Place and Time Coding of Frequency in the Peripheral Auditory System: Some Physiological Pros and Cons

Evidence for and against classical theories of ‘place’ and ‘period’ mechanisms for the coding of frequency, and the modifications of the theories invoked to account for the pitch of ‘residue’ and other types of stimuli, are examined in the light of physiological data. These include new data on the temporal discharge patterns of cochlear nerve fibres under stimulation with two-tone complexes, harmonic and inharmonic three-tone complexes, and five-tone complexes of differing relative phase. They show, in particular, that certain arguments against ‘period’ coding of ‘residue’ pitch are invalid. The interspike intervals in the discharge patterns of cochlear fibres under these conditions are consistent with the pitches heard. On the other hand, the classical ‘period’ theory needs to be modified to take into account the normally relatively sharp frequency selectivity of cochlear fibres, and requires certain inefficiencies on the part of the central processor for pitch.

Comparison of measures of cochlear fibre frequency selectivity with analogous psychophysical data in man, including those on the ‘existence region’ of ‘residue’ pitch, suggests that ‘residue’-type stimuli judged to be tonal in quality could both: (a) be sufficiently resolved spectrally at the cochlear fibre level to serve as input to any of the current spectral ‘pattern recognition’ mechanisms proposed for the pitch extraction of complex signals, and also, (b) could generate patterns of temporal discharge reflecting enough waveform interaction between the harmonics to convey the pitch heard, because of the shape of the cochlear filters. (This conclusion might have to be qualified in the light of further physiological experiments on the ‘second effect’ of pitch shift.)

The present evidence, both psychophysical and physiological, suggests the following synthesis: musical interval recognition and relatively crude frequency discrimination can be accomplished by trained observers on signals where the frequency appears to be coded exclusively in terms of temporal information. However, the pitch quality of these signals is judged to be poor or absent. Likewise, signals, apparently coded exclusively by ‘place’ mechanisms, while having tonality, allow relatively crude frequency discrimination and judgment of musical intervals. With the possible exception of psychophysical data on the phenomenon of diplacusis, the present evidence cannot exclude the possibility that the central pitch extractor mechanism utilizes both the ‘place’ and ‘period’ cues produced by pure-tone signals (below 5 kHz) and ‘residue’-type signals, both signals evoking strong pitch and fine acuity of frequency discrimination. The degree of salience of a signal's pitch could well depend on the coherence of the two types of cue.

However, the greatest obstacle to the acceptance of ‘place’ coding mechanisms for frequency, particularly of the frequency components of a complex sound, is the restricted dynamic range of the peripheral elements of the auditory nervous system. Because of this, it is not clear how differences in the spectral energy distribution in signals at medium to high sound levels can be established in terms of patterns of mean discharge rate across the cochlear fibre array. At high sound levels, physiological evidence suggests that the discharge rates of the majority of stimulated fibres will be saturated, whereas psychophysical evidence suggests that the coding of the frequency and the relative level of even single-component signals can be carried out over a wide dynamic range in the absence of cues derived from spread of activity across the fibre array. Some new data, however, indicate that this problem may be circumvented at the cochlear nucleus level, but the coding mechanisms involved at the primary neurone level are obscure. One intriguing possibility exists that the auditory nervous system may utilize the fine temporal structure of cochlear fibre discharge patterns for the transmission of ‘place’ information.     

A Modified Protocol with Vincristine,Topotecan, and Cyclophosphamide for Recurrent/Progressive Ewing Sarcoma Family Tumors

Purpose: Topotecan has recently been used in the treatment of pediatric cancer. We evaluated our experience with the modified combination of vincristine, topotecan, and cyclophosphamide (VTC) given in 3 days, in children with recurrent Ewing sarcoma. Method: Children received vincristine (1.5 mg/m²/1st day), cyclophosphamide (600 mg/m²/day × 2 days) + mesna, and topotecan (1 mg/m²/day × 3 days) every 21 days. Result: A total of 118 courses of VTC were given to 13 patients. One patient received VTC both at first and at second relapse. Thus, 14 relapse episodes in 13 patients were evaluated. After three courses of VTC chemotherapy (CT), two achieved complete response (CR), five achieved partial response, thus an objective response was attained in 7/14 (50%) episodes. Two patients had stable disease and two patients progressed. In three episodes, CR was achieved by surgery before CT. One of them had a second relapse and attained CR with VTC. Median time from diagnosis to relapse was 23 months (5–45 months). Site of relapse was local in four patients, and metastatic in 10 episodes of nine patients. Seven patients are alive, three with no evidence of disease and four alive with disease; six have died of disease. Local treatment was used in 11 episodes. The toxicity of the VTC combination was limited mainly to the hematopoietic system. Conclusion: In conclusion, the modified VTC protocol in 3 days every 3 weeks seems to be effective and tolerable in children and adolescents with recurrent/progressive Ewing sarcoma.     

Graft-versus-host disease after liver transplantation is associated with bone marrow failure,hemophagocytosis, and DNMT3A mutations

Graft-versus-host disease after liver transplantation (LT-GVHD) is rare, frequently fatal, and associated with bone marrow failure (BMF), cytopenias, and hyperferritinemia. Given hyperferritinemia and cytopenias are present in hemophagocytic lymphohistiocytosis (HLH), and somatic mutations in hematopoietic cells are associated with hyperinflammatory responses (clonal hematopoiesis of indeterminate potential, CHIP), we identified the frequency of hemophagocytosis and CHIP mutations in LT-GVHD. We reviewed bone marrow aspirates and biopsies, quantified blood/marrow chimerism, and performed next-generation sequencing (NGS) with a targeted panel of genes relevant to myeloid malignancies, CHIP, and BMF. In all, 12 marrows were reviewed from 9 LT-GVHD patients. In all, 10 aspirates were evaluable for hemophagocytosis; 7 had adequate DNA for NGS. NGS was also performed on marrow from an LT cohort (n = 6) without GVHD. Nine of 10 aspirates in LT-GVHD patients showed increased hemophagocytosis. Five (71%) of 7 with LT-GVHD had DNMT3A mutations; only 1 of 6 in the non-GVHD LT cohort demonstrated DNMT3A mutation (p = .04). Only 1 LT-GVHD patient survived. BMF with HLH features was associated with poor hematopoietic recovery, and DNMT3A mutations were over-represented, in LT-GVHD patients. Identification of HLH features may guide prognosis and therapeutics. Further studies are needed to clarify the origin and impact of CHIP mutations on the hyperinflammatory state.