Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].
\r\n\tThe aim of this book will be to describe the most common forms of dermatitis putting emphasis on the pathophysiology, clinical appearance and diagnostic of each disease. We also will aim to describe the therapeutic management and new therapeutic approaches of each condition that are currently being studied and are supposed to be used in the near future.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"278931ae110500350d8b64805c70f193",bookSignature:"Dr. Eleni Papakonstantinou",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/7934.jpg",keywords:"Atopic eczema, Interleukin, Topical corticosteroids, Hand eczema, Blisters, Pruritus, Irritant contact dermatitis, Allergic contact dermatitis, Discoid eczema, Sebaceous glands, Inflammatory dermatitis, Facial rash",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 5th 2019",dateEndSecondStepPublish:"March 19th 2019",dateEndThirdStepPublish:"May 18th 2019",dateEndFourthStepPublish:"August 6th 2019",dateEndFifthStepPublish:"October 5th 2019",remainingDaysToSecondStep:"2 years",secondStepPassed:!0,currentStepOfPublishingProcess:5,editedByType:null,kuFlag:!1,biosketch:null,coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"203520",title:"Dr.",name:"Eleni",middleName:null,surname:"Papakonstantinou",slug:"eleni-papakonstantinou",fullName:"Eleni Papakonstantinou",profilePictureURL:"https://mts.intechopen.com/storage/users/203520/images/system/203520.jpg",biography:"Dr. med. Eleni Papakonstantinou is a Doctor of Medicine graduate and board certified Dermatologist-Venereologist. She studied medicine at the Aristotle University of Thessaloniki, in Greece and she continued with her dermatology specialty in Germany (2012-2017) at the University of Magdeburg and Hannover Medical School, where she completed her dissertation in 2016 with research work on atopic dermatitis in children. During this time she gained wide experience in the whole dermatological field with special focus on the diagnosis and treatment of chronic inflammatory skin diseases and also the prevention and treatment of melanocytic and non-melanocytic skin tumors. Her research interests were beside atopic dermatitis and pruritus also the pathophysiology of blistering dermatoses. In addition to lectures at german and international congresses, she has published several articles in german and international journals and her work has been awarded with various prizes (poster prize of the German Dermatological Society for the project: 'Bullous pemphigoid and comorbidities' (DDG Leipzig 2016), 'Michael Hornstein Memorial Scholarship' (EADV Athens 2016), travel grant (EAACI Vienna 2016). Since 2017, she works as a specialist dermatologist in private practice in Dortmund, in Germany. Parallel she co-administrates an international dermatologic network, Wikiderm International and she writes a dermatology public guide for patients, as she is convinced that evidence-based knowledge has to be shared not only with colleagues but also with patients.",institutionString:"Private Practice, Dermatology and Venereology",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"0",institution:null}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"16",title:"Medicine",slug:"medicine"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"270941",firstName:"Sandra",lastName:"Maljavac",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/270941/images/7824_n.jpg",email:"sandra.m@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6550",title:"Cohort Studies in Health Sciences",subtitle:null,isOpenForSubmission:!1,hash:"01df5aba4fff1a84b37a2fdafa809660",slug:"cohort-studies-in-health-sciences",bookSignature:"R. Mauricio Barría",coverURL:"https://cdn.intechopen.com/books/images_new/6550.jpg",editedByType:"Edited by",editors:[{id:"88861",title:"Dr.",name:"R. Mauricio",surname:"Barría",slug:"r.-mauricio-barria",fullName:"R. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"49961",title:"Current and Future Asthma Treatments: Phenotypical Approach on the Path to Personalized Medicine in Asthma",doi:"10.5772/62411",slug:"current-and-future-asthma-treatments-phenotypical-approach-on-the-path-to-personalized-medicine-in-a",body:'\nInternational [1] and national [2] guidelines for the management of asthma highlight the importance of finding the effective treatments for achieving and maintaining control. In spite of the existence of uniform treatment guidelines, as well as of quite accessible and effective treatments, achieving asthma control often remains a constant challenge. Recent studies indicate that over 50% of patients with asthma are not controlled [3, 4], not even when receiving a combination of inhaled corticosteroids (ICSs) and a long-acting beta-2-agonist (LABA) [5] as controller treatment. These data suggest that the search for alternative treatments is required, particularly for patients with severe uncontrolled a-wrap id="tab1" position="anchor">\nsthma.
\nWhen searching for new treatment options in asthma, it is important to remember that different drugs, particularly biological agents, act on different pathogenic pathways. So, the individual profile of physiopathological alterations of each patient should be determined to prescribe the most appropriate treatment in each case [6].
\nAsthma management, from both a current as well as a future risk perspective, must comprehend the stratification of patients into the recently defined phenotypes (such as clinical, inflammatory, and molecular) [7] and endotypes (such as allergic asthma, aspirin-sensitive asthma, late-onset hypereosinophilic asthma) [8], in the attempt to find a more personalized treatment for each patient. Moreover, in the last 10 years, significant efforts have been made to identify the characteristics that differentiate severe asthma from mild to moderate asthma, preparing the ground for the development of new selective treatments.
\nThe main goal of the treatment is to achieve and maintain the control of the disease as soon as possible, to prevent chronic airflow obstruction, and to reduce mortality. The goals of the treatment, both in its current control domain and in preventing exacerbations and accelerated loss of lung function (future risk), could be achieved in most of the patients with appropriate treatment [9, 10].
\nMaintenance treatment to achieve asthma control currently includes inhaled or systemic glucocorticoids (ICS), leukotriene antagonists, LABAs, theophylline, monoclonal antibodies (mAbs) anti-IgE (omalizumab), and recently, newly included in the latest clinical practice guidelines, tiotropium bromide [1, 2]. The parasympathetic or cholinergic system is the most important bronchoconstrictor and hypersecretory neurological mechanism of the airways [11], and blocking specific muscarinic receptors is a therapeutic alternative to reduce the increase in parasympathetic activity that characterizes the main pulmonary obstructive diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Therefore, the natural alkaloids from the Solanaceae family plants (Atropa belladonna and Datura stramonium) represent one of the traditional remedies against bronchospasm. Atropine, the prototype nonselective muscarinic receptor antagonist, with “tertiary ammonium” structure, was widely used from the late nineteenth century in oral, parenteral, and inhaled forms for the treatment of asthma; however, its use is constrained by the cardiovascular side effects. Following the introduction of ephedrine and adrenaline, in the early twentieth century, atropine fell into disuse. Later, anticholinergic therapy has returned to the forefront in the treatment of COPD, with the introduction of synthetic quaternary derivatives of atropine, short acting (ipratropium bromide) and long acting (tiotropium, aclidinium, umeclidinium, and glycopyrronium), the latter known under the acronym LAMA (long-acting muscarinic antagonists). The “quaternary ammonium” structure [12] makes them soluble in water and insoluble in lipids, therefore preventing the passage through biological barriers that are easily crossed by “tertiary ammonium” components, such as atropine, hence their lack of central nervous system effects; also they are poorly absorbed from the lung and gastrointestinal tract and do not inhibit the mucociliary clearance [13].
\nTiotropium bromide is the first long-acting anticholinergic agent (24 hours action), widely used for treatment of COPD. At the end of 2014, it was also approved by the FDA as an additional treatment of asthma in patients >12 years in the United States and in adult patients with asthma not controlled by the ICS in the European Union (Spiriva® Respimat). Such approval has been obtained based on sound scientific evidence on the effectiveness and safety of treatment with tiotropium in patients with mild-to-moderate and severe asthma. The major evidence is discussed below and is summarized in Table 1\n [14].
\nStudy | \nPatients’ characteristics | \nMain results and Conclusions | \n
---|---|---|
Park et al. 2009 [15] | \nOne hundred and thirty-eight patients with severe asthma on conventional medications and with decreased lung function. | \n– Forty-six of the 138 (33.3%) of patients with severe asthma were found to respond to adjuvant tiotropium bromide. – The presence of Arg16Gly in ADRB2 (coding beta-2 adrenoreceptor) may predict response to tiotropium bromide. | \n
Peters et al. 2010 [17] | \nTwo hundred and ten patients with poorly controlled asthma with an ICS alone. | \n– Tiotropium bromide, added to an IC, improved symptoms and lung function in patients with inadequately controlled asthma. – Its effects appeared to be equivalent to those with the addition of salmeterol. | \n
Bateman et al. 2011 [16] | \nThree hundred and eighty-eight patients with asthma with the B16-Arg/Arg genotype whose symptoms were not controlled by ICS (moderate asthma). | \n– Tiotropium bromide was more effective than placebo and as effective as salmeterol in maintaining improved lung function in B16-Arg/Arg patients with moderate persistent asthma. – Safety profiles were comparable. | \n
Kerstjens et al. 2011 [18] | \nOne hundred patients with uncontrolled severe asthma, despite receiving treatment with high-dose ICS plus a LABA. | \n– The addition of once-daily tiotropium to asthma treatment significantly improved lung function over 24 hours in patients with inadequately controlled, severe, persistent asthma. | \n
Kerstjens et al. 2012 [19] | \nNine hundred and twelve patients (814 finished the study) with uncontrolled asthma in spite of ICS/LABA (studies PrimoTinAsthma 1 and 2). | \n– The addition of tiotropium (409 patients) compared with placebo (405 patients) significantly increased the time to the first severe exacerbation and provided a modest but sustained bronchodilation. | \n
Summary of studies that demonstrate the efficiency of tiotropium bromide in asthma [14].
\nICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists.\n
A study published in 2009 [15] showed additional improvement in lung function in patients with severe asthma when tiotropium was added to conventional treatment, according to the guidelines (LABA/ICS, theophylline, antagonists of leukotriene receptor, and oral steroids). A total of 138 severe asthmatics with decreased lung function were recruited. Tiotropium 18 μg (via HandiHaler) was added once a day, and lung function was assessed every 4 weeks. Responders were defined as those with an improvement of ≥15% (or 200 mL) in FEV1 that was maintained for at least 8 successive weeks. Of the 138 people with asthma, 46 (33.3%) responded to tiotropium.
\nPeters et al. [16] conducted an independent three-way, double-blind, crossover study in 210 patients with asthma to evaluate the effect of the addition of tiotropium to ICS, when compared with doubling the dose of ICS (primary superiority comparison) or adding salmeterol (secondary comparison of non-inferiority). Use of tiotropium was superior when compared with doubling the dose of ICS; it also demonstrated superiority in the secondary endpoints, including evening PEF, the proportion of asthma control days, prebronchodilator FEV1, and daily symptom scores. The addition of tiotropium was not inferior to the addition of salmeterol on all evaluated results and increased FEV1 prebronchodilator more than salmeterol. In summary, when added to an ICS, tiotropium improved symptoms and lung function in poorly controlled patients with asthma, and its effects appear to be equivalent to those obtained with the addition of salmeterol.
\nBateman et al. [17] carried out a double-blind, double-dummy, placebo-controlled trial to compare the efficacy and safety profile of tiotropium (Respimat 5 μg, administered daily in the evening with the Respimat device) with that of salmeterol and placebo added to an ICS, in 16-Arg/Arg patients with asthma that was not controlled by ICS alone. The study population comprised patients aged 18–67 years, with reversibility to bronchodilators and symptoms that were not controlled by regular therapy with ICS (400–1000 μg of budesonide or equivalent maintained throughout the trial). Changes in weekly primary endpoint (PEF) from the last week of the run-in period to the last week of treatment showed that tiotropium was not inferior to salmeterol.
