Cadence Schematic Editor

Opyright © 2013 Society For Music Theory

Hollywood Cadences: Music and the Structure of Cinematic

Frank Lehman

NOTE: The examples for the (text-only) PDF version of this item are available online at: http://www.mtosmt.org/issues/mto.13.19.4/mto.13.19.4.lehman.php KEYWORDS: film music, cadence, phrase, modulation, genre theory, Western, Caplin, Newman, Korngold, Moross,

Goldsmith, Howard, Williams, Jurassic Park

ABSTRACT: Cadences are one of the most powerful tools at a film composer’s disposal. The structure and placement of a cadence can shape the emotional arc of a scene, accentuate narratival information, and manipulate generic expectations. Drawing from theories of film genre and cadential definition from Altman (1999) and Caplin (2002), I explore several cinematically significant “cadential genres”—harmonic routines arising through the convergence of independent musical phenomena that together project a punctuative function. Through processes of attribute substitution and subtraction, a cadential genre can adapt to shifting scoring practices and generic expectations.

I showcase four such cadential genres. The mixed plagal cadence imports transcendent harmonic associations from the Romantic era. Phrasal “mickey mousing” arises through cadential synchronization, as shown in an analysis of Korngold’s Robin Hood. The subtonic half cadence is strongly linked with a specific film genre: the Western. Through analysis of Jerome Moross’s subtonic-saturated scores and subsequent adapted and abstracted usages, I show the value of the generic approach to style-based analysis. Lastly, I inspect the chromatically modulating cadential resolution (CMCR): the strategy of initiating a diatonic cadence in one key only for the dominant to discharge onto the tonic of a chromatically related key. Through a variety of intrinsic and contextual traits describable by linear, transformational, and cognitive models, I explain the strong association of CMCRs with cinematic evocations of wonderment. This is illustrated through a case study of Williams’s Jurassic Park.

Owboy Chromaticism [4.1]

IV. Chromatically Modulating Cadential Resolutions [5.1]

The Hollywood Sound(1)

[1.1] One of the fruits of film musicology’s extraordinary growth during the past decade is an increasing appreciation of the exuberant complexity of meaning in musical multimedia. Several attempts have been made to establish broad principles for musical meaning-making across film styles and eras, particularly for “Classical Hollywood” (roughly 1930–1960).(2) At the same time, other, more targeted studies—several from music theorists—have striven to characterize meaning in terms more cellular than holistic.(3) From this vantage, film music is seen as a play of particles and routines that accumulate associations and generate expectations through various inter- and intratextual means. One such particle that has, as yet, received minimal attention is among music’s most fundamental elements: the cadence.

[1.2] Cadences contribute to the distinctive, if difficult to pin down “film music sound.”(4) Take, for example, the symphonic statement shown in the reduced transcription of Example 1.(5) One of the most widely played and recognized pieces of American film music, Alfred Newman’s “Twentieth Century Fox Fanfare” was composed in 1933 for the newly formed film studio, 20th Century Pictures. In 1953, Newman extended the fanfare with a bold cadence to celebrate the advent of Cinemascope technology. This version continues to be heard today, and serves the same suite of functions that it did during the birth of the studio system in the ’30s. The fanfare is part heraldic celebration of a studio, part “ballyhoo” to arrest the viewer’s attention, and part mini-overture to formally demarcate the onset of the film. Perhaps most importantly, it is part icon for all the desired affective states the Hollywood cinematic experience strives to evoke—glamour, escape, sentiment, and wonder.

[1.3] Though a late addition, the CinemaScope Extension is crucial in conjuring those associations. A great deal rests on Newman’s choice of harmonic progression: a ii7–iiø7–V –I modally-mixed perfect authentic cadence (PAC). With its blend of bittersweet melodrama and intimations of the transcendent, this cadential idea possessed connotations of romantic sentiment that were well-worn even in the 1930s; it is a sound that would have struck 1953 audiences as a throwback, as it does today as well.(6) Newman’s gesture is a variant of a more generalized routine, the –

– Cadence, Or More Simply

“mixed cadence” (M-C). In this harmonic formula, the sixth scale degree in major drops directly from its natural to flattened state prior to the capture of major tonic at a phrase’s end. In the “Fanfare,” G 4 in an inner voice descends through G 4 en route to F4 ( ), producing a half-diminished supertonic and altered dominant on the way. The fanfare brings to mind what Steven Laitz describes as the “Hollywood Cadence,” a type of plagal motion for which he cites the familiar stock melody shown in Example 2. Laitz bases this ascription on an assumption of widespread use in modern film and commercial repertoires, the cadence being “commonly heard in popular music of the 1920s through 1950s and in films today” (Laitz 2012, 429–30).

[1.4] Laitz’s “Hollywood Cadence” is a latter-day manifestation of the nineteenth-century harmonic proclivity for modal inflection of the subdominant in order to suggest sentiment or sublimity. It is an inclination that courses through the works of Schumann, Chopin, and Mendelssohn and reaches its peak with the act-concluding plagal sighs of Wagner.(7) The mixed plagal cadence (M-PC) in Hollywood drips with a sort of harmonic nostalgia that the prolific Newman recognized and was skillful in reproducing.(8) Studio logo themes are decisive components in establishing the sound world of a particular movie, and—even more so—the sound world of “Classic Hollywood” with its promise of spectacle, big stars, and narratival coherence.(9) By employing such a consciously retrospective harmonic gesture, Newman’s fanfare harkens back to an imagined earlier experience, not only recalling, in James Buhler’s words a “‘heroic’ era of filmmaking,” but a heroic era of

Film-Going As Well (Buhler 1996, 33).(10)

[1.5] And yet Newman’s fanfare, despite bearing that tell-tale modal inflection, does not resemble Laitz’s paradigm in all its details and, indeed, in several of its attributes is strikingly distinct from it: note the patently un-plagal - bass, for example.

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Apt though the label may seem, Laitz overrates the prevalence of the specific cadential formula expressed in Example 2. Few films, even from the “Golden Age” of Hollywood, feature cadences with all the characteristics embedded within the supposed paradigm. Certainly, some classics bear the progression prominently (particularly during end scenes and credits), such as Franz Waxman’s score to Rebecca and Erich Wolfgang Korngold’s to Captain Blood.(11) But even in a style where Romantic over-ripeness is often a virtue rather than vice, film composers rarely recruit the mixed plagal cadence in the literal form of Example 2, opting instead for various alternatives with family resemblances to an M-PC prototype.(12) Difficulty in locating an exact instance of Laitz’s model in the repertoire should not lead us to abandon it. As William E. Caplin states: “A category is not necessarily meant to reflect frequency of occurrence in a statistical sense: it is often the case that relatively few instances in the repertory correspond identically to the complete definition of a given category” (1998, 4). It is possible for instances to draw meaning from a conceptually significant model, even if that model is itself stylistically elusive.

[1.6]. Example 3 presents a handful of voice-leading models for “Hollywood-esque” cadences. In the “paradigmatic form,” we see the expansion of the dissonant tritone formed by and resolving outwards to a major sixth while the melodic line grasps upwards to . This rising melodic contour is a contravention of the downward tug of most conventional cadences.

Combined with the tritonal friction, it effectively merges the linear rhetoric of spiritual elevation with a resigned semitonal sigh. The alternatives, meanwhile, subtract one contrapuntal element, be it bass line, melody, or inner voice, while keeping the essential “feel” of the cadence intact. A more distantly related quartet of models subtracts all but one of the paradigm’s lines. Newman’s fanfare conforms roughly to the outlines of the final model. Such delineation of criteria for family resemblances between cadences suggests a way to reconcile the apparent mismatch between repertoire and model created by Laitz’s exemplar. This mutable and definition-frustrating relationship will be a central concern of this article.

[1.7] Textbook “Hollywood Cadence” or not, the density of meaning packed into Newman’s succinct fanfare is typical of the art of film composition. Movie scoring relies on efficient, audience-intelligible, and often heavily conventionalized procedures. Cadences such as the M-PC count among the most powerful tools at a film composer’s disposal. The way in which Newman’s cadence generates a swell of anticipation while asserting syntactic closure hints at how well such pithy tonal gestures can deliver both formal and associative content. A cadence’s structure and placement may shape the emotional arc of a scene, lend accentuation to narrative information, and even determine the genre of its film. With their ability to close off one stage of musical discourse, cadences are uniquely well-suited to absorbing and producing meaning. And because tonal syntax in film music tends to be significant only insofar as it operates on a surface or middle-ground level, cadences should be among the first elements we consider when investigating matters of musical tension and emphasis in film.(13) Indeed, many cadential routines are so well-mined by film composers that they, like Laitz’s plagal melody, sound to our ears distinctly “cinematic” in both provenance and affect.

