physical changes in sequences of non-attended auditory stimuli.
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Potenciais Evocados Auditivos/fisiologia , Lobo Frontal/fisiologia , Estimulação Acústica , Idoso , Mapeamento Encefálico , Estudos de Casos e Controles , Infarto Cerebral/fisiopatologia , Eletroencefalografia , Feminino , Lobo Frontal/irrigação sanguínea , Humanos , Masculino , Pessoa de Meia-Idade , Tempo de Reação/fisiologiaRESUMO
Auditory event-related brain potentials (ERPs) were recorded during auditory and visual selective attention tasks. Auditory stimuli consisted of frequent standard tones (1000 Hz) and infrequent deviant tones (1050 Hz and 1300 Hz) delivered randomly to the left and right ears. Visual stimuli were vertical line gratings randomly presented on a video monitor at mean intervals of 6 s. During auditory attention, the subject attended to the stimuli in a designated ear and responded to the 1300-Hz deviants occurring among the attended tones. During visual attention, the subject responded to the occasional visual stimuli. ERPs for tones delivered to the attended ear were negatively displaced relative to ERPs elicited by tones delivered to the unattended ear and to ERPs elicited by auditory stimuli during visual attention. This attention effect consisted of negative difference waves with early and late components. Mismatch negativities (MMNs) were elicited by 1300-Hz and 1050-Hz deviants irrespective of whether they occurred among attended or unattended tones. MMN amplitudes were unaffected by attention, supporting the proposal that the MMN is generated by an automatic cerebral discrimination process.
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Atenção/fisiologia , Córtex Cerebral/fisiologia , Eletroencefalografia , Reconhecimento Visual de Modelos/fisiologia , Percepção da Altura Sonora/fisiologia , Adulto , Mapeamento Encefálico , Dominância Cerebral/fisiologia , Potenciais Evocados Auditivos/fisiologia , Potenciais Evocados Visuais/fisiologia , Feminino , Humanos , MasculinoRESUMO
Auditory event-related brain potentials (ERPs) were recorded to tones of different frequencies and locations in a dichotic selective attention task in which Ss responded to occasional deviant tones of a prespecified location and frequency. Attention effects were isolated as negative difference (Nd) waves by subtracting ERPs to tones with no attended features from ERPs to the same tones when they shared target frequency, location, or both cues. The N1/P90 (latency 80-100 ms), originating in a tonotopically organized generator, was enhanced for all tones in the attended ear. Nd waves, beginning at 80 ms and lasting up to 700 ms, were seen to tones with either attended feature. Nd waves to frequency and location features had different scalp distributions consistent with generation in different cortical fields. Conjunction-specific Nds began 30-50 ms after Nds to individual features. The relative timing suggests that feature conjunction began before the analysis of individual features was complete.
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Testes com Listas de Dissílabos , Potenciais Evocados Auditivos do Tronco Encefálico , Estimulação Acústica , Adolescente , Adulto , Atenção , Percepção Auditiva , Eletroencefalografia , Movimentos Oculares , Feminino , Humanos , Masculino , Percepção da Altura Sonora , Análise e Desempenho de TarefasRESUMO
Auditory event-related brain potentials (ERPs) were recorded for 250- and 4,000-Hz tone bursts in an intermodal selective attention task. Tonotopic changes were evident in the scalp distribution of the rising phase of the auditory N1 (mean peak latency 116 ms); the N1 was more frontally distributed following the 4,000-Hz than following the 250-Hz tone bursts, and it included a contralateral P90 component that was absent following 250-Hz tones. ERPs related to intermodal selective attention were isolated as negative and positive auditory difference waves (Ndas and Pdas). Neither the Nda nor the Pda showed changes in distribution with tone frequency, but both showed Ear x Frequency changes in distribution. ERPs for deviant tones included mismatch negativities (MMNs) and, in attend auditory conditions, N2b and P3 components. These components did not change in scalp distribution with tone frequency. One possible explanation is that tonotopic displacements of ERP distributions on the scalp surface depend on angular displacements in generator fields on gyral convexities. The results are consistent with the possibility that auditory processing radiates outward with increasing latency from tonotopic fields on Heschl's gyri to more gyrus-free regions of the planun temporale and anterior superior temporal plane.