\nIt has been also assessed whether tiotropium could be an effective bronchodilator in patients with severe asthma who remain symptomatic and obstructed despite maximum recommended treatment with the combination of ICS and LABA. Kerstjens et al. [18] compared the efficacy and safety profile of two doses of tiotropium (Respimat, 5 and 10 μg daily) with placebo as an add-on therapy in 100 patients with uncontrolled severe asthma despite maintenance treatment with at least a high dose ICS combined with a LABA, in a randomized, double-blind, crossover study with three treatment periods of 8 weeks each. The PEF was peak FEV1 at the end of each treatment period. Peak FEV1 was significantly higher with 5 μg and 10 μg of tiotropium than placebo, whereas there was no significant difference between the two active doses. Domiciliary PEF values were higher with both tiotropium doses. Adverse events were balanced across groups, except for dry mouth, which was more common in patients taking tiotropium 10 μg. This study shows that the addition of once-daily tiotropium for asthma treatment, including a high-dose ICS combined with a LABA, significantly improves lung function over 24 hours in patients with uncontrolled severe asthma.
\nSubsequently, Kerstjens et al. [19] have evaluated the influence of add-on treatment with tiotropium on exacerbations, an important marker, as is well known, of asthma control. Two parallel, randomized, double-blind placebo-controlled trials (PrimoTinAsthma 1 and PrimoTinAsthma 2) were conducted between October 2008 and July 2011 in 15 countries, involving 912 patients with severe asthma and fixed airflow obstruction, who were randomized for tiotropium (Respimat, 5 μg) or placebo once daily for 48 weeks.
\nIt was concluded that in patients with poorly controlled severe asthma despite the use of ICS and LABA, the addition of tiotropium significantly increased the time to the first severe exacerbation and provided a modest but sustained bronchodilation.
\nAs mentioned in the introduction, we once more insist on the importance of determining the asthma phenotype: a small study (17 patients) showed that tiotropium is more effective in asthmatic smokers or non-smokers treated with medium-to-high doses of ICS if the inflammatory phenotype according to induced sputum is non-eosinophilic [20]. This suggests that perhaps early phenotyping poorly controlled asthmatic patients with high doses of ICS and even systemic corticosteroids (SC) could give tiotropium a corticosteroid-sparing effect in patients who turn out to have steroid-resistant asthma phenotypes. In fact, given its mechanism of action, the bronchodilator additive effect of tiotropium makes most sense in the following circumstances [21]: patients with asthma–COPD overlap syndrome (ACOS) [12], asthma of psychogenic origin, bronchospasm triggered by beta blockers, asthma with chronic airflow limitation, and severe asthmatics with Arg/Gly variation in codon 16 of the ADRB2 gene [15].
\nHowever, it seems that the effect of tiotropium goes beyond the bronchodilation because it has significant anti-inflammatory and antiproliferative capacities, such as reduction of hyperplasia of bronchial smooth muscle and inhibition of proliferation of fibroblasts and myofibroblasts [22]. Furthermore, in vitro studies using experimental models of asthma (ovalbumin-sensitized guinea pigs) have shown that tiotropium inhibits airway remodeling induced by allergens in a similar way to budesonide [23, 24], so its role in the management of allergic asthma may be more important than it seems at first glance.
\nRegarding adverse effects, tiotropium is a safe drug and is generally well tolerated, the most common side effect being dry mouth. The heart rhythm disturbances are rare (atrial fibrillation, atrial sinus, or supraventricular tachycardia). The TIOSPIR [25] study concluded that tiotropium Respimat was safe in COPD patients with ischemic heart disease and/or stable arrhythmias. The study excluded patients with myocardial infarction in the past 6 months, class III–IV NYHA heart failure, potentially fatal arrhythmias, and chronic renal failure.
\nBecause combination therapy with ICS and LABA is the usual therapeutic option for the treatment of asthma, there is great interest in developing combinations of administration once a day, in an attempt to simplify treatment and improve treatment compliance [26], a currently achievable challenge with the new ICSs (such as ciclesonide, mometasone, and fluticasone furoate) and the emergence of new ultra-LABAs (such as indacaterol, vilanterol, and olodaterol), which can be administered in a single-daily dose. Currently, new combination therapies of ultra-LABA/ICS have been developed, are in clinical trial phases II–III, or have even recently marketed (vilanterol/fluticasone furoate), like several other LAMA–LABA combinations for the treatment of COPD: tiotropium/ olodaterol, aclidinium/ formoterol, umeclidinium / indacaterol, vilanterol / umeclidinium, and so on [27]. However, the use of some of these drugs in asthma is still being investigated (see also Table 2\n).
\n\nLong-acting muscarinic antagonists (LAMA):\n \n
| \n
\nUltra-long-acting muscarinic antagonists (ultra-LAMA):\n \n
| \n
\nUltra–long-acting beta-2-agonists (ultra-LABA):\n \n
| \n
\nNew combinations of ultra–long-acting beta-2-agonists (ultra-LABA) and inhaled corticosteroids (ICS):\n \n
| \n
\nNew combinations of LAMA or ultra-LAMA and LABA or ultra-LABA:\n \n
| \n
\nTriple therapy of ultra-long-acting beta-2-agonists (ultra-LABA), inhaled corticosteroids (ICS), and ultra–long-acting muscarinic antagonists (ultra-LAMA):\n \n
| \n
New bronchodilators, either available or under clinical development, with probable upcoming indication for asthma (monotherapy and combinations).
\nCOPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta-2-agonists; LAMA = long-acting muscarinic antagonists.\n
When talking about the triple combination, it refers to ICSs, such as beta-2-agonist and inhaled anticholinergics, but mainly to long-acting drugs (LAMA–LABA–ICS). The possibility of associating these three drugs can contribute to better compliance, better control of the symptoms, and improved quality of life, as well as to a decrease in exacerbations. There are several clinical studies in development: fluticasone/salmeterol/tiotropium and budesonide/formoterol/tiotropium [28]. The first triple combination formoterol/tiotropium/ciclesonide (Triohale®, Cipla) is now available in India [29], and its probable effectiveness in asthma is yet to be proven in future clinical trials.
\nIn the last decade, significant efforts have been made to identify the characteristics of severe asthma, which are different from those described in the mild-to-moderate asthma, setting the stage for the development of new personalized therapies [7, 30]. The most promising options are represented by biological therapies, including mAbs against selective targets [10]. Later, we summarize the evidence of the only mAb that is available today to treat patients with severe asthma (omalizumab) and review those biological treatments that are currently in clinical trials, but in a more advanced stage of development and will be available for the clinical practice in the upcoming years.
\nOmalizumab is currently approved as an additional treatment in patients older than 6 years with severe allergic asthma [31]. The antibody is an IgG1 kappa that binds to IgE and prevents it binding to FCεRI and FCεRII (IgE receptors of, respectively, high and low affinity), expressed on mast cells, basophils, and dendritic cells [32]. Several post-marketing studies have been conducted in European countries [33–37] to assess the effectiveness of omalizumab: despite obvious differences between countries, all studies confirmed the usefulness and safety of omalizumab in real-life conditions. The discontinuation rate was variable, but the lack of efficacy was less than 20%, whereas in clinical trials, it was 30–40%. A probable explanation is that the “real” patients are more serious and less selected than those included in clinical trials. In Spain, a multicenter study was conducted within the routine clinical practice, in Pulmonology and Allergology departments, to evaluate the efficacy and tolerability of omalizumab [38]. With the participation of 30 centers nationwide, 266 patients who had received at least one dose of omalizumab, with 2 years of follow-up at least, were analyzed. The global evaluation of therapeutic efficacy (GETE) was good or excellent in most treated patients: 74.6% at 4 months, reaching 81.6% of the patients after 2 years, with statistically significant differences from baseline. Significant improvements in asthma control test (ACT), lung function, and exacerbation frequency were also demonstrated. In terms of medication, the doses of ICSs were significantly decreased, and the maintenance treatment with oral corticosteroids was suspended in many patients [38].
\nThe interaction between IgE and omalizumab prevents a fundamental step in the inflammatory cascade. The rapid decrease in the free circulating IgE leads to a progressive and significant decrease in the expression of IgE receptors on the inflammatory cells, so it is important to take into consideration certain entities in which IgE may also play a part even if the allergic etiology is not well established, such as nasal polyposis (NP) or non-allergic asthma.
\nWhile the inflammation in allergic or “extrinsic” asthma is clearly caused by outdoor allergens (such as dust mites and animal dander), in the intrinsic disease, there is no identifiable allergen, at least not by currently available methods. In this case, an unidentified exogenous antigen (without systemic sensitization), an infectious agent, or an endogenous “allergen” might be responsible for triggering the mechanism of atopy or in this case “entopy” [39]. The finding of specific IgEs against Staphylococcus aureus enterotoxins in patients with severe asthma, intolerance to NSAIDs and NP allowed to speculate that they were susceptible of having their airways colonized by S. aureus, which through the release of superantigens could trigger an inflammatory response with formation of local IgE [40]. NP may be present in asthma with or without concomitant atopy, but it is particularly associated with non-allergic aspirin-sensitive asthma and is one of the most common comorbid conditions in patients with severe asthma. NP is not a life-threatening condition, but the patients see their quality of life severely compromised and must undergo prolonged treatments with topical and systemic corticosteroids and multiple sinus surgeries in most cases. Over time, the lack of effective alternative treatments and the need to respond to these IgE-mediated diseases led professionals to use omalizumab off-label, with very promising results, as discussed later.
\nIn 2010, a multicenter study performed in Spain described the evolution of nasal polyps in 19 patients with NP and severe asthma treated with omalizumab [41]. The average treatment time was 16 (15–28) months. Thirteen patients (68%) had undergone at least one endoscopic surgery. The size of the polyps (assessed by calculating a score of 0–8 points by means of nasal endoscopy and confirmed by CT scan) diminished significantly in both nasal cavities after the treatment. Later, Bachart et al assessed the usefulness of anti-IgE in severe or recurrent NP associated with asthma, in a prospective double-blind placebo-controlled study (24 patients) [42]. There was a significant improvement at 16 weeks of treatment in clinical terms: nasal congestion, rhinorrhea, and loss of smell. An overall reduction in polyp size (primary end-point, assessed using the same above-mentioned score) when compared to baseline was observed [41].
\nAs to non-allergic asthma, in Spain it was first demonstrated, in a retrospective observational study [43], the efficacy of omalizumab in 29 patients with “non-atopic” asthma. GETE, ACT, the number of exacerbations and lung function improved significantly after treatment with omalizumab. There was no statistically significant difference in the response of the non-atopic asthmatics when compared with 266 patients with positive prick tests to usual inhalants. These results were subsequently confirmed in a prospective double-blind placebo-controlled trial [44].