[1.8] In this article, I shall explore the multifarious guises and functions played by phrase ending formulae—“Hollywood Cadences,” to broaden the purview of Laitz’s term to include all idiosyncratically cinematic cadential procedures. Example 4, inspired by and partly adapted from Janet Schmalfeldt’s typology (1992, 10–16), provides a listing of the various (highly blendable) cadences and abbreviations I will employ in this study. One should not take these definitions too literally, for reasons that will soon become clear. I will also on occasion employ an arrow symbol (⇒) to draw attention to more progressive resolutions and noteworthy post-cadential destinations.(14) [1.9] I will argue that because they contribute formal and semantic information in standardized but variation-prone ways, cadences should be considered essential components of a broader film analytic methodology. Cliché-prone paradigm cases, such as the stock melody of Example 2, no doubt exist for many Hollywood cadences. Nevertheless, I will emphasize progressive variation over rigid formal duplication by film composers, whom I view as always striving to strike the right balance of novelty and musical legibility for their audiences. Taking a cue from modern film genre theory, this leads me to formulate cadence-types in terms of flexible clusters of musical attributes—as “cadential genres”—rather than through firm definitions. Throughout I will place emphasis on the variety of ways in which composers manipulate cadences to fit diverse narratival situations and changing audience expectations.

[1.10] I will concentrate on a variety of cadential formulae of special prominence in American genre films, including Westerns and adventure movies. My analytic focus will fall on three cadential genres of particular stylistic and rhetorical

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importance to the experience of expectation in film.(15) In Section II, I introduce the first of these: phrasal mickey-mousing, in which the coincidence of phrase length and visual action is manipulated. A theoretical interlude in Section III will lead to a second procedure in Section IV, the subtonic half cadence, whose production of film generic expectations will be explored.

Sections V and VI are dedicated to the chromatically modulating cadential resolution (CMCR), a pervasive but previously unacknowledged component of many of the most stereotypically “movie-music sounding” events in film. Though examples will be culled from several eras of Hollywood scoring practice, I will spotlight a number of cues from the singular figure of John Williams, particularly from his score to Jurassic Park. With his symphonic scoring style and chameleonic versatility, featuring his music prominently in my analyses, I hope to ground an eclectic project with the voice of a composer very much connected to the “Hollywood Sound” in today’s cultural imagination.

Adential Synchronization

[2.1] Among film music’s many functions, the two tasks of emotional intensification and narrative reference are particularly well realized through cadential strategies.(16) Cadences are natural funnels for expectation and its (potentially withheld) realization. As with any musical parameterization of expectation, cadences influence the ebb and flow of tension; when combined with image, this dynamic is lent in turn to a film sequence. Similarly manufactured is a sense of intentionality, or musical “pointing-to,” that can direct filmgoer attention, sometimes subtly, sometimes with great stress.(17) The conceptually simplest—albeit often most technically demanding—use of cadence in film music relies on this dual capacity for intensification and reference. A single cadence, coinciding with a dramatic event (and its dissonant buildup generating anticipation for that event) can be called cadential synchronization. The accumulation of tonal tension prior to resolution is an efficient conduit for viewer expectation, providing a cue that something is going to happen at the tonal and formally projected instant of cadential resolution. Cadential impact is enhanced by the coincidence of a film cut with cadential onset, or, as is often the case with half cadences and elided PACs, with dominant resolution. Savvy composers therefore arrange their cues to take advantage of the heightening effect of harmonic/visual correspondence, planning phrase rhythms meticulously, adding or subtracting beats from regular melodic scaffolds to enable this combinatorial “pointing.” [2.2] Two passages in Examples 5 and 6 demonstrate the versatility of cadential synchronization, while also illustrating an important distinction for cadential analysis in general—the difference between determinate and indeterminate resolutions.

Example 5, from John Williams’s score to Jurassic Park (1993, dir. Spielberg), is the climactic cadence within the lengthy “Jurassic Park Theme.” This melodic centerpiece of the score is organized through fairly conservative “classical” formal functions, with 4-measure units each ending with a cadence of varying strength. In Example 5, an HC at the fourth measure leads into the last phrase of the melody, and coincides with an archetypal Spielbergian awe-struck close up. The effect of this cadence is magnified by the successful discharge of the dominant onto the tonic in measure 5, fulfilling the linear tug of the climactic melodic leading-tone and contributing to a bit of tonal rhetoric—if not formal function—much like that of an elided PAC. The following cut reveals that object of wonderment, a panoramic shot of a herd of dinosaurs. This switch in perspective matches exactly the beginning of the next phrase, a tutti swell upon the arrival at B major.

[2.3] Williams’s phrase offers an instance of a determinate cadence: a formal unit within a theme where the telegraphed tonal resolution (or half-resolution) occurs exactly when it should given previously established expectations of harmonic rhythm and melodic and metrical structure. Almost all cadences within symmetrical theme structures behave this way. However, synchronizing metrically regular melodies to specific events on screen is a difficult task, and this kind of foursquare musical/visual correspondence is actually fairly uncommon in practice. The trickiness of lining up metrically regular themes with pertinent visual events leads to the employment of a different tonal strategy in film music: the indeterminate cadence. This is a formal unit, part of a theme, or quite often a transitional or sequential passage, in which a tonal resolution is strongly projected but the point of arrival is not overdetermined by melodic/metrical/harmonic-rhythmic factors. Rather, it is attained through a looser preparation phase, often over a pedal and/or dissonant buildup. The strategy has the quality of delaying resolution, and has analogues in Classical/Romantic practices such as “standing on the dominant” in cadenzas and

(Re)Transition Sections.(18)

[2.4] A celebrated instance of indeterminate cadential synchronization, partially reproduced in Example 6, occurs in Bernard

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Herrmann’s score to Alfred Hitchcock’s Vertigo (1958). For the climactic moment when Scotty witnesses his girlfriend Judy fully transformed into his lost love Madeleine, Herrmann finally resolves a dominant pedal that has been held for a full fifty seconds. At measure 8 this dominant resolves onto the A -major chord that concludes the pedal and initiates the film’s principle C-major love theme; the immediate resolution to A 6 makes this an indeterminate evaded cadence. The “evaded” qualifier is due to the arrival on a non-root position tonic triad, though the viewer’s foreknowledge of the theme’s standard VI6 opening will partially override the sense of immediate tonic denial. Intolerably deferred resolution contributes to emotional catharsis, a fleeting release from an unbearable thanato-erotic tension that courses through film and score.(19) This moment lacks the concatenation of linear, temporal, and thematic cues that makes the Jurassic Park cue lock so tightly to image, and it is not a cadence in the same sense as the conventionalized, motive-liquidating phrase endings in Mozart or Haydn are.(20) Nevertheless, indeterminate resolutions like this are often entirely cadential in rhetoric, and represent a strategy so well-mined by film composers that Section V will be entirely devoted to a particular form of them.

[2.5] When cadential synchronization occurs repeatedly, rather than as a one-off occurrence, phrasal mickey-mousing takes place. This is the matching of numerous discrete musical phrases with specific events onscreen.(21) With phrasal mickey-mousing, musical units are made to correspond to film editing rhythms through manipulation of phrase tempi and durations (and, rarely, after-the-fact edits to match precomposed score). The amplification of music’s gestural synchronization can call additional attention to visual accents, which may explain some of phrasal mickey-mousing’s appeal to cartoon composers. In artful instances, the spectator is invited to marvel at the dexterous combination of parameters otherwise at odds with each other; this is especially true if determinate cadences are chiefly employed. Done with particular virtuosity by composers like Carl Stalling and Scott Bradley, an entire scene—even of the most irreverent subject matter—can take on a “balletic” quality thanks to the alignment of sight and sound.

[2.6] The Russian composer and film music critic Leonid Sabaneev found mickey-mousing to be a violation of music’s very nature, inappropriate for all but “comic films and animated cartoons” (see excerpt from Sabaneev in Hubbert 2011, 217). To Sabaneev, the approach is flawed because it requires that music “sacrifice the principles governing its form: no matter what is happening on the screen, the music must have its melodic structures, its phrases and cadences, and it must not be asked to suffer dilution by the rhythms and occurrences of the picture” (216; italics added). Doubtlessly, crude cadential mickey-mousing may produce music that is incoherent outside of the context of the individual film. However, the most skillful employers of the technique were, pace Sabaneev, perfectly capable of generating music pleasing both in and outside the film.

[2.7] Erich Wolfgang Korngold’S 1938 Score To The

Adventures of Robin Hood (dir. Curtiz) is full of examples of cadential syntax—particularly cadences of the determinate variety —serving formal and expressive ends. Phrasal mickey-mousing accompaniment for an action sequence is shown in Examples 7a and 7b as a melodic transcription with annotations for dramatic events. In the scene, Robin Hood and his companion Will Scarlett arrive at a stream crossing guarded by Little John. A playful fight ensues as Robin and John duel on the stone bridge, with the former eventually knocked into the water by a well-timed quarterstaff thrust. Korngold constructs the cue out of one of the score’s many leitmotifs, principally what Ben Winters calls the “Jollity” theme (Winters 2007, 98, 115–23).(22) “Jollity” unfolds through three variations of progressively denser orchestration and rhythmic play (starting at measures 3, 11, and 19), each ending with a scene-structuring cadence.

