{"doi":"10.1113/jp280958","title":"Response to: The post‐inspiratory complex (PiCo), what is the evidence?","abstract":"We thank Dr Swen Hülsmann for his thoughtful and supportive letter to the editor regarding our recent publication (Dhingra et al. 2020). Dr Hülsmann (2021) noted the absence of a discussion of the role of the recently described post-inspiratory complex (PiCo) in the generation of the post-inspiratory phase of the breathing pattern. Indeed, post-inspiratory control of glottal adduction is an essential element controlling expiratory airflow during the eupneic three-phase breathing pattern and during both expulsive (coughing, sneezing, etc.) and non-respiratory behaviours (swallowing, vocalisation, etc.); and loss of airway-protective post-inspiratory glottal constriction, for instance during swallowing, may result in aspiration pneumonia in neurodegenerative diseases (Dutschmann et al. 2014; Anderson et al. 2016). In our study, it was striking that respiratory local field potentials (LFPs) occurring at the transition from inspiration (I) to post-inspiration (PI) were the most widely distributed of any respiratory phase transition. In general, LFPs are thought to largely reflect the summation of synchronous synaptic conductances because of their long-time constants. Therefore, our observation suggests that synaptic conductances within many respiratory network areas were maximal precisely at the I–PI transition. This observation certainly negates the conceptual model put forward in the ‘triple-oscillator hypothesis’ that interactions between only the pre-Bötzinger complex, PiCo and parafacial respiratory group/retro-trapezoid nucleus account for the three-phase respiratory motor pattern (Anderson & Ramirez, 2017). This conclusion is further underscored by our previous publication, which demonstrated at the motor output level that perfused brainstem preparations containing all elements of the ‘triple-oscillator hypothesis’, but lacking pontine components of the network, are insufficient to generate eupnea, and instead produce a pathologic apneustic inspiratory motor pattern expressed synchronously on vagal, hypoglossal and phrenic nerves (Jones & Dutschmann, 2016). As noted in Dr Hülsmann's letter, Anderson et al. (2016) has 100+ citations. Yet, to our knowledge, only one of those studies sought to confirm its findings (Toor et al. 2019). Together, these two papers fail to demonstrate that the PiCo is necessary for the generation of the eupneic post-inspiratory motor pattern under intact network conditions, especially when compared with similar perturbations of the activity of the Kölliker–Fuse nuclei (KFn). Inhibition of the KFn with isoguvacine completely ablates post-inspiratory laryngeal, cervical vagal nerve activity (cVNA) (Dutschmann & Herbert, 2006; Dutschmann et al. 2021), whereas inhibition of the PiCo with isoguvacine only reduces the peak amplitude of cVNA (Toor et al. 2019). Modulation of KFn activity with DAMGO, a μ-opioid receptor agonist, also results in a complete ablation of post-inspiratory cVNA (Levitt et al. 2015), whereas modulation of PiCo activity with DAMGO only reduces the amplitude of cVNA (Anderson et al. 2016). Clearly, the pons is necessary for the expression of post-inspiratory cVNA, and hence the three-phase respiratory motor pattern, and its absence disrupts PI more than any medullary counterpart including the PiCo. On the other hand, our recent work suggests to us that focusing on the pons, medulla or any particular respiratory area in isolation might also be short-sighted since local modulation of excitability within any key respiratory network area is sufficient to severely disrupt the three-phase respiratory motor pattern (Dhingra et al. 2019a,b), and since LFPs associated with the inspiratory off-switch (e.g. I–PI transition) can be detected in areas even we did not previously consider (Dhingra et al. 2020). Alternatively, Toor et al. (2019) convincingly demonstrated that the PiCo is necessary for sequential swallowing in vivo and may relate more to the ventral swallowing group (for review, see","journal":"The Journal of Physiology","year":2020,"id":110687,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":6,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9626,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":351492,"name":"Werner I. Furuya","orcid":"0000-0002-7244-2313","position":1,"is_corresponding":false},{"id":351491,"name":"Thomas E. Dick","orcid":"0000-0003-3287-8566","position":2,"is_corresponding":false},{"id":351494,"name":"Mathias Dutschmann","orcid":"0000-0002-0692-746X","position":3,"is_corresponding":false},{"id":351490,"name":"Rishi R. Dhingra","orcid":"0000-0002-4684-5215","position":0,"is_corresponding":true}],"reference_count":18,"raw_metadata":null,"created_at":"2026-07-18T23:13:01.914939Z","pmid":"33197048","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}