\nTotal IgE levels are a marker of immune activity in another severe lung disease, often without any effective therapeutic alternative to systemic corticosteroids: allergic bronchopulmonary aspergillosis (ABPA). The anti-IgE treatment was also evaluated in this pathology (also off-label). In 2011, a multicenter research conducted in Spain included 18 patients with ABPA from 11 hospitals [45]. Patients were followed for a median of 36 (28–42) weeks. In this series, the largest published so far, omalizumab was beneficial in reducing daytime symptoms (44%) and nighttime awakenings (22%), significantly reduced exacerbations and improved FEV1 (p = 0.03), allowing a reduction or even discontinuance of systemic corticosteroids.
\nThe inverse correlation between free IgE levels and asthma control, found in several studies [46], suggests that a more profound suppression of free IgE could lead to an even more marked clinical improvement, so new, more potent anti-IgE mAbs are currently being assessed in clinical trials.
\nQGE031B (ligelizumab) is a new anti-IgE mAb (Novartis). It is a humanized IgG1 that binds with higher affinity to the Ce3 region of IgE. QGE031 is designed for greater suppression of IgE, with a dissociation constant (Kd) of 139 pM, representing an increase in almost 50 times of the affinity for IgE when compared with omalizumab (Kd = 6–8 nM). This is hypothesized to overcome some of the limitations associated with the dosage of omalizumab and lead to better clinical outcomes in asthma.
\nUp to date, December 2015, we have only data from preclinical experiments, and the results of two phase I, randomized, double-blind placebo-controlled studies investigating the pharmacokinetics, pharmacodynamics, and safety of ligelizumab in atopic but otherwise healthy subjects [47]. Ligelizumab was superior to omalizumab in the suppression of free IgE and FceRI expression on surface of basophils. These effects resulted in the almost complete suppression of skin response to allergens, which was higher in extent and duration when compared with omalizumab. In the 156 patients who completed the study, no serious adverse effects were reported, and only one patient developed urticaria accompanied by systemic symptoms. QGE031B’s effectiveness is currently being evaluated in patients with allergic asthma (GINA step 4/5) in a phase IIa clinical trial, with omalizumab as an active comparator.
\nQuilizumab (MEMP1972A, Genentech/Roche), another mAb anti-IgE, is being studied now in a phase IIb, randomized, double-blind, placebo-controlled clinical trial aimed to evaluate the efficacy and safety of three different doses (150, 300, and 450 mg, subcutaneously) in adults with allergic asthma not controlled with ICS and a second controller (NCT01582503). Quilizumab already has been proven effective in decreasing total and specific IgE in patients with allergic rhinitis (NCT01160861) and mild allergic asthma (NCT01196039), with a good safety profile [48].
\nInterleukin-5 (IL-5) is a hematopoietic cytokine produced by various cells such as Th2 lymphocytes, eosinophils, basophils, mast cells, and natural killer T-cells, and it is the main eosinophil modulator cytokine [49] because it enhances eosinophil chemotaxis, activation, and degranulation, while reducing apoptosis and prolonging eosinophils’ survival. The IL-5 receptor (IL-5R), expressed on both basophils and eosinophils, is made up of two subunits: an α-subunit (IL-5Rα) that is IL-5-specific and a βc-subunit (IL-5Rβc) that is responsible for signal transduction and is shared with the specific α-receptor subunits of IL-3 receptors and granulocyte–macrophage colony–stimulating factor (GM-CSF).
\nTwo mAbs (mepolizumab and relizumab) that neutralize IL-5 and another mAb (benralizumab) that blocks the IL-5Rα have been developed and are currently being evaluated in clinical trials [50].
\nMepolizumab in a fully humanized anti-IL-5 IgG1 mAb that binds to the free IL-5 with high affinity and specificity, thus preventing its binding to the α chain of the IL-5R on the eosinophil cell surface. It was the first IL-5 antagonist used in randomized, controlled trials in patients with mild asthma [51, 52] and with moderate uncontrolled persistent asthma [53]. A reduced eosinophil count was observed in both sputum and peripheral blood asthma in biopsies of bronchia and bone marrow, but with no effect on bronchial hyperresponsiveness (BHR), late asthmatic response, lung function, symptoms, or use of rescue medication whatsoever [51–53]. The reduction in the percentage of exacerbations [53] did not reach statistical significance though.
\nIn these studies, patients were not selected according to the presence of eosinophilic airway inflammation, and the number of exacerbations, a parameter directly and causally related with eosinophilic airway inflammation, was not evaluated as a principal variable of the response to treatment [49]. Two new trials were subsequently performed in patients with refractory severe persistent asthma with recurrent exacerbations, who had bronchial eosinophilic inflammation [54, 55]. Both trials reported a very significant reduction in the number of exacerbations and in the dose of oral corticosteroids in the active group when compared to those in the placebo group, as well as a major improvement in asthma control questionnaire (ACQ) scores. This response was accompanied by a significant reduction in eosinophil numbers in blood and sputum.
\nA phase IIb multicenter study (GlaxoSmithKline) has also been performed in order to determine the optimal dose of mepolizumab and to confirm its efficacy and safety in patients with severe eosinophilic asthma (the DREAM study) [56]. A total of 621 patients were randomized to placebo or one of three mepolizumab doses (75, 250, or 750 mg respectively) in parallel groups for 1 year. Mepolizumab reduced the number of severe exacerbations by 50% approximately in all the mepolizumab groups when compared with placebo, irrespective of the dose. Also, no dose–response effect was reported. The blood and sputum eosinophil counts were also reduced, and a dose–response effect was observed for eosinophil counts in sputum. On the other hand, no changes in asthma symptoms, quality of life, FeNO or lung function were observed. The drug was safe and effective. A multivariant analysis established that blood eosinophilia and the number of exacerbations in the 12 months prior to the study only were associated with a good response to mepolizumab. A meta-analysis performed on published clinical trials with mepolizumab, including a total of 1131 patients, confirmed that in cases of eosinophilic asthma, mepolizumab reduced the number of exacerbations and improved asthma-related quality of life [57].
\nReslizumab, a humanized IgG2, is another IL-5 inhibitor that is administered intravenously, although it has not been studied at such extent as mepolizumab. The only published clinical trial in patients with poorly controlled eosinophilic asthma proved that patients treated with reslizumab showed a significant improvement in FEV1 and, interestingly, patients with concomitant polyposis showed better asthma control compared to the placebo group [58].
\nBenralizumab is a humanized IgG1 mAb targeting IL-5Rα, which reduces eosinophilia by antibody-dependent cell-mediated cytotoxicity. Intravenous benralizumab has shown acceptable safety and tolerability in a phase I, dose-escalating study, with a marked reduction in circulating eosinophils [59].
\nIn a phase I, multicenter, double-blind, placebo-controlled study, 13 patients were randomized to receive a single intravenous dose of placebo or 1 mg/kg benralizumab, and other 14 patients were randomized to receive a monthly subcutaneous dose of placebo, or either 100 or 200 mg benralizumab, for 3 months. The study concluded that both the single intravenous dose and the multiple subcutaneous doses of benralizumab reduced the percentage of eosinophils in the bronchial biopsies and in induced sputum and suppressed eosinophil counts in the bone marrow and peripheral blood [60]. Additional studies are further required.
\nIL-4 and IL-13 are key therapeutic targets in Th2 high asthma, due to their significant role in Th2 lymphocyte responses and in B lymphocyte isotype switching for IgE synthesis and also for their intervention in mast cell selection (see Figure 1). The strong evidence existing upon the involvement of this pathogenic pathway in asthma, initially ranging from genetic studies up to convincing data from animal studies, leads to the development of a wide range of biological agents aimed at these targets, including anti-IL-13, anti-IL-4Rα and anti-IL-13Rα1 mAbs, IL-4Rα/IL-13Rα1 fusion protein, IL-4/IL-13 vaccines, anti-IL-4Rα antisense oligonucleotides, and double mutein IL-4 [61]. However, although many of these drugs are under development, to date only a few have been evaluated in patients with asthma [62] (see also Table 3).
\nThe IL-4/ IL-13 receptor.
\n | Drug | \nPharmaceutical company | \n|
---|---|---|---|
mAb anti IgE | \nQuilizumab (MEMP1972A) | \nGenentech/Roche | \n|
8D6 | \nUnited BioPharma | \n||
Ligelizumab (QGE031B) | \nNovartis | \n||
mAb anti IL-5 | \nIgG1 | \nMepolizumab | \nGlaxoSmithKline | \n
IgG2 | \nReslizumab | \nTEVA | \n|
mAb anti IL-5 | \nASO anti-IL-5Rβc and anti-CCR3 | \nTPI-ASM8 | \nBioCentury | \n
mAb anti IL-5Rα | \nIgG1 | \nBenralizumab | \nAstraZeneca | \n
mAb anti IL-13 | \nLebrikizumab | \nRoche | \n|
Anrukinzumab | \nAstraZeneca | \n||
Tralokinumab | \nAstraZeneca | \n||
mAb anti IL-4α/IL-13Rα1 | \nDupilumab | \nSanofi | \n|
Other IL-4/IL-13 antagonists | \nmAb anti IL-4 | \nPascolizumab | \nGlaxoSmithKline | \n
Recombinant soluble IL-4 receptor (sIL-4 R) | \nAltrakincept | \nGlaxoSmithKline | \n|
AcMo anti IL-4 | \nPascolizumab | \nGlaxoSmithKline | \n|
\n | IL-4RI-selective mutein (IL-4/Q116E) | \nPitrakinra | \nAerovance | \n
Monoclonal antibodies for the treatment of asthma.
\nASO = “anti-sense” oligonucleotide; CCR3 = cysteine–cysteine chemokine receptor-3; IL = interleukin; mAb = monoclonal antibodies; sIL-4 R = recombinant soluble IL-4 receptor.\n
Corren et al. [30] first studied the effects of lebrikizumab in 219 adults with moderate-to-severe persistent uncontrolled asthma. Lebrikizumab was administered subcutaneously every month for 6 months. A significant improvement in prebronchodilator FEV1 was recorded at 12 weeks in patients treated with lebrikizumab when compared to the placebo group. The study drug was significantly more effective in patients with pretreatment circulating periostin levels above the median and also in those with Th2-high phenotype (total IgE > 100 IU/ml and eosinophilia > 140/mm3), when compared to those with Th2-low phenotype. Exacerbations were not significantly reduced in the active group compared to placebo, but when sub analyzed in the Th2-high subgroup, the rate of exacerbations was 60% lower in patients receiving lebrikizumab compared to placebo. These data suggest that therapy with anti-IL-13 antibodies may be more effective when directed to a selected subgroup of patients (i.e. Th2-high –phenotype).
\nDupilumab (Sanofi) is a humanized mAb that targets the α-subunit of the IL-4–IL-13 shared receptor. The efficacy and safety of dupilumab in the treatment of patients with persistent eosinophilic asthma were evaluated in a phase IIa, randomized, double-blind, placebo-controlled study [63]. One hundred and five patients with moderate-to-severe persistent asthma and eosinophilia ≥300/mm3 in blood or ≥3% in sputum were included. All patients were on moderate-to-high doses of ICS and LABA. They were randomized to receive either dupilumab 300 mg (n = 52) or placebo (n = 52), subcutaneously, once a week for 12 weeks, or until the development of a moderate or severe exacerbation (primary endpoint).