[2.8] The precision with which Korngold’s music fits this eventful sequence is due partly to the composer’s skill at synchronization and partly to the absorptive nature of film,(23) through which even accidental musical events have a way of fastening to onscreen action.(24) Nevertheless, the most structurally important cadences are also the most firmly wedded to significant narrative events. Structure-defining cadences occur at measures 1–3 for Robin’s consent to the fight; measures 11–12 for the onset of the duel; measures 26–27 for an exchange of symmetrical blows; and measures 46–47 for the confrontation’s conclusion.(25) The main section of fight music, starting at measure 19, can be loosely construed as a small ternary form (measure 19=A, measure 28=B, measure 34=A1). With this formal plan in place, elements of thematic repetition and tonal expectation help offset Korngold’s puckish metrical unpredictability. Excepting the first and final cadences, all are either elided ACs or half cadences, both of which end discrete musical phrases with the dominant (as opposed to an inter-phrase dominant-to-tonic progression.) The preponderance of dominant-oriented punctuation keeps

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Korngold’s musical prose from coming to a definitive end until Robin hits the water. Sustained irresolution imparts a restless energy to the heat of the fight. But even when sonically absent, D major’s control over the cue is affirmed by the cadences placed at most every phrase boundary. This is a fitting tactic to combat the disruptive potential of the chromaticism that Korngold’s excitable idiom allows casually to intrude, as in measures 30–34. Whereas a scene with more profound narratival stakes might be suited by a less stable key scheme, here the retention of D major through these cadences matches the relaxedly self-enclosed nature of Robin Hood’s encounter.

Efining Cadences

[3.1] Despite a dash of chromatic wanderlust, Korngold’s scoring for this Robin Hood sequence is resolutely monotonal, comfortably in a single key throughout thanks to phrasal symmetry and steadfast cadential enforcement. Nevertheless, some smaller moments of harmonic resolution, such as the miniature fanfares first established mid-period at measure 22, are less strongly cadential in character, despite falling at phrase boundaries and providing moments of dominant to tonic resolution.(26) Ultimately, the cadential weight of the event at measure 22 is less important than its interaction with screen action; in this case, the gesture does not coincide with any unique visual event, and it acts more as one of many musical flourishes that mimic the clashing of staves.

[3.2] How we determine what counts as a cadence, and how we sort affined cadences into categories, are nevertheless essential questions that have provided much grist for theorists (see, for example, Dunsby 1980, Schmalfeldt 1992, Hepokoski and Darcy 2006, Mirka 2009, and Nobile 2012). Noting the wide and disparate array of definitions for the term “cadence” across theory textbooks, Ann Blombach proposes a comprehensive definition to authoritatively determine what comprises this fundamental piece of musical vocabulary: “A cadence is any musical element or combination of musical elements, including silence, that indicates relative relaxation or relative conclusion in music” (Blombach 1987, 231). Blombach’s definition possesses repertoire-independent broadness and admirable clarity (eschewing, for example, the common trap of circular reliance on the related notion of “phrase”). Yet it does not distinguish merely tension-relaxing musical events from more form-generative phrase-ending ones; Blombach’s definition can draw no distinction between the effects of a perfect authentic cadence and, say, an intraphrasal V ⇒I6.

[3.3] Caplin (2004) follows up Blombach’s endeavor of cadence-clarification, not by offering a synthetic definition, but rather by proposing a number of qualifications that specify what a cadence does, where it falls, and what conditions are necessary for its realization. Those criteria include the obligatory presence of a root position V chord and the closing-off of a formal musical unit. Caplin’s conditions are rigid, ruling out some phenomena (notably plagal codettas) for not fulfilling actual cadential form or function.(27) This strictness is justified by the intended application of Caplin’s criteria to the heavily conventionalized musical syntax of the Classical period. Yet beyond the benefit of corpus-specificity, Caplin suggests a more

Philosophical Rationale For Stringency:

To be sure, we might ask why it is necessary to circumscribe the notion of cadence in the ways I have proposed. Why not let it remain a looser, more flexible concept, so as better to embrace a multiplicity of phenomena? I would counter that whereas open-ended definitions may give the impression of inclusiveness, they actually result in blurring distinctions that truly matter. By limiting the concept of cadence, the intent is not to shut out our perception of varying phenomena, but rather to encourage us to be more precise about how phenomena that seem similar in some respects can actually be experienced as aesthetically different.

(Caplin 2004, 59–60)

Caplin’s preference for limitation is meant to ensure that musical phenomena with fundamentally different characters are not inappropriately lumped together merely because they appear to serve similar purposes (namely, of projecting closure and tension-release). The narrowness of his stipulations is fitting for the rule-bound style of Classical era music, even where they mandate elimination of events such as plagal cadences. Despite its attractions, however, such conceptual rigidity does not entirely befit the analysis of music for film.(28) [3.4] Cinema scores comprise a repertoire of profoundly greater tonal and formal eclecticism than that of the Classical style.

The stylistically heterogeneous and intrinsically programmatic repertoire lacks a central normative harmonic idiom (and

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attendant constraints on cadential syntax) and can rarely rely on a set of architectural paradigms like sonata form to regulate phrases, tonal design, essential structural closure, and so on. It is therefore often the case that the expressive demands of film place highest emphasis on cadential rhetoric, not syntax. Caplin distinguishes rhetoric from form-functional syntax (which exclusively determines the identity of a cadence for him), defining the former as the “unique compositional realization entailing the entire range of musical parameters, including rhythm, meter, texture, intensity, and instrumentation” (Caplin 2004, 107). Though capable of lending formal sense to a sequence, the power of a cadence within a film is not primarily to erect a syntactical edifice to prop up a cue; rather it is to grant an expressive quality to the scene, such as the production and release of anxiety or the cessation of momentum. (29) [3.5] This does not entail that syntactical features of cadences—even Caplinesque “Classical” ones—are absent in film scores.

Korngold’s Robin Hood cue is remarkable in its accommodation of cadential syntax within its metrically irregular, fight- choreography determined musical prose.(30) For scores written in a less fastidiously synchronized manner, the local occurrence of cadences may have nothing to do with intentionally “pointed-up” visual events, arising instead from the inherent tonal patterns of antecedent/consequent structures.(31) Nevertheless, even incidentally placed cadences manufacture points of tension or closure. They can, for example, convey a continuous musical thought that effectively stitches a series of disconnected images into a coherent sequence. In such cases, the rhetorical effect of non-synchronized cadences is simply placed at a remove from the instantaneous musico-visual surface on which phrasal mickey-mousing operates. Korngold’s mêlée music, it is clear, entrusts its expressive effect to both the immediate impact of the cadential moment, and to the long-accustomed expectations built around the structure of tonal phrases.

[3.6] In some ways, these recognizable but non-prescriptively enforced cinema cadences resemble an Ur-concept of film criticism: genre. Genres such as “Western” or “noir” serve to structure narrative and guide expectations through every stage of a film’s existence, from production to marketing, and at both inter- and intra-textual levels of reception. Modern genre theory moves away from treating genres as stable transhistorical categories, instead considering genre-as-process and the element of discursive participation in their generation. Film theorist Rick Altman’s influential monograph Film/Genre signaled this change towards a more dynamic view. Genres, for Altman “are not just post facto categories, but part of a constant category-splitting/category-creating dialectic” (2011, 65). Drawing on Ludwig Wittgenstein’s notion of family resemblances, a “complicated network of similarities overlapping and criss-crossing,”(32) Altman argues that genre is inherently unstable: A fundamental problem of genre studies stems from the ever-present desire for a stable and easily identifiable object of analysis. . We do better, I suggest, to treat genre as a complex situation—a concatenated series of events regularly repeated according to a recognizable pattern. Traditional genre criticism has tended to treat a single aspect of this process [of producing and disseminating texts] as representative of the whole situation. Yet no isolated part of this process actually is the genre; instead, the genre lies somewhere in the overall circulation of meaning constitutive of the process. a genre must be defined in a manner consistent with the complexity of an overall situation made up of three-dimensional events spread out over space and

Time. (2011, 84)

Altman’s critique of the then prevailing steady-state ontology of genre can be applied to cadences, which similarly resist transhistorical definitions in the context of film scoring. With Altman’s notion of “a concatenated series of events regularly repeated according to a recognizable pattern” in mind, I propose a system for characterizing cadences in film music: that of cadential genres.

[3.7] These genres are inspired by Caplin’s lists of cadential criteria, but they lack the prescriptive force intended for the regulated Common Practice idiom. Instead of a single firm definition, ill-suited to the multiplicity of styles of film music, I characterize cadential genres as convergences of independent musical attributes throughout shifting scoring practices and audience expectations. Cadential genres in film are best formulated in terms of paradigm cases and attributes. A paradigm case contains each and every of those independent attributes, and can be thought of as the transhistorical “source” of one Hollywood cadential routine or another.(33) However, this paradigm is a construct, abstracted out of the family resemblances of numerous cadences for which I have observed certain “recognizable patterns” repeated through practice.(34) Many other examples that bear resemblance to the exemplar may partake of only some of the attributes, while remaining in an important

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sense outgrowths of the underlying paradigm. Caplin’s “blurring of distinctions” is thus strategically built into my model. I list attributes within the constellation of a certain cadential type (which include both pitch- and non-pitch-based criteria) in a rough hierarchical order, with the first qualities being the most structurally and rhetorically salient. Nevertheless, I do not wish to overrate the importance of the orderedness of any list; the arrangement is based on an informal judgment of relative pertinence, and other listeners may rank differently.