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Atenção/fisiologia , Potenciais Evocados Auditivos/fisiologia , Estimulação Acústica , Encéfalo/fisiologia , Mapeamento Encefálico , Eletroencefalografia , Humanos , Estimulação Luminosa , Tempo de Reação/fisiologia , Análise e Desempenho de TarefasRESUMO
The effects of intermodal selective attention on event-related brain potentials (ERPs) were examined in 2 experiments. In experiment 1, auditory ERPs were compared (1) when subjects responded to easy and difficult-to-detect target tones in sequences of tone bursts; and (2) when they ignored the same auditory sequences and played a demanding video game. In experiment 2, auditory ERPs to tone bursts and visual ERPs to vertical line gratings were compared as subjects responded to difficult-to-detect targets in one modality or the other. Attention to auditory stimuli resulted in biphasic enhancements in auditory ERPs, the Nda (negative auditory difference wave, latency 120-160 msec) and the Pda (positive auditory difference wave, latency 200-240 msec) waves. These had longer latencies and somewhat different scalp distributions than N1 and P2 components evoked by non-attended tones. The Nda and Pda could be contrasted with the monophasic processing negativities typically found in dichotic selective attention tasks. Nda amplitudes were larger for difficult-to-detect targets (closely resembling standards) than for standards themselves, but no Ndas were recorded to highly deviant targets. Deviant auditory stimuli evoked mismatch negativities (MMNs) that persisted during visual attention. MMN amplitudes to difficult-to-detect deviants were enlarged with attention, but no change was found in MMN amplitudes to easy-to-detect deviants. In experiment 2 intermodal attention was associated with biphasic changes in visual ERPs over the posterior scalp: the occipital Pdv (100-130 msec), and contralateral-temporal Ndv (120-320 msec) deflections. Deviant visual stimuli also elicited mismatch negativity/N2b components, largest over the inferotemporal cortex contralateral to the stimulated visual field. Like the auditory MMN, the MMN increased in amplitude with attention, but it was also evident during attend auditory conditions. The results suggest that sustained, intermodal attention depends primarily in processing modulations in modality-specific cortex. We found no evidence of the participation of modality non-specific cortex. This excludes the possibility that intermodal attention depends on a single, supramodal attention system. The relatively long latency of intermodal effects suggests that they may depend on the reafferent (top down) modulation, and do not index "template matching" operations.
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Atenção/fisiologia , Potenciais Evocados Auditivos , Potenciais Evocados Visuais , Estimulação Acústica/métodos , Percepção Auditiva/fisiologia , Comportamento/fisiologia , Córtex Cerebral/fisiologia , Humanos , Estimulação Luminosa/métodos , Tempo de Reação , Percepção Visual/fisiologiaRESUMO
The effect of processing load on event-related brain potentials (ERPs) was investigated in an intermodal selective attention task in which subjects attended selectively to auditory or visual stimuli. Processing load was manipulated by requiring subjects to detect either difficult-to-detect (deviant) or easy-to-detect (DEVIANT) targets in separate blocks of trials. Attention to auditory stimuli was associated with negative (Nda, 90-170 msec) and positive (Pda, 190-270 msec) enhancements in the ERPs to auditory stimuli. The Nda increased in amplitude with increasing processing load. Deviant auditory stimuli occurring among auditory standard stimuli elicited frontally distributed mismatch negativities (MMNs). The MMN persisted during visual attention and was unaffected by visual processing load. However, the MMN to deviants but not DEVIANTS was enhanced in amplitude with auditory attention. Attention to visual stimuli resulted in positive (Pdv, latency 70-130 msec) and negative (Ndv, 170-270 msec) modulations of visual ERPs, that increased with increasing processing load. Prominent visual deviance-related negativities were observed at occipital and infero-temporal scalp sites (latencies 90-290 msec), but only to DEVIANT visual stimuli. The early MMN-like portion of the visual deviance-related negativity was independent of attention, with equal amplitudes during different auditory and visual conditions.
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Atenção/fisiologia , Percepção Auditiva/fisiologia , Percepção Visual/fisiologia , Estimulação Acústica , Adolescente , Adulto , Córtex Cerebral/fisiologia , Potenciais Evocados Auditivos , Potenciais Evocados Visuais , Feminino , Humanos , MasculinoRESUMO
We recorded event-related brain potentials (ERPs) to random dichotic tone sequences as subjects attended to tone bursts of a designated pitch (250, 1000 or 4000 Hz) and ear of delivery. The effects of attention were isolated as negative difference (Nd) waves by subtracting ERPs to ignored tones from ERPs to the same tones when either one or both features were attended. Early sensory components of the ERP changed tonotopically in scalp distribution, while the distributions of Nd waves were feature-specific (pitch processing differed from location processing) but not tonotopic. At longer latencies, Nd waves specific to feature-conjunction operations were isolated. These began 40-50 ms after Nds to isolated cues and continued for hundreds of ms.