\nAsthma exacerbations were reduced by 87% in the active group (6% exacerbations in the patients receiving dupilumab versus 44% in the placebo group), being this difference statistically significant. Significant differences in favor of dupilumab in the time until the first exacerbation and in the risk of exacerbations were also recorded. In the dupilumab patient group, both the morning peak expiratory flow (PEF) and the asthma symptoms evaluated by the ACQ5 improved significantly. Nocturnal awakenings and the use of short-acting beta-2 agonists were also reduced.
\nRegarding adverse effects, more local reactions at the injection site, nasopharyngitis, nausea, and headache were reported in patients on active treatment, and there was one case of angioedema. The authors of this study emphasize the effect of dupilumab on the reduced frequency of exacerbations, even after withdrawal of ICS and LABA. Nevertheless, they admit that the definition of “exacerbation” used in their protocol does not coincide with that usually employed in clinical practice and, accordingly, recommend that larger studies should be further performed [63].
\nAs we have seen, most new mAbs under development are directed against different targets of the Th2 pathway [62]. A summary of all these drugs is found in Table 3. Figure 2 briefly sketches the allergic inflammatory cascade, so that we might easily visualize these therapeutic targets.
\nTherapeutic targets within the allergic cascade.
Unfortunately, for patients belonging to severe asthma phenotypes other than eosinophilic asthma, current therapeutic options are scarce, and many of these patients are steroid-dependent and even steroid-resistant [2]. Clinical trials with anti-tumour necrosis factor (TNF)-α mAbs (such as infliximab, adalimumab, and golimumab) have been performed with discouraging results. A study including 309 patients with severe persistent asthma, randomized to receive placebo or three different doses of golimumab (50, 100, and 200 mg), showed no significant improvement in any of the efficacy variables [64]. More importantly, the trial had to be prematurely discontinued due to serious adverse events (SAEs), namely infections and malignancies, in the golimumab group. A post-hoc analysis suggested that patients with a prestudy history of sinusitis and FEV1 reversibility (≥12%) who received golimumab (100 and 200 mg) had fewer severe asthma exacerbations, apparently associated with a dose–response effect. Perhaps, if biomarkers were developed for predicting response to anti-TNF-α agents, then they could be used for selected subgroups of patients with severe asthma, but the contradictory efficacy results and especially the potential safety concerns have prevented the performance of any additional clinical trials so far.
\nThermoplasty is a bronchoscopic procedure that reduces the bronchial smooth muscle layer by applying heat by radiofrequency. The results of the studies showed, in patients with moderate and severe asthma, a significant improvement in their quality of life, increased disease control, and a reduction of exacerbations. These results persist for years after the procedure, without medium- to long-term secondary effects [65–67]. While new evidence is needed to identify the ideal candidate, it is currently considered to be preferably indicated in patients with severe uncontrolled asthma, with chronic airflow limitation (FEV1 > 50% and <80%), and without bronchial hypersecretion. Likewise, its application is recommended to be performed in centers with experienced and sufficiently trained endoscopists [2].
\nWe are witnessing the rapid development of new molecules and also of promising new combinations in terms of efficacy, safety, and dosage for the treatment of asthma, except perhaps for treatment for a subgroup of patients with severe non-eosinophilic asthma, in which therapeutic options still remain limited. Given the heterogeneity of the disease, we consider it is important to establish the phenotype or endotype as a first step on the road to the “personalized” medicine in asthma.
\nFrom a practical point of view, in Table 4 we present the personal opinion of the authors of this chapter on the individualized” utility of the new asthma treatments, already existing or proximally available.
\nAsthma phenotype/endotype and its major characteristics | \nTherapeutic options | \n|
---|---|---|
\n1. Extrinsic or allergic asthma\n | \n– Allergen avoidance, montelukast, allergen-specific immunotherapy, omalizumab – Tiotropium bromide | \n|
\n2. Intrinsic or non-allergic asthma\n | \n\n | |
\nEosinophilic, may associate atopy or entopy\n | \n\nAERD (or NERD): Th2-high and extensive eosinophilic infiltration, potentially severe or difficult-to-control asthma, glucocorticoid-dependent/glucocorticoid-resistant asthma | \n– Montelukast, tiotropium bromide, aspirin desensitization – Omalizumab (anti-Th2 effect, off-label). – In the future: assess new treatments with anti-IL-5 and anti-IL-13 | \n
\nLate-onset hypereosinophilic asthma: similar to AERD, increased airway remodelling, fixed airflow limitation, usually glucocorticoid-dependent asthma | \n– Tiotropium bromide – Omalizumab (off-label). – Future: anti-IL-5 | \n|
Non-eosinophilic, non-atopic | \nNon-eosinophilic asthma: obese females, neutrophilic or paucigranulocytic inflammation, Th2-low: worse prognosis, glucocorticoid-resistant asthma | \n– Tiotropium bromide, ultra-LABA/LAMA – Bronchial thermoplasty. – Anti-TNF-α???* | \n
The path to personalized treatment of asthma insufficiently controlled with ICS/LABA: Present and future.
\nAERD = aspirin-exacerbated respiratory disease (or Samter’s triad); ICS = inhaled corticosteroids; IL = interleukin; LABA = long-acting beta-2-agonists; LAMA = long-acting muscarinic antagonists; NERD = non-steroidal anti-inflammatory drugs-exacerbated respiratory disease; Th2 = helper type 2 lymphocyte; TNF = tumour necrosis factor\n
\n* Clinical trials with anti-TNF agents (infliximab, adalimumab, and golimumab) had to be suspended prematurely due to the appearance of serious adverse events, especially severe infections and malignancies [64].\n
Mammalian sensory systems are composed in cortex of many functionally specialized areas organized into hierarchical networks [1, 2, 3, 4, 5, 6]. The most fundamental sensory information is embodied by the organization of the sensory receptors, which is maintained throughout most of the cortical hierarchy of sensory regions with repeating representations of this topography in cortical field maps (CFMs) [5, 7, 8, 9, 10, 11, 12, 13]. Accordingly neurons with receptive fields situated next to one another in sensory feature space are positioned next to one another in cortex within a CFM.
\nIn auditory cortex, auditory field maps (AFMs) are identified by two orthogonal sensory representations: tonotopic gradients from the spectral aspects of sound (i.e., tones), and periodotopic gradients from the temporal aspects of sound (i.e., period or temporal envelope) [5, 10, 14]. On a larger scale across cortex, AFMs are grouped into cloverleaf clusters, another fundamental organizational structure also common to visual cortex [8, 10, 15, 16, 17, 18, 19, 20]. CFMs within clusters tend to share properties such as receptive field distribution, cortical magnification, and processing specialization (e.g., [18, 19, 21]).
\nAcross the cortical hierarchy, there is generally a progressive increase in the complexity of sensory computations from simple sensory stimulus features (e.g., frequency content) to higher levels of cognition (e.g., attention and working memory) [6, 13, 22]. CFM organization likely serves as a framework for integrating bottom-up inputs from sensory receptors with top-down attentional processing [12, 17]. With the recent ability to measure AFMs in the core and belt regions of human auditory cortex along Heschl’s gyrus (HG) using high-resolution functional magnetic resonance imaging (fMRI), the stage is now set for investigation into this integration of basic auditory processing with higher-order auditory attention and working memory within human AFMs (Figure 1) [5, 12, 15, 23].
\nPrimary auditory cortex. (A) The lateral view of the left hemisphere is shown in the schematic. Major sulci are marked by black lines. The approximate position of primary auditory cortex (PAC) is shown with the red overlay inside the black dotted line. The white dotted line within the red region indicates the extension of PAC into the lateral sulcus (LS) along Heschl’s gyrus (HG; hidden within the sulcus in this view). Inset refers to anatomical directions as A: anterior; P: posterior; S: superior; I: inferior. PAC: primary auditory cortex (red); LS: lateral sulcus (green; also known as the lateral fissure or Sylvian fissure); CS: central sulcus (purple); STG: superior temporal gyrus (blue); STS: superior temporal sulcus (orange). (B) The cortical surface of the left hemisphere of one subject (S2) is displayed as a typical inflated 3-D rendering created from high-resolution, anatomical MRI measurements. Light gray regions denote gyri; dark gray regions denote sulci. The exact location of this subject’s hA1 auditory field map is shown in red within the black dotted lines. Note that HG in S2 is composed of a double peak, seen here as two light gray stripes, rather than the more common single gyrus. The locations of the three cloverleaf clusters composed of the core and belt AFMs are shown along HG by three colored overlays as yellow: hCM/hCL cluster; red: HG cluster including hA1, hR, hRM, hMM, hML, hAL; and magenta: hRTM/hRT/hRTL cluster (cite?). Additional cloverleaf clusters are under investigation along PP, PT, STG, and the STS. Green-labeled anatomical regions are sections within the lateral sulcus—CG: Circular gyrus (green); PP: planum polare (green); PT: planum temporale (green). (C) This single T1 image shows a coronal view of hA1 on HG (red within dotted white line). Adapted from Refs. [5, 12].
This chapter first provides a brief history of research into models of auditory nonverbal attention and working memory, with comparisons to their visual counterparts. Next, we discuss the current state of research into AFMs within human auditory cortex. Finally, we propose directions of future research investigating auditory attention and working memory within these AFMs to illuminate how these higher-order cognitive processes interact with low-level auditory processing.
\nAttention, the ability to select and attend to aspects of the sensory environment while simultaneously ignoring or inhibiting others, is a fundamental aspect of human sensory systems (for reviews, see [24, 25, 26, 27]). Given the limited resources of the human brain, attention allows for greater resources to be allocated to processing of important incoming sensory stimuli by diverting precious resources from currently unimportant stimuli. Such allocation can be controlled cognitively, in what is generally referred to as ‘top-down’ attentional control in models of attention, in reference to the higher-order cognitive processes controlling attention from the ‘top’ of the sensory-processing hierarchy and acting ‘down’ on the lower levels (Figure 2) [24, 28, 29, 30, 31]. Despite lower priority being assigned to the currently unimportant stimulus locations, change is constant, so the resource diversion to attended stimuli is not absolute, allowing for the sensory environment to continue to be monitored. If, instead, processing resources were evenly distributed throughout the sensory field, without regard to salience, more resources would be wasted on unimportant aspects of the field. If something in the unattended sensory field should become important, the system requires a mechanism to reorient attention to that aspect of the field. Such stimulus-driven attentional control is referred to as ‘bottom-up’, referring to the ability of incoming sensory input at the bottom of the hierarchy to orient the higher-order attention system. This broad framework of attentional models is common at least to the senses most commonly studied, vision and audition [25, 27, 31, 32].
\nAttention and working-memory model. A model of the interactions between perception, trace memory, attention, working memory, and long-term memory in the visual and auditory systems, as well as the central executive. Ovals represent neural systems. Arrows represent actions of one system on another. Attention is the term for the action of perception and trace memory on working memory and vice versa. Rehearsal is the term for maintaining information in working memory. This model is not intended to indicate that these systems are discrete or independent; within each sense, they are in fact highly integrated.