[3.8] The advantage of this attribute-over-definition approach is the insurance that no one aspect (nor, indeed, no group of aspects) are taken to be intrinsic. A cadence featuring some, but not all, attributes, will still have the formal and affective qualities of the original cadential genre. This flexibility is a boon to film composers who seek audience-intelligible musical topics without resorting to clichéd reiterations of the same paradigm (ideally). Subtraction of one or more attributes opens up the door for variants, adaptations, and even distantly related abstractions of the paradigm case cadence. It is because traditional cadences are such highly regulated components of musical discourse that desirable expressive qualities such as theory emphasizes the mutability of genre, so too this music-analytical approach aims to draw our attention to strategic transformations of fuzzy paradigms, not rote reproduction of a platonic cadential form.

[3.9] Examples 8a and 8b treat the PAC as a cadential genre, furnished with an attribute inventory and a paradigm case. Laid out thus, the attribute/paradigm model provides a useful tool for hermeneutic, as well as formal, analysis.(36) We can see, for example, that many phrase-ending gestures in the Robin Hood cue partake of some of the elements of a paradigmatic PAC, even though the majority are strictly HCs. Cadential analysis becomes an investigation of which attributes Korngold opts to subtract for dramatic and expressive reasons. The cadence that initiates the passage (Example 7a, measures 1–3) features a lengthy pause between V and I, taking attributes 13 and 14 out of play. Korngold sacrifices these in order to produce the scene’s playful “stop-and-go” tone. Tentative yet cocky, this and other “broken” HCs rouse tonal expectations without committing to action, as Robin Hood analogously sounds out the pugilistic Little John, cheekily assessing him before risking actual injury. On the other hand, the cadence that concludes the passage (measures 45–46) bears all the PAC attributes save 7 (the presence of a traditional predominant). The preparatory harmony here is V (enharmonically IV), a serviceable if decidedly unconventional option. This chromaticized reentry to the tonic D major is part and parcel of Korngold’s distractible but ultimately non-destabilizing tonicization of foreign keys, a way of capturing the thrill and ultimate low-stakes of the character’s combat. These partial PACs would be lost to analysis were we to adopt unbending prescriptive definitions. With the attribute inventory system, we can understand a cadence’s relatedness to a clear if necessarily fuzzy norm while appreciating how selective variation contributes to specific filmic purposes.

Owboy Chromaticism

[4.1] The cadence’s capacity to index film genre is as potent as its ability to punctuate and structure dramatic action. The power of cadential associativity can be observed in the reliance of a genre such as the Western on a small class of continually employed cadential gestures. Conventions of style and plot have informed, and in many cases outright determined, the makeup of the Hollywood Western throughout its cinematic evolution.(37) Through the many Western subgeneric guises (“A,” “B,” “spaghetti,” “revisionist,” etc.), a host of expectations—comprising an attribute inventory, in fact—remain in play.

These include conventions of narrative (e.g., “sheriff cleans up lawless township”), setting (e.g., the Mexican-American border, a saloon), dramatis personae (e.g., “ruthless cattle baron”), and scoring.(38) Musically, the genre has always been marked by standardized (and occasionally vulgar) style topics pertaining to cowboys and Indians, often drawing from country-and-western music or adapted/invented folksong (see Kalinak 2007, 1–17). Pentatonicism, in particular, has long infused the Western musical landscape—including cadences, with characteristic melodic touches like approached by instead of .(39) Today, however, pentatonicism does not hold the status of singularly preferred harmonic idiom that it enjoyed from the 1920s through ’40s. Since the 1950s, another option became popular for Hollywood composers, one that involved the integration of these earlier Western topics with syncopated, brass-heavy, open-fifth saturated “Americana” music, generally ascribed to the influence of Aaron Copland, and to a lesser extent Virgil Thompson and Roy Harris.(40) This too had ramifications for cadential structure.(41)

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[4.2] The most conspicuously prevalent “Cowboy” cadential genre takes root at the same time as the Coplandesque influences set in the late 1950s: the subtonic half cadence (S-HC).(42) The feature of highest salience in this routine is the

Insertion Of The Non-Diatonic Bass Pitch

before the dominant. Example 9 presents the linear paradigm for the S-HC. The trace of the mixolydian scale—the strongest link to Copland’s Americana style—is present in its exemplars, often bearing in both outer voices. However, the flattened leading tone often manifests in an inner-voice while the melody retains across

The Half Cadence. The

is harmonized by a VII chord, which proceeds to the dominant with a minor third progression. Thus, the progression is not purely mixolydian, but indulges a richer sort of “cowboy chromaticism”—nicely summarized by the neo-Riemannian compound RP.(43) This compound accounts for the transference from VII to V (R shifts to ) and the hasty neutralization of the diatonically foreign pitch (P neutralizes

).(44)

[4.3] As a component of an HC, VII tends to occur near the conclusion of the antecedent phrase of a thematic period. By contrast, the authentic cadence that closes the consequent phrase rarely partakes of the same dominant-preparing VII, featuring a more traditional predominant (e.g., ii7, IV, or I6). Such phrase-functional specificity has its associative advantages.

In order to be an unambiguous marker of genre, the subtonic half cadence works best as a special and narrowly employed routine, a case of an extraordinarily determinate cadential function. The sequestration of the subtonic to a unique moment in a period melody heightens its distinctiveness, and thus its associative adhesiveness. Example 10 provides an attribute inventory for the cadential genre in its most well-known thematic guises—a number of which I will now investigate.

[4.4] Several musicologists have noted the prevalence of the subtonic half cadence in Western film scores, though they do so typically without discussing its role within a larger period structure.(45) The advent of this new “Cowboy Cadence” is customarily attributed to Jerome Moross, and his influential and film-musicologically canonized score to William Wyler’s The Big Country (1958) in particular.(46) Scattered precedents can be found in other sources, including Moross’s earlier score to The Proud Rebel (1958), Hugo Friedhofer’s scores to The Best Years of Our Lives (1946) and Hondo (1953), and Gene de Paul and Alexander Courage’s score for the film musical Seven Brides for Seven Brothers (1954).(47) But the gesture is overwhelmingly Moross’s signature, used pervasively (if with considerable manipulation and adjustment) in his compositions for both concert and film. And the most famous and likely formative employment is in his main title to The Big Country. The opening 39 measures are given in Example 11.

[4.5] The famously vigorous credits sequence features the VII–V in two contexts.(48) The motion is first heard as a detached harmonic motive during the title’s opening fanfare, where it acts as a mini-auxiliary cadence into C major. A distinctive linear feature here is the accented dissonance – over the chord root (measure 2), creating a tritone against the bass with slight Lydian flavor, even as the overall modal impression is of mixolydian borrowing. – is later integrated into the film’s motto theme as a half cadence to close off its antecedent phrase (measures 22–25) and contrasting middle section (measures 36–39). All usages support a retained melodic , with the characteristic

Motion Occurring In An

inner voice. [4.6] The Big Country’s main title demonstrates that while liquidation of the mixolydian subtonic drives the half cadence itself, it is introduced as a fresh element, not strongly presaged by previous tonal information. Moross’s subtonics result from (a) dovetailing fifth progressions or (b) dovetailing third progressions. In measures 1–4, the producing motion IV– VII mirrors an implied I–IV that gets the harmonic wheel spinning, and thereby doubles the flatward plagal and strongly folk-associated T (transposition up five semitones). VII thus serves not only as a chromatic preparation of the dominant, but also as an extension of the flat-side purview of IV. The true S-HC at measure 24 is preceded by a V/V chord. This produces a chain of chromatic mediants [E7–C–A7] that arpeggiate the minor dominant. Example 12 shows the basis of this progression, with attendant transformations for idealized triadic motions. With both these origins, VII is the product of a localized harmonic pattern with a strong associative profile. For the subdominant-spawned subtonics, the expressive effect rests on the magnified pastoral/agrarian undertone of plagal material. For the third-chained subtonics, the invigorating and surprising character of a chromatic transformation lies in an unexpectedly form-functional location.(49) [4.7] After Moross’s The Big Country, the subtonic half cadence becomes the quintessential harmonic gesture of the American

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Western film. The usage in Elmer Bernstein’s heroic theme to The Magnificent Seven (1960, dir. Sturges) (Example 13) is similarly iconic—perhaps because of its cooption by Marlboro for their TV ad campaigns of the 1960s (see Slotkin 2010, 211). Bernstein’s rousing theme solidified the “Coplandesque” trend in Western scoring initiated by The Big Country. In short order, the S-HC became a harmonic default for bright, optimistic Western themes, such that movies that bear major melodies but lack the S-HC sound as though they come from an earlier era of film scoring. The gesture is such a hallmark of the Westerns of the ‘50s and ‘60s that its presence is de rigueur for films that parodize that genre, such as Blazing Saddles (1974), City Slickers (1991), and Der Schuh des Manitu (2001). Example 14 provides a list of media that employ the S-HC.

Special note is made when the gesture appears in a film’s genre-staking main title/opening credits. With the exception of the 1980s (which witnessed a temporary decline of film Westerns), the persistent use of the S-HC attests to its attractiveness to composers and generic legibility to listeners.