In the effort to elucidate the parameters of auditory attention, researchers have taken a myriad of approaches in numerous contexts. Researchers have attempted to decipher at what level of the sensory-processing hierarchy stimulus-driven attention occurs (after which sensory-processing steps does attention act) [24, 30, 31, 33, 34, 35], how attention can be deployed (to locations in space or particular sensory features) [36, 37, 38, 39, 40], and how can attention be distributed (to how many ‘objects’ or ‘streams’ can attention be simultaneously deployed) [41, 42, 43, 44]. Many studies have narrowed the range of possibilities without precisely answering these questions, and so remain active areas of research. Modern models of attention generally agree that stimuli are processed to some degree before attention acts, accounting for the stimulus-driven ‘bottom-up’ attentional shifts, though it is unclear to precisely which degree [24, 30, 33]. Neuroscientific evidence suggests that attention acts throughout sensory-processing hierarchies, so the idea of attention being located at a particular ‘height’ in the hierarchy may not be a particularly useful insight for identifying the cortical locus of attentional control [45, 46]. Modern attentional models also generally agree that attention can be deployed to locations in or features of sensory space, both of which are fundamental aspects to the sensory-processing hierarchy [24, 35]. Finally, modern models of attention agree that attention is very limited, but not about precisely how it is limited. Some models are still fundamentally ‘spotlight’ models [25, 44], in which attention is limited to a single location or feature set, while others posit that attention can be divided between a small number of locations or features [41, 47]. Based on related working-memory research, the latter theory is gaining prominence as likely correct.
\nWorking memory (i.e., a more accurate term for ‘short-term memory’) is the ability to maintain and manipulate information within the focus of attention over a short period of time after the stimulus is no longer perceptible (for reviews, see [48, 49, 50, 51]). Without explicit maintenance, this retention period is approximately 1–2 s, but is theoretically indefinite with explicit maintenance. Working memory should not to be confused with ‘sensory memory’, also known as ‘iconic memory’ in vision and ‘echoic memory’ in audition [52]. Sensory memory is a fundamental aspect of sensory systems in which a sensory trace available to attention and working-memory systems persists for less than ~100 ms after stimuli are no longer perceptible. Models of working memory are nearly indistinguishable from models of attention; the key difference is that working memory is a ‘memory’ of previously perceptible stimuli, whereas attention is thought to act on perceptible stimuli or sensory traces thereof. Working-memory models posit, by definition, that working memory acts after perception processing has occurred (Figure 2; for review, see [53]). However, it has been difficult to isolate exactly where working-memory control resides along the cortical hierarchy of sensory processing, likely because low-level perceptual cortex is recruited at least for visual working memory and attention [40, 46, 54, 55].
\nLike attention, working-memory models also posit that working memory is a highly limited resource, in which a small set of locations or objects (e.g., 3–4 items on average) can be simultaneously maintained [42, 49]. In fact, some modern measures of attention and working memory are nearly identical. The change-detection task is a ubiquitous one in which subjects are asked to view a sensory array, then compare that sensory array to a second one in which some aspect of the array may have changed, and indicate whether a change has occurred (Figure 3) [56, 57, 58, 59, 60]. A short delay period (i.e., retention interval) is included during each array, which may include a neutral presentation or, if desired, a mask of the sensory stimuli to prevent the use of ‘sensory memory’. The length of the delay period can be then be altered to either measure attention or working memory. If the delay period is on the order of ~0–200 ms, it is considered an attentional task; if it is longer, on the order of 1–2 s, it is considered a working-memory task [53]. Therefore, attention and working-memory systems are at a minimum heavily intertwined and very likely the same system studied in slightly different contexts, with attention being a component of a larger working-memory framework.
\nVisual change-detection task. This task can be used to probe visual attention or working memory and is very similar to its auditory counterpart. Such tasks have three phases: first is encoding, when subjects are given ~100–500 ms to view the sample array; next is maintenance, which is short (~0–200 ms) for measuring attention and longer (~1000 ms) for working memory; last is the probe (lasting until the subject responds or with a time limit, often ~2000 ms). In this example, a set size of four is presented for the sample array and a probe array of one is used, though different set sizes are commonplace and often the probe array will be the same set size as the encoding array with a possibility of one object being changed. Typically there is an equal chance (50%) of the probe array containing a change or not. Generally subjects will be required to fixate centrally, particularly if fMRI, EEG, or PET recordings are being made. (A) Simple colored square stimuli are depicted here, often drawn from a small set of easily distinguished hues (in this case, 6). As a result, changes are always low in similarity, requiring low resolution to make accurate comparisons between encoding and test arrays, which is important at least for visual working-memory measurements. More complex stimuli can also be used as in (B) and (C). These stimuli are shaded cubes with the same hue set as in (A), but also have 6 possible shading patterns with the dark, medium, and light shaded sides on each cube. Changes between hues, as in (B), are equivalently low similarity to (A) and result in similar performance under visual working-memory conditions. Changes in shading patterns, as in (C), result in worse performance than (B) despite having the same number of possible pattern changes as hue changes in (A) or (B), because such changes require higher resolution representations in visual working memory. Adapted from Barton and Brewer [50].
With the relatively recent invention of fMRI, researchers have been able to begin to localize these models of attention and working memory to their cortical underpinnings (e.g., [6, 37, 40, 50, 55, 61, 62]). FMRI, through its exquisite ability to localize blood oxygenation-level dependent (BOLD) signals (and thus the underlying neural activity) to just a couple of millimeters is the best technology available for such research [63, 64]. Two broad approaches have been employed for studying these high-order cognitive processes: model-based and perception-based. Model-based investigations tend to use tasks based on behavioral investigations into attention and working memory, adapt them to the strict parameters required of fMRI, and compare activity in conditions when attention or working memory are differentially deployed [61, 62]. Perception-based investigations tend to measure low-level perceptual cortex that has already been mapped in detail and measure the effects of attention or working memory within those regions [50, 55, 65]. Both approaches are important and should be fully integrated to garner a more complete and accurate localization of these attentional and working-memory systems.
\nResearch into attention began in earnest in the auditory system after World War II with a very practical motivation. It had been noted that fighter pilots sometimes failed to perceive auditory messages presented to them over headphones despite the fact that the messages were completely audible. To solve this problem, Donald Broadbent began studying subjects with an auditory environment similar to the pilots, with multiple speech messages presented over headphones [34]. Based on his findings, he proposed a selective theory of attention, which was popular and persuasive, but ultimately required modification. Environments such as the one Broadbent studied are more commonly encountered at cocktail parties, in which multiple audible conversations are taking place, and people are able to attend to one or a small set of speech streams while attenuating the others. To study the ‘cocktail party phenomenon,’ the dichotic listening task was developed in the 1950s by Colin Cherry [66, 67]. Subjects were asked to shadow the speech stream presented to one ear of a set of headphones while another stream was presented to the other ear, and they demonstrated little knowledge of the nonshadowed (unattended) stream (Figure 4).
\nAuditory spatial attention. Schematic of an example auditory spatial attention task (e.g., see [35, 40, 66, 67]). Each block typically starts with cue (auditory or visual) for the subject to attend left or right on the upcoming trial. Two simultaneous auditory streams of digits are presented as binaural, spatially lateralized signals. Behavioral studies in an anechoic chamber often use speaker physically located to the left and right of the subject; fMRI measurements do not have the option of such a set up, but instead can use differences in the interaural time difference (ITD) to produce a similarly effective lateralization for the two digit streams. The subjects attend to the cued digit stream and perform a 1-back task.
A host of studies followed up on the basic finding, revealing several attentional parameters within the context of that type of task (e.g., [30, 35, 40, 68, 69, 70, 71]). Importantly, preferential processing of the attended stream relative to the unattended streams is not absolute; for example, particularly salient information, such as the name of the subject, could sometimes be recalled from an unattended stream, presumably by reorienting attention [39, 66, 67, 69]. The streams were typically differentiated spatially (e.g., to each ear through a headset), indicating a spatial aspect to attentional selection and therefore the attentional system. Similarly, the streams were also typically differentiated by the voice of the person speaking, indicating attentional selection based on the spectrotemporal characteristics of the speaker’s voice such as the average and variance of pitch and speech rate (often reflecting additional information about the speaker, such as gender) [66, 67, 68, 72].
\nThese findings are very similar to findings in the visual domain, indicating that attentional systems across senses are similarly organized. Visual attention can similarly be deployed to a small set of locations or to visual features with very little recall of nonattended visual stimuli [41]. Roughly analogous to speech shadowing are multiple-object-tracking tasks, which require subjects to visually track a small set of moving objects out of a group [47, 73]. Visual change-detection tasks are also very common, and they demonstrate very similar results as their auditory counterparts [50, 74, 75]. In sum, the evidence suggests that attentional systems are organized very similarly, perhaps identically, between at least vision and audition.
\nDespite these broad contributions, these types of tasks are of limited utility when tying behavior to cortical activity because the types of stimuli used are rather high-order (e.g., speech) with relatively uncontrolled low-level parameters. For example, the spectrotemporal profile of a stream of speech is complex, likely activating broad swaths of low-level sensory cortex in addition to higher-order regions dedicated to speech comprehension, including working and long-term memory [68, 72, 76, 77]. If one were to compare fMRI activity across auditory cortex in traditional dichotic listening tasks, the differences would have far too many variables for which to account before meaningful conclusions can be made about attentional systems. It may seem intuitive to compare cortical activity between conditions where identical speech stimuli have been presented and the subject either attended to the stimuli or did not. However, areas that have increased activity when the stimuli were attended could simply reflect higher-order processing that only occurs when attention is directed to the stimuli rather than directly revealing areas involved in attentional control. For example, recognition of particular words requires comparison of the speech stimulus to an internal representation, which requires activation of long-term memories of words [77]. Long-term memory retrieval does not happen if the subject never perceived the word due to attention being maintained on a separate speech stream, so such memory-retrieval activity would be confounded with attentional activity in the analysis [70].
\nThus, simpler stimuli that are closer in nature to the initial spectrotemporal analyses performed by primary auditory cortex (PAC) are better suited for experiments intended to demonstrate attentional effects in cortex [24]. Reducing the speech comprehension element is a good first step, and research approached this by using a change-detection task and arrays of recognizable animal sounds (cow, owl, frog, etc.; Figure 5) [59]. These tests revealed what the researchers termed ‘change deafness,’ in which subjects often failed to identify changes in the sound arrays. Such inability to detect changes is entirely consistent with very limited attentional resources, and very similar to results of working-memory change-detection tasks [30, 53, 60, 78].
\nAuditory feature attention. Schematic outlines a simple proposed attention task utilizing spectral (narrowband noise) and temporal (broadband noise) stimuli taken from the stimuli used by [10] to define auditory field maps. Subjects are asked to attend to one of two simultaneously presented stimuli, which are either (A) narrowband noise, in this case with central frequencies of 6400 and 1600 Hz and the same amplitude modulation (AM) rate of 8 Hz, or (B) broadband noise, in this case with AM rates of 2 and 8 Hz. (C) A proposed task that varies auditory feature attention, in which subjects are instructed to attend to each of the stimuli in an alternating pattern, cued by a short sound at the beginning of each block.
However, even these types of stimuli are not best suited to fMRI investigation at this stage of understanding due to their relative complexity compared to the basic spectrotemporal features of sounds initially processed in auditory cortex [12, 50]. As discussed in detail below, the auditory system represents sounds in spectral and temporal dimensions, and stimuli similar to those used to define those perceptual areas would be best suited now to evaluating the effects of attention in the auditory system (Figure 6) [5, 10].
\nAuditory object attention and working memory. Schematic of one trial in an auditory change-detection task (e.g., see change-deafness experiments in [59]). Subjects are first presented with an array of four distinct auditory objects (e.g., four different recordings of real animal sounds, randomized each trial from a larger set of iconic animal calls). In the initial memory array, the four animal sounds are initially presented binaurally and are temporally overlapped for a short time (e.g., 2 s). Within an anechoic chamber setup often used in psychoacoustic studies, these speakers may be physically positioned at the corners of a square; fMRI measurements do not have the option of such a set up, but instead can use differences in the interaural time difference (ITD) and interaural level difference (ILD) to produce a similarly effective virtual space. The subject’s goal is typically to identify and remember all four animal sounds. The interstimulus interval is commonly filled with silence or white noise and can be varied in length to create shorter or longer retention intervals for attention or working-memory tasks, respectively. During the subsequent test array, subjects attempt to identify which one of the four auditory objects is now missing from the simultaneous animal sound presentations. In such auditory change-deafness paradigms, subjects fail to notice a large proportion of the changes introduced between the initial and test arrays.
Visual and auditory working memory were discovered in quick succession and discussed together in a very popular and influential model by Baddeley and Hitch linking sensory perception, working memory, and executive control [79, 80, 81]. The generally accepted modern model of working memory has changed somewhat from the original depiction, but the vast majority of research has been working within the framework (for reviews, see [30, 51, 53, 79, 81]). Each sense is equipped with its own perceptual system and three memory systems: sensory memory, working memory, and long-term memory. Direct sensory input, gated by attentional selection, is one of the two primary inputs into working memory. Sensory memory is a vivid trace of sensory information that persists after the information has vanished for a short time and is essentially equivalent to direct sensory input into working memory, again gated by attentional selection; one can reorient attention to aspects of the sensory trace as if it were direct sensation. Long-term memory is the second primary input into working memory, which is gated by an attention-like selection, generally referred to as selective memory retrieval. Working memory itself is a short-term memory workspace lasting a couple of seconds without rehearsal, in which sensory information is maintained and manipulated by a central executive [82]. The central executive is a deliberately vague term with nebulous properties; as a colleague often quips, “All we know of the central executive is that it’s an oval,” after its oval-shaped depiction in the Baddeley and Hitch model. There is ongoing debate as to the level of the hierarchy at which each system is integrated into that of the other senses, with no definitive solutions.
\nVisual working memory and visual sensory memory (i.e., ‘iconic memory’) were fundamentally measured by George Sperling in 1960 [52]. He presented arrays of simple visual stimuli for short periods of time and asked subjects to report what they had seen after a number of short delays. He discovered that subjects could only recall a small subset of stimuli in a large array, representing the limited capacity of visual working memory. Furthermore, they could recall a particular subset of the stimuli when cued after the presentation but before the sensory trace had faded (≤100 ms), indicating that visual sensory memory exists and that visual attention can be deployed to stimuli either during sensation or sensory memory. Over the next decade, George Sperling went on to perform similar measurements in the auditory system, delineating very similar properties for auditory perception, sensory memory, and working memory [83].
\nWithout directly measuring brain activity, researchers concluded that sensory systems must be operating independently with dual-task paradigms in which subjects were asked to maintain visual, auditory, or both types of information in working memory. It was shown that subjects could recall ~3–4 ‘chunks’ of information (which may not precisely reflect individual sensory locations or features) of each type, regardless of whether they were asked to maintain visual, auditory, or both types of information [49, 78]. If the systems were integrated, one would be able to allocate multisensory working-memory ‘slots’ to either sense, with a maximum number (e.g., 6–8) that could be divided between the senses as desired. Instead, subjects can maintain on average ~3–4 visual chunks and ~3–4 auditory chunks, without any ability to reallocate any ‘slots’ from one sense to the other.
\nWhile electroencephalogram (EEG) and positron emission topography (PET) recordings could broadly confirm the contralateral organization of the visual system and coarsely implicate the parietal and frontal lobes in attention and working memory, it was not until the advent of high-resolution fMRI that researchers could begin localizing attention and working memory in human cortex with any detail [6, 17, 37, 50, 84, 85, 86, 87, 88, 89, 90]. Model-based fMRI investigations have attempted to localize visual working memory by comparing BOLD activity in conditions where subjects are required to hold different numbers of objects in working memory [50, 62, 91, 92]. The logic goes that, because visual-working-memory models posit that a maximum of ~3–4 objects can be held in visual working memory on average, areas that increase their activity with arrays 1, 2, 3 objects and remaining constant with arrays of 4 or more objects should be areas controlling visual working memory. Such areas were found bilaterally in parietal cortex by multiple laboratories [57, 62, 91, 93], but activity related to visual working memory has also been measured in early visual cortex (e.g., V1 and hV4) [55, 65, 94], prefrontal cortex [95], and possibly in object-processing regions in lateral occipital cortex [62], indicating that working-memory tasks recruit areas throughout the visual-processing hierarchy. (We note that the report of object-processing regions is controversial, as the cortical coordinates reported in that study are more closely consistent with the human motion-processing complex, hMT+, than the lateral occipital complex [15, 17, 96, 97]). However, little has been done to measure visual-working-memory activity in visual field maps, and so these studies should be considered preliminary rather than definitive. Measurements within CFMs would, in fact, help to clear up such controversies.
\nAuditory-working-memory localization with fMRI has been quite limited compared to its visual counterpart, and largely concentrated on speech stimuli rather than fundamental auditory stimuli [30, 68]. As noted above with attention localization with fMRI, too many variables exist with highly complex stimuli, and as such, a different approach is necessary. Furthermore, even low-level auditory sensory areas have only very recently been properly identified [5, 10].
\nAuditory processing is essential for a wide range of our sensory experiences, including the identification of and attention to environmental sounds, verbal communication, and the enjoyment of music. The intricate sounds in our daily environments are encoded by our auditory system as the intensity of their individual component frequencies, comparable to a Fourier analysis [98]. This spectral sound information is thus one fundamental aspect of the auditory feature space (Figure 7A,C). The basilar membrane of the inner ear responds topographically to incoming sound waves with higher frequencies transduced to neural signals near the entrance to the cochlea and progressively lower frequencies transduced further along the membrane. This organized gradient of frequencies (i.e., tones) is referred to as tonotopy (i.e., a map of tones); this topography may also be termed cochleotopy, referring to a map of the cochlea. Tonotopic organization is maintained as auditory information is processed and passed on from the inner ear through the brainstem, to the thalamus, and into PAC along Heschl’s gyrus (HG; Figure 1; for additional discussion, see [2, 5, 6, 12, 99, 100]). The preservation of such topographical organization from the basilar membrane of the inner ear to auditory cortex allows for a common reference frame across this hierarchically organized sensory system [6, 7, 12, 13, 22, 23].
\nExample tonotopic and periodotopic stimuli for auditory field mapping. (A) Three stimulus values for one dimension of auditory feature space (e.g., tonotopy) are depicted in the graph: 1—low (L, red); 2—medium (M, green); 3—high (H, blue). (B) Three stimulus values for a second dimension of auditory feature space (e.g., periodotopy) are depicted in the second graph: 1—low (L, orange); 2—medium (M, aqua); 3—high (H, purple). (C) Tonotopic representations can be measured using narrowband noise stimuli, which hold periodicity constant and vary frequency. (i) Sound amplitude (arbitrary units) for this stimulus set as a function of time in seconds. (ii) Sound spectrograms for two example narrowband noise stimuli with center frequencies (CF) of 1600 Hz (top) and 6400 Hz (bottom). Higher amplitudes in decibels (dB) are represented as ‘warmer’ colors (see dB legend below). (D) Periodotopic representations can be measured using broadband noise stimuli, which maintain constant frequency information and vary periodicity. (i) Sound amplitude (arbitrary units) for this stimulus set as a function of time in seconds. (ii) Sound spectrograms for two example broadband noise stimuli with amplitude modulation (AM) rates of 2 Hz (top) and 8 Hz (bottom). Higher amplitudes are again depicted as ‘warmer’ colors (see dB legend on bottom).
A second fundamental aspect of the auditory feature space is temporal sound information, termed periodicity (Figure 7B,D) [10, 101, 102]. Human psychoacoustic studies indicate that there are separable filter banks (i.e., neurons with distinct receptive fields) for not only frequency spectra—as expected given tonotopy, but also temporal information [103, 104, 105]. The auditory nerve likely encodes such temporal information through activity time-locked to the periodicity of the amplitude modulation (i.e., the length of time from peak-to-peak of the temporal envelope) [101, 106]. Temporally varying aspects of sound are thought to preferentially active neurons selective for the onset and offset of sounds and for sounds of certain durations. Organized representations of periodicity in primates have been measured to date in the thalamus and PAC of macaque and human, respectively, and are termed periodotopy, a map of neurons that respond differentially to sounds of different temporal envelope modulation rates [5, 10, 107]. Repeating periodotopic gradients exist in the same cortical locations as, but are orthogonal to, tonotopic gradients, which allows researchers to use measurements of these two acoustic dimensions to identify complete AFMs.
\nMeasurements of the structure and function of human PAC and lower-level auditory cortex have been relatively few to date, with many studies hampered by methodological issues (for reviews, see [5, 23]. Precise measurements of AFMs across primary and lower-level auditory cortex are vital, however, for studying the neural underpinnings of such prominent auditory behaviors as attention and working memory. Recent research has now successfully applied fMRI methods commonly used to measure visual field maps to the study of AFMs in human auditory cortex.
\nThe phase-encoded fMRI paradigm provides highly detailed in vivo measurements of CFMs in individual subjects [9, 10, 15, 108, 109, 110, 111]. This technique measures topographical representations using stimuli that periodically repeat a set of values in an orderly sequence (Figure 7). The phase-encoded methods are specialized for AFM measurements by combining this periodic stimulus with a sparse-sampling paradigm (Figure 8) [10, 112, 113, 114, 115]. Sparse-sampling separates the auditory stimulus presentation from the noise of the MR scanner during data acquisition to avoid contamination of the data by nonstimulus sounds [116, 117, 118].
\nSchematic of phase-encoded fMRI paradigm for auditory field mapping experiments. (A) Diagram of a single stimulus phase shows the components of a single block of one auditory stimulus presentation (striped green) followed by an fMRI data acquisition period (solid green). This sparse-sampling paradigm separates the auditory stimulus presentation from the noisy environment of the MR scanner acquisition. The timing of the acquisition (2 s delay) is set to collect the approximate peak response of auditory cortex to the stimulus, in accordance with the estimated hemodynamic delay. (B) Each phase (block) of an example tonotopic stimulus is displayed within the gray box above the colored blocks; one block thus represents one stimulus position in the ‘phase-encoded’ sequence. The diagram of an example stimulus cycle below this depicts six presentation blocks (striped green+ solid green) grouped together into one stimulus cycle (blue). Each block, or stimulus phase, in each cycle represents a specific frequency; e.g., for tonotopic measurements, the stimulus that is presented sequentially changes to each of the Hz listed in the gray box. The term ‘traveling-wave’ is also used to describe this type of phase-encoded stimulus presentation, as the stimuli produce a sequential activation of representations across a topographically organized cortical region. (C) Diagram shows a full, single scan comprising six cycles. (D) Legend denotes color-coding for diagrams above.