[4.8] Most of the examples listed in Example 14 adhere directly to the half-cadential paradigm established by The Big Country. However, numerous variants and allusions are also included that stray from pure paradigmatic usage. Even in Big Country, we find notable manipulations of the mode-mixing logic behind the cadence. In the “Main Title,” Moross mirrors the pre-cadential chromaticism of VII–V at several moments with an alternative harmonization of

, Via Iii To V. The

altered paradigm, a flat mediant half cadence (FM-HC), is shown in Example 15, and is realized or alluded to in the Big Country “Title” at measures 7, 11, and 25. III in major is less characteristic of the Western than the subtonic, but serves an analogous function.(50) With this variant, the cadence installs an arpeggiation of the minor tonic, with chromatic mediant relationships now in place between both chords that flank the flattened mediant. Moross puts both VII–V and III–V to good use in a theme derived from the Big Country’s opening fanfare; this idea, shown in Example 16, accompanies scenes of a heavily armed posse galloping through the desert. The mediant-to-dominant cadence voids the number one attribute of the S-HC inventory (as well as attributes 5 and 12). Yet, in the case of Big Country’s riding music, the swerve from D to F is clearly a permutation of the initial A –F, and sufficient attributes of the paradigm are present to preserve the generic “Western” aspect of the melody.

[4.9] Adaptation of the S-HC often involves manipulating or substituting the dominant.(51) The Magnificent Seven’s theme is already something of an atypical example if The Big Country is taken as norm: note the alteration of attribute 4 by the inclusion of an A /B chord. Jerry Goldsmith is among the composers who reliably adapted the subtonic half cadence in creative ways throughout his scores for Westerns in the 1960s and ’70s. His theme to 100 Rifles (1966, dir. Gries), shown in Example 17, contains no paradigm-adhering instance of the S-HC cadential genre but several cunning permutations. Sandwiched within the overall key of D aeolian, the theme’s mariachi-tinted B section begins what appears to be a new period melody in B major. Goldsmith feints at an S-HC at measure 5 of the section by landing on A . But it is the minor dominant, F minor, that follows, and two beats too late to be heard as a half cadence. The increasing prevalence of chromatic chords and the sped-up harmonic rhythm that attends F minor loosens the grip of B major, and culminates in a re-modulation to the original key of D. This is achieved, remarkably, by a recursive application of the subtonic to dominant progression, proceeding through three minor thirds: first from E to C6 ( VII–V/F), then from C to A ( VII–V/d), and finally landing with a PAC back in the home key. In the process, all but attributes 1–4, 8–9, and 15 are subtracted, with the removal of 6 (non-modularity) being particularly remarkable as it amounts to dismantling the period structure seen in all previous examples. Nevertheless, the repetition of the S-HC progression recoups any associative shortfall from the paradigm’s heavy alteration.(52) The iterated application doubles the bright affect attendant with the plucky neutralization of

, Prevailing Against The Digressive Forces Of

chromatic inertia. The vast distances traversed by Goldsmith’s theme suggest a wide tonal landscape every bit as generically appropriate as the broad horn melodies and expansive P4/P5-laden chord voicing more traditionally linked with the Western sound.

[4.10] In contemporary cinema, a common adaptive strategy involves substituting IV for V within the VII–V pair of the S-HC, necessitating a change of attributes 2–5 and 11. This procedure seems to begin around John Barry’s score to Dances with Wolves (1992, in the cues “Ride to Fort Sedgwick” and “Buffalo Hunt”) and can be heard in themes for Mychael Danna’s Ride with the Devil (1999) and James Newton Howard’s Wyatt Earp (1994) and Hidalgo (2004); indeed, today it may have reached the status of independent cadential archetype, a “subtonic plagal cadence” (S-PC).(53) The main theme to Hidalgo—used to accompany panoramic shots of the American west—is noteworthy for integrating the subdominant in place of the traditional dominant. Howard’s theme is shown in Example 18. The transcription provides three optional

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continuation phrases that are employed on different occasions to conclude the same sentential presentation. The melody’s first four measures crane gradually to , enabling retention of at the moment of the subtonic plagal/half cadences. The delayed resolution of F 4 to G4 produces the same tritonal dissonance against C that was a distinctive feature of the cadence’s paradigm. But here it serves as an accented passing tone up to rather than down to . The theme’s endings are no less redolent of the Cowboy-cadence constellation. The first and third endings share the interphrasal iii– III motion distinctive of the riding theme from Big Country.(54) The second ending’s final two bars hint at an expanded S-PC with an interpolated Gma7, sandwiched between C and the half-cadential A. The third ending offers a genuine cadence to the tonic, with the flat mediant again serving as predominant. But it does so without the aid of the dominant, opting instead for the pure VII–I motion of an unvarnished mixolydian mode.

[4.11] The adaptability of the S-HC allows it to be realized not only in a variety of modified musical contexts, but also in films that transform Western genre conventions or share associative traits with it. One such transformation is the negation of attribute 2, allowing for subtonic authentic cadences. This adaptation seems capable of encoding a combination of Americana and ethnic Irishness in the historical thriller JFK (Williams 1992, with a ii– VII–V–I), as well as in the sports drama Rudy (Goldsmith 1993, with a I– VII–V–I).(55) In these cases, any reference to gunslingers or the frontier spirit is absent. Even so, an associative residue remains, a suggestion of “American-ness” and “mixolydian ethnic-ness” that contributes to a connotatively apt progression.(56) That Williams and Goldsmith also wrote numerous “pure” Westerns using that progression is relevant, as it suggests an at least unconscious intra-oeuvre influence. Such connections depend as much on familiarity with Western harmonic conventions as on the selective tapping from a wider pool of “modal Americana” that happens to host both Cowboy cadences and their permutations.

[4.12] Films that blend the Western with other genres are fertile sites for adapted Cowboy cadences. Though the presence of advanced technology and an interstellar setting marks Star Wars (1977, dir. Lucas) first as a science-fiction movie, its narrative and iconography partake from elements of swashbuckling adventure, Japanese historical action, war drama, and Western genres. Indeed, Star Wars is cited as frequently as a “space western” as it is other mixed genres (like “space opera”; see Brode 2012, 1–12). John Williams’s symphonic score is idiomatically eclectic, mixing musical styles in a fashion that such intermingling of genres would demand. Though he eschews outright nods to classic Western scores, Williams does incorporate an unambiguous S-HC in the film’s title sequence, as part of its famous main theme, shown in Example 19. The heraldic melody has generally been linked to the idiom of Korngold (particularly the Kings Row theme it superficially resembles; see Lerner 2001, 99–100), but the presence of an S-HC also connects it to the classic Western, with its brash energy and larger-than-life heroes.

[4.13] Williams’s use of the S-HC, already a borrowed gesture from another genre, is itself detached within the Star Wars score to become an independent leitmotif. The “Rebel Fanfare,” which attaches to the series’ protagonists, distills the chromatic half cadence down to an underlying minor third transformation (an oscillatory T followed by T of root position triads). As the hexalogy progresses, that short leitmotif is further abbreviated into thoroughly abstracted rhythmic or harmonic allusions—a long way from the “Main Title” theme that first hosted the subtonic cadence, and further still from that shown in Example 20, one may hear vestiges of the same harmonic verve that infused The Big Country.

[4.14] This tiny moment from the long action setpiece “The Battle of Coruscant” in Episode III: Revenge of the Sith (2005), is called “Get ‘Em R2!” Williams’s variation of the Rebel motif here approximates an absolute progression—recursively applied T s that drive the fanfare up three-fourths of an octatonic cycle from A to E major. The motivic transformation accompanies the droid R2D2’s moment of glory. It does not attempt to project a cadence in any traditional sense, and indeed, the rhetorical attributes 15–18 are wholly absent. Nevertheless, the overall T s fulfill something of the cadence’s phrase-formal role, particularly its punctuative capacity. The modified “Rebel Fanfare” first concludes one tonal region (the mounting pressure of F-phrygian of the first notated measure, and much preceding), calling a close to one narrative stage of the space battle. During its duration, the E-natural pedal beneath the bookend A-major chords gives off residual hints of a cadential in A major. Like a cadenza within a concerto movement, we pause with expectancy as R2 performs, soloistically, a feat of virtuosic robotic derring-do. The two “Rebel Fanfare” derived measures finally serve to initiate, by way of their new

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triadic orientation, the chaotic buzz of another region (initiated by an F-“rooted” {0348}), signaling the hectic conclusion of the dog-fighting sequence. Through a long evolution involving cadential subtraction, alteration, and at this stage veritable abstraction, the mixolydian sounds of the prairie can be heard faintly echoing in the chromaticism of this space battle.

Hromatically Modulating Cadential Resolutions

[5.1] Many of Hollywood’s musical conventions can be traced back to the prolific pen of Max Steiner, active in the industry from 1929 until his death in 1971. Steiner’s claim that “there is nothing more effective in motion-picture music than sudden changes of mood cleverly handled” could well be his compositional motto, given the preponderance and variety of musical gear-shifts in his dramatic scoring (Steiner 2011, 225). Cadential synchronization is an especially favored Steinerism.

Consider the triumphal conclusion of his score to the noir Key Largo (1948), whose final forty seconds worth of music is organized into a small binary form, reproduced in Example 21. As is typical of these sorts of succinct endings, Steiner pulls off confirmation and quick re-confirmation of the tonic: first with a PAC (measures 15–16), then with a more rhetorical iiø –I motion (measures 17–19).