The periodic stimulus allows for the use of a Fourier analysis to determine the value of the stimulus (e.g., 800 Hz frequency for tonotopy) that most effectively drives each cortical location [110]. The cortical response at a specific location is said to be ‘in phase’ throughout the scan with the stimulus value that most effectively activates it, hence the term ‘phase-encoded’ mapping. The alternate term ‘traveling-wave’ mapping arises from the consecutive activation of one neighboring cortical location after the other to create a wave-like pattern of activity across the CFM during the stimulus presentation. The phase-encoded paradigm only captures cortical activity that is at the stimulus frequency, thus excluding unrelated cortical activity and other sources of noise. Similarly, cortical regions that are not organized topographically will not be significantly activated by phase-encoded stimuli, as there would be no differential activation across the cortical representation [8, 15, 16]. The statistical threshold for phase-encoded cortical activity is commonly determined by coherence, which is a measure of the amplitude of the BOLD signal modulation at the frequency of the stimulus presentation (e.g., six stimulus cycles per scan), divided by the square root of the power over all other frequencies except the first and second harmonic (e.g., 12 and 18 cycles per scan) [15, 17, 110].
\nMeasurement and analysis of phase-encoded CFM data must be performed within individual subjects rather than across group averages to avoid problematically blurring together discrete CFMs and their associated computations (for extended discussions, see [5, 15, 17]). CFMs may differ radically in size and anatomical position among individual subjects independent of brain size; this variation is reflected in associated shifts in cytoarchitectural and topographic boundaries [119, 120, 121, 122, 123, 124]. In the visual system, for example, V1 can differ in size by at least a factor of three despite its location on the relatively stable calcarine sulcus [120]. Accordingly, when such data are group-averaged across subjects, especially through such approaches as aligning data from individual brains to an average brain with atlases such as Talairach space [125] or Montreal Neurological Institute (MNI) coordinates [126], the measurements will be blurred to such a degree that the measured topography of the CFMs is inaccurate or even lost. Blurring from such whole-brain anatomical co-alignment will thus cause different CFMs to be incorrectly averaged together into a single measurement, mixing data together from adjacent CFMs within each subject and preventing the analysis of the distinct computations of each CFM.
\nIn order to avoid the imprecise application of the term ‘map’ to topographical gradients or other similar patterns of cortical organization, the designation of an AFM—and CFMs in general—should be established according to several key criteria (Figure 9) (for reviews, see [5, 8, 15]). First, by definition, each AFM must contain at least the two orthogonal, nonrepeating topographical representations of fundamental acoustic feature space described above: tonotopy and periodotopy (Figure 9A) [10, 17, 21, 108, 110, 111]. When this criterion is ignored and the measurement of only one topographical representation is acquired (e.g., tonotopy), it is impossible to correctly identify boundaries among cortical regions. Measurements of the organization and function of specific regions of early auditory cortex in human long have mostly relied on tonotopic measurements alone, which has resulted in variable, conflicting, and ultimately unusable interpretations of the organization of human PAC and surrounding regions (for detailed reviews, see [5, 23]).
\nDefinition of auditory field maps (AFMs). (A) (i) Schematic of a single gradient of dimension 1 (e.g., tonotopy). Black arrow shows the low-to-high gradient for this tonotopic gradient. With only measurements of the single dimension of tonotopy, it cannot be determined whether the region within dimension 1 contains one or more cortical field maps without measuring a second, orthogonal gradient. (ii) Schematic of a single gradient of dimension 2 (e.g., periodotopy) overlapping the tonotopic gradient in (i) to form a single AFM like hA1. Black arrow shows the low-to-high gradient for this periodotopic gradient. Note the orthogonal orientation of the two gradients (i vs. ii) composing this AFM. (iii) schematic of an alternative gradient organization for periodotopy overlapping the same tonotopic gradient in (i). Black arrows now show two low-to-high gradients (G1: gradient 1, G2: gradient 2) of this second dimension within the same territory as the orthogonal low-to-high gradient in (i). The gray dotted line marks the boundary dividing this region into two AFMs. (B) (i) In a properly defined AFM, measurements along the cortical representation of a single value of tonotopy (e.g., green) span all values of periodotopy (e.g., orange to cyan to purple), and vice versa. (ii) Schematic of vectors drawn along a single CFM from centers of low-stimulus-value regions of interest (ROIs) to high-stimulus-value ROIs for dimensions 1 (e.g., red to blue) and 2 (e.g., orange to purple). The offset measured between the low-to-high vectors for each dimension should be approximately 90° to be considered orthogonal and thus allow for each voxel/portion of the map to represent a unique combination of dimension 1 and dimension 2 values. (C) The diagram demonstrates how gradient boundaries for one dimension of an AFM are determined. Black dots denote hypothetical measurement points along the cortical surface shown in (A, iii). Black arrows note gradient directions (low, L, to medium, M, to high, H). Dashed gray lines mark gradient reversals. Two gradients that span the full range of dimension 2 measurements can be divided into G1 and G2, with the representations of stimulus values increasing from low to high across the cortical surface in one gradient to the boundary where the representations in the next map then reverse back from high to low along the cortical surface in the next gradient. G3 and G4 (gradients 3 and 4, respectively) denote additional gradients continuing at reversal to regions outside the diagram. (for review, see [23]).
The representation of one dimension of sensory space—one topographical gradient along cortex like tonotopy—is not adequate to delineate an AFM, or CFMs in any sensory system. The measurement of a singular topographical dimension merely demonstrates that this particular aspect of sensory feature space is represented along that cortical region. The CFMs within that cortical region cannot be identified without measuring an orthogonal second dimension: a region of cortex with a large, confluent gradient for one dimension could denote a single CFM (Figure 9Ai,ii) or many CFMs (Figure 9Ai,iii), depending upon the organization of the overlapping second topography. Similarly, the two overlapping gradients must be approximately orthogonal, as they will otherwise not represent all the points in sensory space uniquely (Figure 9B) [15, 16, 127, 128]. As the complexity of adjacent gradients increases, the determination of the emergent CFM organization grows increasingly complicated.
\nDue to the relatively recent measurements of periodotopic representations in human auditory cortex and monkey midbrain, AFMs in core and belt regions can now be identified [10, 102]. The identification of periodotopy as the second key dimension of auditory feature space is strengthened by psychoacoustic studies, which show that separable filter banks occur not only for frequency spectra, but also temporal information, indicating the presence of neurons with receptive fields tuned to ranges of frequencies and periods [14, 103, 104, 105]. Additionally, representations of temporal acoustic information (i.e., periodicity) have been measured in the auditory system of other model organisms, including PAC in domestic cat and inferior colliculus in chinchilla [129, 130].
\nA second AFM criterion is that each of its topographical representations must be organized as a generally contiguous and orderly gradient [16, 128]. For such a gradient to develop, the representation must be organized such that it covers a full range of sensory space, in order from one boundary to the other (e.g., from lower to upper frequencies for tonotopy; Figure 9C). A topographical gradient is thus one of the most highly structured features of the cortical surface that can be measured using fMRI. The odds of two orderly, orthogonal gradients arising as a spurious pattern from noise in an overlapping section of cortex is extraordinarily low (for a calculation of the probability of spurious gradients arising from noise, see [19]).
\nThird, each CFM should contain representations of a considerable amount of sensory space. Differences in cortical magnification are likely among CFMs with different computational needs, but a large portion of sensory space is still expected to be represented (e.g., [15, 16, 19, 21, 97, 127, 131]). A high-quality fMRI measurement of the topography is necessary to adequately capture the sensory range and magnification. The quality of the measurement is dependent upon choosing an appropriate set of phase-encoded stimuli. The sampling density and range of values in the stimulus set both affect the accuracy and precision of the measurement. For example, the intensity (i.e., loudness) of the tonotopic stimulus alone can alter the width of the receptive fields of neurons in PAC and consequently increase the lateral spread of the BOLD signal measured in neuroimaging [132]. In addition, some degree of blurring in the measurements of the topography is expected due to such factors as the overlapping broad receptive fields, the inherent spatial spread of the fMRI signal, and measurement noise [64, 109, 133, 134]. The stimulus parameters and how they may affect the cortical responses should therefore be given careful consideration.
\nFourth, the general features of the topographies composing the CFMs and the pattern of CFMs across cortex should both be consistent among individuals. It is essential to remember, nevertheless, that cytoarchitectural and topographic boundaries in PAC vary dramatically in size and anatomical location independent of overall brain size [119, 121, 122, 123, 124, 135], as do CFMs across visual cortex [16, 17, 120, 136]. Regardless of these variations, the overall organization among specific CFMs and cloverleaf clusters will be maintained across individuals.
\nThe measurement of AFMs is one of the few reliable in vivo methods to localize the distinct borders of the auditory core and belt regions in individual subjects [5, 10, 12, 23]. The boundaries of an AFM—and of CFMs in general—are determined by carefully defining the edges of overlapping sections of tonotopic and periodotopic gradients within a specific cortical region in an individual hemisphere (Figure 9). If a set of overlapping representations of the two dimensions is present in isolation, the boundary of the AFM can be estimated to be where the gradient responses end, although there will likely be some spatial blurring or spreading of the representation along these edges (Figure 9Ai,ii) [16, 17, 110, 137]. For multiple, adjacent representations that each span the full range of one dimension (e.g., low-to-high frequencies of tonotopy) can be divided into two sections at the point at which the gradients reverse (Figure 9Ai,iii). At the gradient reversals, the representations of stimulus values increase from low to high (or vice versa) across the cortical surface in one section to the boundary where the representations in the next AFM then reverse back from high to low (or vice versa) along the cortical surface in the next section (Figure 9C). Such phase-encoded fMRI measurements of the boundaries of the AFMs in human auditory cortex have been shown to be closely related to those determined by invasive human cytoarchitectural studies and nonhuman primate cytoarchitectural, connectivity, and tonotopic measurements [2, 5, 10, 121, 138, 139, 140, 141, 142, 143, 144].
\nAt a scale of several centimeters, groups of adjacent CFMs are organized within both auditory and visual cortex into a macrostructural pattern called the cloverleaf cluster, named for the similarity of the organization of the individual CFMs composing a cluster to the leaves of a clover plant [8, 10, 15, 16, 17, 18, 19, 20]. Within a cluster, one dimension of sensory topography is represented in concentric, circular bands from center to periphery of the cluster, and the second, orthogonal dimension separates this confluent representation into multiple CFMs with radial bands spanning the cluster center to periphery. In AFM clusters, a confluent, concentric tonotopic representation is divided into specific AFMs by reversal in the orthogonal periodotopic gradients. Neighboring cloverleaf clusters are then divided along the tonotopic reversals at the cluster boundaries.
\nWhile CFM clusters have consistent positions relative to one another across the cortical surface, CFMs within each cluster may be oriented differently among individuals as if rotating about a cluster’s central representation. This inter-subject is consistent with the variability in molecular gradient expression that gives rise to the development of cortical topographical gradients [145, 146, 147, 148, 149]. This unpredictability of cluster anatomical location and rotation emphasizes the need for careful data analysis to be performed in individual subjects, in which common CFMs can be identified by analyzing the pattern of CFMs and cloverleaf clusters within that sensory system.
\nAuditory processing in human cortex and in nonhuman primates occurs bilaterally along the temporal lobes near the lateral sulcus (Figure 1; e.g., [5, 10, 115, 121, 139, 140, 141, 142, 144, 150, 151, 152, 153]). In the macaque monkey model system upon which much of our understanding of human audition is based, converging evidence from cytoarchitectural, connectivity, electrophysiological, and neuroimaging studies have generally identified 13 auditory cortical areas grouped into core, medial and lateral belt, and parabelt regions that are associated with primary, secondary, and tertiary levels of processing, respectively (for extended discussions, see [2, 5, 154]). Auditory processing in macaque cortex begins along the superior temporal gyrus (STG) within three primary auditory areas: A1, R, and RT [140]. In contrast to early visual processing in which primary visual cortex is composed of V1 alone, primary auditory cortex is considered to be a core region composed of these three AFMs; all three areas contain the expanded layer IV arising from dense thalamic inputs and the high expression of cytochrome oxidase, acetylcholinesterase, and parvalbumin distinctive to primary sensory cortices [2, 142, 143, 150, 152, 154, 155, 156, 157]. The eight belt regions are divided into four areas along both the lateral (CL, ML, AL, RTL) and medial (CM, RM, MM, RTM) sides of the core [158, 159, 160]. Along the lateral belt, two additional areas create the parabelt, which allocates auditory information to neighboring auditory cortex as well as to multimodal cortical regions [2, 161].
\nBased on cytoarchitectural, connectivity, and neuroimaging measurements, early auditory processing in human cortex has been shown to resemble the organization of lower-level macaque auditory processing [10, 23, 121, 144, 151, 152, 153, 162]. Over the ~25 million years of evolutionary separation between the species, the core, belt, and parabelt areas have rotated from the STG to Heschl’s gyrus (HG), an anatomical feature unique to humans [11, 163]. The specific structure of HG differs across individuals, variably existing as a single or double gyrus. PAC is then either mostly centered on the single HG or overlapping both gyri in the case of two (Figure 1B,C) [122, 135, 136]. Core, belt, and parabelt areas have thus shifted in orientation from a strictly rostral-caudal axis for A1 to R to RT along macaque STG to a medial-lateral axis along human HG for hA1, hR, and hRT. The naming of the AFMs in human is based on the likely homology to macaque, but adds an ‘h’ to signify human [10].
\nWith our new understanding of periodotopic representations overlapping the previously identified tonotopic gradients, in vivo fMRI measurements can now identify the 11 AFMs that compose the core and belt regions of human auditory cortex (Figure 10) [5, 10, 12, 23]. Running from STG to the circular sulcus (CiS) along HG are three distinct, concentrically organized, tonotopic representations. The primary circular tonotopic gradient is one dimension of the HG cloverleaf cluster, with a confluent low-tone representation located centrally and expanding smoothly to high-tone representations at the outer edge (Figure 10B,C) [5]. The HG cluster is divided along the orthogonal periodotopic reversals into two AFMs each of core, medial belt, and lateral belt: hA1, hR, hMM, hRM, hML, and hAL (Figure 10D,E). Positioned at the tip of HG, hA1 is the largest of these core and belt AFMs, with the posterior/lateral region representing low tones and the anterior/medial region representing high ones. HA1 is involved in the most basic of cortical auditory computations, which is reflected in its representations of broad ranges of tonotopy and periodotopy [2].
\nAuditory field maps and cloverleaf clusters in human cortex. (A) Anatomical views of Heschl’s gyrus (HG), superior temporal gyrus (STG) and surrounding auditory cortex in an individual subject’s left hemisphere (S2). (i) Inflated 3-D rendering of the cortical surface. Light gray denotes gyri; dark gray denotes sulci. The approximate region presented in the other panels is indicated by the dotted black line. Note that this subject has a double peak along HG. (ii) flattened cortical surface of the region indicated by the dotted black line in (i). AFM boundaries between maps along tonotopic reversals are indicated by solid black lines. These tonotopic reversals constitute the separation of cloverleaf clusters from one another. AFM boundaries along periodotopic reversals are indicated by dotted black lines. These periodotopic reversals compose the separation between maps within a cloverleaf cluster. Red text indicates AFM names. (B) Tonotopic gradients measured using narrowband noise stimuli with a phase-encoded fMRI paradigm (example single-subject data from [10]). Color overlay indicates the preferred frequency range for each voxel. CF: center frequency in Hz. For clarity, only voxels within the core and belt AFMs are shown. Solid and dotted black lines are as in (A). Coherence ≥0.20. Inset scale bar designates 1 cm along the flattened cortical surfaces in (B, D). Inset legend indicates anatomical directions for (B-E). M: medial; L: lateral; A: anterior; P: posterior. (C) Diagram is based on individual-subject data measured by [10] in multiple phase-encoded fMRI experiments. Approximate positions of core AFMs (hA1, hR, hRT) are shown in white, and approximate positions of belt AFMs (hML, hAL, hRTL, hRTM, hRM, hMM, hCM, hCL) are shown in gray. Darker beige background indicates the plane of the lateral sulcus, while lighter beige overlay indicates gyri. Gyri are also marked with dashed black lines. HG: Heschl’s gyrus. CG: circular gyrus; CiS: circular sulcus; a/p STG: anterior/posterior superior temporal gyrus. Diagram depicts the locations of tonotopic representations overlaid along the core and belt AFMs, with low (L) and high (H) tonotopic representations are marked in red and blue, respectively. Dotted black lines designate the boundaries between AFMs within three cloverleaf clusters: HG cluster with hA1; hCM/hCL cluster (partial cluster defined to date); hRTM/hRT/hRTL cluster (partial cluster defined to date). (D) Periodotopic representations measured using broadband noise stimuli with a phase-encoded fMRI paradigm. Data are from the same subject as shown for tonotopy in (B), with the color overlay now indicating the preferred period range for each voxel. AM rate: amplitude modulation rate in Hz. Other details are as in (B). (E) Diagram depicts periodotopic representations overlaid on the same example region of cortex as in (C). L and H now designate to the approximate locations of low (orange) or high (purple) periodotopic representations, respectively. Adapted from Barton et a.[10]. For a detailed review, see [5].
A reversal in the tonotopic gradient along the anteromedial edge of the HG cluster divides it from the CM/CL cluster just past the tip of HG (Figure 10B,C). A high-periodicity gradient reversal splits this tonotopic gradient into hCM, and hCL, two regions associated with early language and speech processing as well as audiovisual integration (Figure 10D,E) [164]. Finally, the reversal in the tonotopic gradient along the posteriolateral edge of the HG cluster separates it from the RT cluster positioned where HG meets STG (Figure 10B,C). Two reversals in the periodotopic representations here divide the RT cluster into hRT, hRTM, and hRTL (Figure 10D,E). In macaque, these AFMs along STG are thought to subserve lower-level processing of auditory stimuli like temporally modulated environmental sounds [158, 159]. More research is needed to determine how what other AFMs form the CM/CL and RT clusters. Based on emerging data, it is likely that AFMs will also be a fundamental organization of auditory cortex adjacent to these cloverleaf clusters, such as planum temporale (PT), planum polare (PP) and STG.
\nThe characterization of AFMs and cloverleaf clusters will be crucial for the study of the structure and function of human auditory cortex, as these in vivo measurements allow for the systematic exploration of computations across a sensory system (for reviews, see [5, 17]). Such AFM organization provides a basic framework for the complex processing and analysis of input from the sensory receptors of the inner ear [5, 12, 17, 23]. The cloverleaf cluster organization of AFMs may also play a role in coordinating neural computations, with neurons within each cluster sharing computational resources such as common mechanisms to coordinate neural timing or short-term information storage [8, 12]. Similarly, vision studies suggest that functional specializations for perception are organized by cloverleaf clusters, as a particular cloverleaf cluster can be functionally differentiated from its neighbors by its pattern of BOLD responses, surface area, cortical magnification, processing specialization, and receptive field sizes [12, 16, 18, 19, 21, 165]. These distinctions indicate that CFMs within individual cloverleaf clusters are not only anatomically but also functionally related [15, 18, 20, 166].
\nThe cluster organization is not necessarily thought to be driving common sensory functions, but rather reflects how multiple stages in a sensory processing pathway might arise during development across individuals and during evolution across species. It is likely that this cluster organization, like the topographic organization of CFMs, allows for efficient connectivity among neurons that represent neighboring aspects in sensory feature space [166, 167, 168, 169]. Since the axons contained within one cubic millimeter of cortex can extend 3-4 km in length, efficient connectivity is vital for sustainable energetics in cortex [170].
\nThe definitions of AFMs and the cloverleaf clusters they compose using phase-encoded fMRI will thus serve as reliable, independent localizers for investigations of attention and working memory in early auditory cortex across individuals. Measurements of individual AFMs along the cortical hierarchy will help reveal the distinct stages of top-down and bottom-up auditory processing. In addition, changes in AFMs can be tracked to study how auditory cortex changes under various attentional and working memory tasks and disorders (e.g., [145, 171, 172, 173, 174, 175, 176, 177]).
\nThe human brain has sophisticated systems for perception, trace memory, attention, and working memory for audition and vision, and likely the other senses as well. These systems appear to be organized in a very similar manner for each sense, despite the inputs to each system and information content being quite different. Behavioral measures of the last several decades have led to the development of well-defined models of each system. These models form the basis for the investigation of their underlying architecture in the cortical structures of the human brain. EEG and PET have allowed for spatially coarse investigation of cortical activity, but with the advent of fMRI, it has become possible to make exceptionally detailed spatial measurements. The methods of investigation must be carefully crafted to best elicit activity reflecting the desired aspects of each system; not only must the tasks be appropriate for fMRI, the stimuli and task must be closely matched not just to the system being studied, but to the inputs into that system as well.
\nFor both audition and vision, the sensory processing in cortex happens in cloverleaf clusters of CFMs. This organizational pattern has clearly been demonstrated in the lower tiers of the processing hierarchy and very likely is organized as such throughout. Because the CFMs across the entire hierarchy (or at least, most) of one sense can be measured in just one session in the fMRI scanner, they make incredibly efficient localizers. CFMs are be measured in individual subjects, and serve as functional localizers that can be used to average more accurately across subjects than anatomical localizers. As such, due to the pervasive and fundamental role CFMs play in sensory systems, they are also excellent candidates for measuring the effects of attention and working memory in cortex. To best accomplish this feat, it is proposed that stimuli that are similar to those used to measure CFMs are excellent candidates for use in traditional tasks used to define attentional and working-memory models.
\nThis material is based upon work supported by the National Science Foundation under Grant Number 1329255 and by startup funds from the Department of Cognitive Sciences at the University of California, Irvine.
\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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