[5.2] The plagal tag recalls a common variant of the paradigm introduced at the beginning of the article (an M-PC without

The

component). But rather than focusing on the final cadence’s subdominant orientation, let us consider an aspect of the gesture (and the larger cue it occupies) that is more uniquely characteristic of Hollywood tonal syntax: the coupling of a rising melodic trichord (e.g., – – ) and chromaticism within a major-mode context. The overall key scheme of this excerpt—C major sandwiching E major—is enabled by two forceful cadences. Between measures 8 and 9, a cadence (locally PAC, globally HC) to a tonicized G is followed by an unmediated modulation to E , without the aid of emphasized common tones or linear continuity from melodic G4 to B 4. This tonal shift accompanies a cut away from the heroine (Lauren Bacall) staring out to sea to a shot of the object of her pensive gaze: the hero (Humphrey Bogart), whose motorboat now returns ashore after a harrowing confrontation with seafaring mobsters. After dwelling in E , Steiner initiates a second modulatory gambit to recover the cue’s nominal home key. A series of nearly identical cadential motions resolve first to E in measures 13 and 14, and then to C major at measure 15. Unlike the first modulation, this recapture of C is accomplished with linear continuity, using the same stepwise melodic motive E 5–F4–G5, first to confirm E , then C major. The vital enabling property of this cadential switch is the reinterpretation of the melodic tone G as /C instead of /E . What was a diatonic authentic cadence in one key becomes a Picardy-aeolian cadence ( VI– VII–I) in another.

[5.3] Example 22 presents a foreground sketch of the conclusion of this cue that highlights the tonal rupture with the shift to and from E . It also introduces notation for the resolutions so brashly denied with these modulations: a supplementary staff is attached beneath the main bass-line, a substratum of unrealized harmonic implication, with arrows indicating where Steiner’s cadences would have gone had their resolutions matched their preparations. Wavy beams in the main system connect dominants to their surprise destinations. These two moments in Key Largo provide instances of a category of tonal motion that straddles the line between cadence and modulation: the chromatically modulating cadential resolution (CMCR). Such occasions of instant harmonic realignment are common in symphonic film music, and in certain guises musical theater and popular music.(57) Often, but not always associated with cadential synchronization, CMCRs are a favorite form of “sudden change, cleverly handled.” The preparation phase of a CMCR features the initiation of a properly behaving diatonic cadence, including determinate and indeterminate varieties; very often, it contains implications of both HC and AC function, falling at the end of a buildup while elided in some manner with the to-be-captured tonic. The modulation phase sees the penultimate chord discharge not onto the expected tonic but to a root-position triad that stands in a chromatic relationship to the anticipated destination. This triad is treated as a new tonic, and may initiate a new phrase securely within its own new diatonic purview, as is the case with the restatement of the Key Largo’s hymn theme at measure 9 after the CMCR into E , and in the concluding phrase in C after the CMCR out of E at measure 15.

[5.4] An attribute inventory for the chromatically modulating cadential genre is furnished in Example 23. The presence of a chromatic root motion between cadential and resolution chords (attribute 1) is the inventory’s most important component. But despite the salience of pitch, I include a greater number of non-pitch attributes compared to previous inventories; this is to reflect the exceptional emphasis composers place on the forces of musical rhetoric for these harmonic swerves. Cinematic

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CMCRs tend to adhere to a predictable profile, in their musical structure as well as the affective trajectory they install for their film. Like more conventional, non-modulating cadences, they are often found at the conclusion of a thematic unit’s consequent phrase, particularly in cases where that phrase’s last bars are stretched out by various resolution-stalling techniques, such as pedal points or repetition. Other musical parameters capable of magnifying tension (and thereby promising resolution) such as register, dynamics, and orchestration density are frequently increased on the pre-modulatory end of the CMCR. Concurrently, these same factors are likely to change once the cadential downbeat of the new chromatic key occurs. The tonal destination of the chromatic cadence is radically distinct from its preceding key, and composers tend to reinforce this freshness rather than undermine it with misplaced continuities of texture or volume.

[5.5] The final modulation in Key Largo demonstrates a strategy composers can use to draw continuity between the two distantly related harmonic stations on either side of the cadence: an ascending cadential – or – line. Both of these subvert the typical downwards-to- tendency for cadential melodies, and therefore betray a distant kinship with the M-PC.

Example 24 provides contrapuntal models for six of the basic dominant to tonic CMCRs, all of which involve two major mode tonics.(58) The underlying diatonic cadential model they deviate from is also indicated, along with the standard deceptive cadence, which in certain special cases can behave as a modulating cadence. While I use ascending trichords in all these paradigms, it should be noted that CMCRs, perhaps moreso than other genres we have explored, come in diverse guises in their melodic figurations, and melodic continuity is often intentionally sacrificed to maximize that useful quality of extreme disjunction. Nevertheless, sorting by trichords does help delineate different families by shared potential linear patterns. The top row makes use of the – – line of the mixed plagal cadence while inflecting or enharmonically reinterpreting as a triadic pitch of the new tonic; as a result, they create chromatic third relations between the dominant of the first key and tonic of resolution. By contrast, the – – lines of the bottom row generate stepwise or tritonal relations between cadential chords, and require sharp inflection of the final note (otherwise, the final chord would be a non-modulatory sounding diatonic chord, either IV or vi). In cases that conform to these contrapuntal models, the upward linear drive fulfills a function of expansion and intensification, rather than termination and relaxation. It is, in the hands of film composers, a harmonic device that strives for new musical vistas, turning away from tonal destinations already

Vouchsafed By Previous Diatonic Syntax.(59)

[5.6] While some of the CMCRs involve common-tone retention between the chromatic chord of resolution and either the preceding dominant or the tonic it displaces, such parsimonious characteristics are not an intrinsic feature of these motions. Indeed, a small measure of voice-leading continuity might run counter to the desired aesthetic of the CMCR, particularly if a retained tone is highlighted by the melody. The surprising impact of these resolutions is maximized by lowering the degree of continuity between regions, while optionally facilitating linear “lead in” through predictably behaving upwards scalar lines rather than held-over pitches. It is useful to think of these modulations in terms of transformations of an underlying diatonic progression. Example 25 reconfigures the CMCRs into transformation networks, and measures their idealized voice-leading properties through the neo-Riemannian operators.(60) A “Type” descriptor differentiates CMCRs by these root motions.

Once again, the two conventional models (Authentic and Deceptive) are also shown to draw contrast with the modulatory alternatives. Each three-node network shows the relation of the tonic to the new tonic, dominant to expected tonic (always RL, or DOM), and dominant to new tonic. Note that the to line CMCRs require more semi-tonal displacements to reach their chromatic destinations, and they necessitate chromatic alteration of the tonic scale degree; this commends them to scenes of more intense mood-reorientation.

[5.7] When combined with image, a successful chromatically modulating cadential resolution can amplify, or in many cases generate, a sensation of wonderment. I define the wonderment sensation as a highly pleasurable combination of two forms of musical surprise, awe and frisson, both of which David Huron characterizes as aesthetic rechanneling of fear responses.(61) The former corresponds with the feeling of having one’s breath taken away by a sustained violation of expectations, while the latter captures the innervation produced by a more abrupt and unanticipated event. Huron notes that the frisson response, which is manifested in strong emotional and physiological indicators like shivers and chills, has been found to be correlated with “sudden changes of harmony and with abrupt changes in dynamic level” (Huron 2006, 281–83)—exactly the stuff of a CMCR.(62) Wonder involves both awe and frisson because the instantaneous modulation may be a brief surprise (hence frisson), but the musical “pulling back” so often accomplished by these cadences leads to sustained, more expansive

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[5.8] The interplay of awe and frisson in a CMCR is accomplished by a frustration of local structural tonal expectations and a deeper satisfaction of rhetorical cadential expectations. As tension accumulates in the dominant, an increasingly inevitable implication of soon-to-arrive harmonic closure is produced. This telegraphed need for release in turn affects the image, planting the expectation for a dramatic change either in tone or in content, such as would be realized by an editorial cut or pan to a new subject of visual focus. With the appropriate degree of anxiety or pregnancy lent to the image, the moment of cadential discharge can occur. The resulting chromatic swerve generates a combination of surprise and release. The shivers- inducing surprise is the product of structural tonal expectations, which predict, even in the chromatic idiom of many film composers, that dominants proceed to their implied tonics; the destinations of most CMCR types are fundamentally unpredictable from the logic of diatonic functionality. The element of release, on the other hand, arises from letting go of the intensified dominant and settling on a consonant major triad. Increased novelty infuses the image, as does added scope and breadth.(64) When the strange new destination is fully accepted, the residual surprise can be channeled away from the frisson response and into a more sustained feeling of awe. In effectively composed CMCRs, the result of this commingling of shock and resolution can be nothing short of the pure musical pleasure that comes from an expectation realized, but in an

Soaring Scoring

[6.1] John Williams is perhaps the most prolific employer of CMCRs in contemporary film music, with many of the heavily foregrounded cues from his iconic scores hosting such cadences. Scenes of wonderment and exultation are common occurrences in the fantastic films he specializes in. This is doubly true in films marketed for, and frequently including as characters, children: E.T., Home Alone, Harry Potter, and so on. The affinity of young persons’ films and these sorts of chromatic modulations has much to do with the air of ingenuousness such musical events can convey. Stripped of the learned deliberation and impression of effort attendant with more conventional modulatory strategies, the CMCR presents itself as a tonally and emotionally direct alternative, something that bypasses diatonic logic and gets to the “heart” of musical associativity. Like a child untrained in the ways of pivot chord modulations and closely related key metrics, the CMCR asks “why not simply move directly to this key?” In Williams’s scores, the seeming naiveté of this strategy might belie the refinement of local techniques that go into manufacturing CMCRs. But, like cadential mickey-mousing, those devices serve to make the inherently discontinuous and surprising sound, retrospectively, as seamless—even inevitable—as possible.

[6.2] Examples 26 and 27 offer two instances from the library of chromatic cadences in Williams’s output, both from films aimed primarily at children and the young at heart. The kindred CMCRs from E.T.: The Extra Terrestrial (1984) and Harry Potter and the Sorcerer’s Stone (2001) both follow a protracted crescendo on a tense cadential chord, and accompany moments of positive emotional release coupled with a freshly unveiled source of wonderment.(66) Example 26, from Williams’s 2001 score to Harry Potter and the Sorcerer’s Stone (dir. Columbus) offers a “textbook” CMCR. During the brief “Change of Seasons” sequence, Harry walks through an empty courtyard with his Snowy Owl, Hedwig, and releases the bird to fly gracefully over the castle Hogwarts. For Potter’s stroll, a short melodic phrase gestures towards a determinate cadence into G major (measure 4), an HC that projects an overlap with the next phrase, “becoming,” projectively at least, an IAC.(67) As soon as he releases Hedwig, the dominant progresses to B major, the tonic of a new lyrical theme (measure 5), making this a Type II CMCR (down a major third—one of Williams’s favorite strategies). A melodic third in the woodwinds (G4–A4–B4) helps stitch the two RP-related chords together. Only three attributes (8, 10, and 11) are subtracted, though the harp arpeggio installs some of the feeling of attribute 8 and the determinate nature of the CMCR obviates 10 and 11 (see Example 23). The rhetorical factors are all at play: the pre-resolution swell, the post-resolution grand orchestral tutti, and the exultant and expansive character as Hedwig flies freely, exposing the magnificent breadth of the fantastic castle.

[6.3] A somewhat less “well-behaved” CMCR occurs in E.T. The passage from “E.T. is Alive!” reproduced in Example 27

Features A Build-Up Over A Pedal Iv

chord in D major.(68) The tonal buildup matches the protagonist Eliot’s rapidly dawning realization that his alien companion is once more alive. E.T.’s resurrection is confirmed musically with the landing on C major and a jubilantly restored rendition of his character theme. This constitutes a Type III CMCR (see Example 25 above), with an adjusted attribute 5 (the cadential chord is rooted on , not , providing an extra tritonal jolt to the bass motion). The amorphous harmonic rhythm makes this a good example of an indeterminate cadence, yet the melody points

Authors:

Peder EZ Larson 1, 2,* , Jenna ML Bernard1, James A Bankson 3, Nikolaj Bøgh 4, Robert A Bok1, Albert P. Chen 5, Charles H Cunningham 6,7, Jeremy Gordon1, Jan-Bernd Hövener 8, Christoffer Laustsen 4, Dirk Mayer 9,10, Mary A McLean11 12, Franz Schilling13, James Slater1, Jean-Luc Vanderheyden5, 14, Cornelius von Morze 15, Daniel B Vigneron1, 2, Duan Xu1, 2, and the HP 13C

94143, Usa.

Denmark. 5 GE Healthcare, Menlo Park, California, USA. 6 Physical Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada.

8 Section Biomedical Imaging, Molecular Imaging North Competence Center (MOIN CC), Medicine, Baltimore, MD, USA. Cambridge, United Kingdom.

14Jlvmi Consulting Llc, Dousman, Wi, Usa

#See Acknowledgements for a list of all HP 13C MRI Consensus Group Members This work was supported by the ISMRM Hyperpolarized Media MR Study Group, the ISMRM Hyperpolarization Methods & Equipment Study Group, and the Hyperpolarized MRI Technology Resource Center (NIH/NIBIB grant P41EB013598).

Abstract

MRI with hyperpolarized (HP) 13C agents, also known as HP 13C MRI, can measure processes such as localized metabolism that is altered in numerous cancers, liver, heart, kidney diseases, and more. It has been translated into human studies during the past 10 years, with recent rapid growth in studies largely based on increasing availability of hyperpolarized agent preparation methods suitable for use in humans. This paper aims to capture the current successful practices for HP MRI human studies with [1-13C]pyruvate - by far the most commonly used agent, which sits at a key metabolic junction in glycolysis. The paper is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification. In each area, we identified the key components for a successful study, summarized both published studies and current practices, and discuss evidence gaps, strengths, and limitations. This paper is the output of the “HP 13C MRI Consensus Group” as well as the ISMRM Hyperpolarized Media MR and Hyperpolarized Methods & Equipment study groups. It further aims to provide a comprehensive reference for future consensus building as the field continues to advance human studies with this metabolic imaging modality.

Keywords: Hyperpolarized MRI, metabolic imaging, carbon-13, pyruvate, dissolution dynamic

Introduction

MRI with hyperpolarized 13C agents, also known as hyperpolarized (HP) 13C MRI, has shown great potential as a novel imaging modality, particularly for its ability to probe metabolic processes in real time. The first human studies with HP [1-13C]pyruvate were performed in 2011 in prostate cancer patients (1).

Since then, there have been over 60 papers published with imaging results of human subjects from 13 different sites, with applications including prostate cancer, brain tumors, breast cancer, kidney cancer, pancreatic cancer, metastatic disease, liver disease, ischemic heart disease, diabetes and cardiomyopathies. The vast majority of these studies used [1-13C]pyruvate (1–63), where [2-13C]pyruvate (64) and 13C-urea (56) have been demonstrated too.

As clinical HP 13C MRI advances, there is a growing need to build consensus for best practices, which are critical for comparing data across sites, performing multi-site trials,deploying methods to new sites, partnering with vendors, and potentially for obtaining broader regulatory approvals.

In March 2022, we initiated an effort to build consensus within the HP 13C MRI community with this opportunity in mind, and it was greeted with strong enthusiasm. The “HP 13C MRI Consensus Group”, containing over 55 members from 27 sites, identified the area of greatest need and opportunity for consensus building to be HP [1-13C]pyruvate human

●

Pyruvate is the most mature and widely used HP agent and has the most significant translational evidence emphasizing the potential clinical impact.

●

Clinical trials, particularly multi-site trials, have the strongest need for consensus methods to ensure that data can be combined across sites. This work is a Position Paper for which the goal is to describe current successful practices and study methods for HP [1-13C]pyruvate human studies along with justification to support those practices. This is divided into four major topic areas: (1) HP 13C-pyruvate preparation, (2) MRI system setup and calibrations, (3) data acquisition and image reconstruction, and (4) data analysis and quantification (Fig. 1). The current successful practices and study methods include a literature review of published peer-reviewed journal papers showing human HP [1-13C]pyruvate study data, up to September 2022 (1–63), as well as new unpublished information from surveys of HP 13C study sites. Based on this information, we also highlight the evidence gaps, strengths, and limitations of current practices which are summarized at the end of each section.

Figure 1: Illustration of the HP 13C MRI human study process, including the 4 major areas covered in this paper: Hyperpolarized 13C-pyruvate preparation, MRI system setup and calibration, Acquisition and Reconstruction, and Data Analysis and Quantification.

Figure 2: Anatomical targets of HP [1-13C]pyruvate MRI human studies published up to September 2022.

Hyperpolarized 13C-Pyruvate Preparation

This section covers the processes for creating the HP agent, 13C pyruvate, and will include many aspects and considerations that are needed to safely and effectively prepare doses for metabolic imaging studies in human subjects. These include material, personnel, equipment and facility, fluid path preparation, quality control, and release.

It is helpful to understand that the specifications of a dose of 13C pyruvate suitable for in vivo MR HP metabolic imaging were shaped in part by early preclinical studies performed by GE HealthCare summarized in Ref. (65). In short, the safety of the two novel drug components, 13C pyruvate and the electron paramagnetic agent (EPA) AH111501, were demonstrated in those studies. The more precise formulation of the dose suitable for human use was then determined from clinical studies (66) that included two Phase 1 clinical trials in young and elderly healthy volunteers without hyperpolarization of the 13C nuclei and another Phase 1/2a dose escalation and imaging feasibility study with HP 13C pyruvate in 31 prostate cancer patients at the With the exception of the first HP 13C imaging clinical trial, which utilized a prototype device in a cleanroom (1), all HP 13C studies performed in humans to date have utilized the SPINlab polarizer (manufactured by GE HealthCare). Consequently all doses of the HP 13C pyruvate delivered by SPINlab have been produced using the “SPINlab Pharmacy Kit” that serves as the container-closure system for the various drug components (13C pyruvic acid and EPA mixture, dissolution medium, and neutralization and dilution medium) during sample polarization, dissolution and quality control (QC) processes. Thus many aspects of the HP sample preparation considerations discussed below are related to the SPINlab instrument and the consumables designed to be used with it (67).

General Considerations

While more than 860 patients or healthy subjects having been injected with HP 13C pyruvate as of January 2022 without reports of any serious adverse events (68), HP 13C pyruvate injection remains an investigational MR contrast agent and can only be administered by those with Investigational New Drug (IND) exemption from the Food and Drug Administration (FDA) in the USA, a Clinical Trial Application (CTA) in Canada, approval from National Research Ethics Committee Services in the UK, or approval from the relevant local regulatory body. Thus, methods and processes involved to produce a dose should have patient safety as the first priority. Since utilizing dissolution dynamic nuclear polarization (dissolution-DNP) for human use is still a relatively new development, there are no existing published regulatory guidelines specifically for this method.

There are two major production styles that determine how various sites approach the agent preparation. In the US, the most common approach is to rely on a sterilizing filter (“Terminal Sterilization”) to ensure sterility of the final product, akin to PET tracer production, where a starting molecule with a radioisotope is processed using various other ingredients to make the final, desired and injectable contrast agent within a necessarily short amount of time (69). For these sites, sterilization of the components and accessories upstream of this filter are not required, although many of them were manufactured and tested following Good Manufacturing Practice (GMP) or Good Laboratory Practice (GLP) requirements. The filling process is usually performed under an ISO 5 laminar flow hood, but a clean room or an isolator is not required.

This approach is typically accompanied by testing the integrity of the sterilizing filter prior to release of the dose for injection. Typically, post release endotoxin and sterility tests are performed using an aliquot reserved from each released dose.

In the UK and EU, the most common approach is to more-closely follow sterile pharmaceutical compounding guidelines (70), where all components and ingredients are required to be sterile or manufactured under GMP guidelines and are assembled and filled within a clean room environment or an isolator system (“Sterile Preparation”). Typically a batch of Pharmacy Kits for HP 13C pyruvate injection are prepared together. The sterility of the final dose is also ensured by batch validation testing, in addition to the sterility of the ingredients and the sterile compounding process. The endotoxin and sterility testing are performed for the process validation but are not performed for each injected dose.

Some institutions fill and assemble the Pharmacy Kit required for a specific study on the same day or the day prior to polarization, dissolution, and patient administration, but others have also demonstrated the feasibility of preparing a batch of kits, keeping them in a -20ºC freezer and using them over a period of a few months.

Beyond the obvious requirements that the process and the facility has to ultimately produce a dose that is safe to inject into a human, regulatory authorities will also focus on the question “Are you in control of your processes?”. To be in control of your process requires an in-depth and broad understanding of all processes involved in pre, post, and during the production process.

Personnel

It is typical and may be required to have licensed personnel involved in the production process depending on local regulations.Typically a pharmacist, radiopharmacist or other similarly qualified person (QP), in charge of the facility where the Pharmacy Kit filling and preparation is taking place, is responsible for the overall process and the release of the injectable dose.

Qualified cleanroom technicians are often involved in the Pharmacy Kit filling under the supervision of the pharmacist or QP. As is required for pharmaceutical compounding or PET tracer production, training requirements and training records for all personnel need to be maintained and available for audit by the FDA or equivalent.

Equipment And Facility

The facility and all equipment need to have standard operating procedures (SOPs) that describe how equipment is used, maintained, and calibrated to comply with relevant legislation. Currently, almost all the filling of the Pharmacy Kit takes place within a compounding laminar flow hood or isolator (typically ISO 5). At some sites, the filling is conducted within a cleanroom, while at others, it is conducted in a dedicated non-cleanroom space, reflecting differences in cleanroom approach and specifications between regulators worldwide (71). Some equipment or facilities, such as the compounding hood or cleanroom, may require external certified laboratories for testing.

Material Handling

Material handling guidelines (69,70) require SOPs detailing a system to track all of the materials involved in the HP production process for a particular patient dose, similar to current good manufacturing practice (cGMP) requirements for material handling for drug compounding. This includes acceptance standards, storage conditions, amount used in the patient dose for each ingredient and materials used in the assembly of the fluid path and Pharmacy Kit. Currently some users choose to open and inspect and sometimes modify the Pharmacy Kits upon arrival, but some users keep them in the sealed packaging until they are required for dose preparation.

Pharmacy Kit Filling And Assembling

As required by an IND or its equivalent, the preparation of the doses of HP 13C agent are detailed in the Chemistry, Manufacturing, and Control (CMC) section of an applicable regulatory submission; an example of this has been made available (72). It describes the processes of filling the Pharmacy Kit with the different components that make up the final drug product, and of assembling the final kit for either storage or immediate use in the polarizer. Special attention should be given to the laser welding process in order to satisfy installation qualification (IQ) and operational qualification (OQ). Typically, the final developed process is validated by process qualification (PQ) runs, during which 3 or more Pharmacy Kits are filled and used and the final HP 13C products are tested for endotoxin and sterility and to confirm that they meet the dose specifications for injections (usually including pyruvate concentration, residual EPA concentration, pH, liquid state polarization level and dose temperature). The data from 3 consecutive PQ runs are submitted as part of the IND submission (or its equivalent), and are often also reviewed by the Institutional Review Board (IRB) where the studies are conducted.

Quality Control And Dose Release

The quality control (QC) and dose release can be separated into two aspects: one is the QC and release of the filled Pharmacy Kit, and second is the QC and release of the HP 13C agent for injection, after polarization and dissolution. For institutions filling a batch of kits and storing them to use over a period of time, typically the batch can be released based on initial validation, environmental monitoring data from the day of kit production, and if filters are used during preparation of any of the components, filter integrity testing. But in some cases one or more kits are used for validation before the batch of kits are released for future use. For institutions that fill only the kits required for specific studies shortly before the experiment, the filled kits often do not go through separate release tests before they are used.

The quality control of the HP 13C pyruvate solution post dissolution is primarily performed to ensure that the agent meets the dose specifications (Table 1) before it is administered to the subject. These specifications target both safety (pH, residual EPA, temperature) and efficacy (pyruvate concentration, polarization, volume). Typically, the pyruvate concentration, residual EPA concentration, pH, dose temperature, dose volume, and liquid state polarization are measured by the QC accessory associated with the SPINlab polarizer. Some users perform a secondary measurement for one of the parameters, such as pH, using a different instrument or pH paper. For sites that do not go through a separate release testing process for batch filled kits, the integrity of the sterilization assurance filter, a part of the Pharmacy Kit, is typically tested as a part of the dose release. It is also common for these users to preserve an aliquot of the final HP 13C pyruvate solution for post-release endotoxin and sterility testing. This testing cannot be completed fast enough to test an individual dose prior to injection, but this is why other processes such as PQ runs and validation testing are done to minimize the chance a subject could be injected with a contaminated dose.

The Final Dose Release And Injection

should be done under the supervision of a licensed professional, based on local regulations.

Some Key Challenges

Many of the challenges associated with HP 13C pyruvate preparation can be attributed to the conditions required for the dissolution-DNP method of high magnetic field (~3-7 T) and very low temperature (~1 K) during polarization, with pressurized and superheated water necessary for the rapid dissolution event. These extreme conditions are quite challenging for the design of the container-closure and fluid path system. In particular, the cryogenic temperature in the polarizer requires special attention to any moisture or ambient (moist) air introduced into that portion of the fluid path, which can form an ice block at ~1 K. This ice can lead to flow restriction during the dissolution event and reduce the strength of the laser welded bond between the cryovial and its cap. This can ultimately produce failures in the dissolution step, including variations in final pyruvate concentration and pH that may fail to meet QC release criteria as well as fluid path ruptures that provide no available dose and result in polarizer down-time.

The polarization of the HP 13C pyruvate sample decays quickly over the span of a few minutes after dissolution, and thus the process of dissolution, QC for release, and injection should be completed as fast as possible to preserve the high polarization level achieved. Any delays in the preparation process, such as transportation time or equipment malfunction, can significantly reduce the final polarization and result in lower quality imaging data.

Current Practices

A summary of data collected from all sites performing clinical trials with HP 13C-pyruvate is shown in Fig. 3 and Table 1, including the specification of the final dose and how the quality control and release of the final dose are performed. There is a split in the Production Style, described in the General Considerations section above, with 8/13 sites using Sterile Preparation versus 5/13 using Terminal Sterilization. While many of the dose specifications show notable differences in acceptable ranges, all of these variations listed in tables have been successfully and safely been used to perform HP 13C pyruvate studies in humans. Their differences depend on the institutions’ preferences, resources and their particular regulatory situation. There is high similarity in pyruvate ranges, temperature ranges, EPA limits, and volume limits. There is modest variability in pH ranges and large variability in the endotoxin test limit. There is a 3-fold difference in acceptable polarization levels, which are measured to ensure a futile dose is not injected since the polarization is directly proportional to SNR. This reflects the decision by several sites to believe that useful data can be still be obtained with suboptimal polarizations.

Figure 3: Hyperpolarized agent preparation methods reported by sites currently performing HP

In House

Table 1: HP 13C-pyruvate preparation parameters, methods, and dose specifications used for quality control testing and release as well as validation. These were obtained from a survey of all sites performing clinical trials with HP [1-13C]pyruvate. The parameters used for product release are noted in bold text, otherwise these parameters are measured for batch validation or other QC measurements. The endotoxin and sterility testing are performed during process validation of the batch and/or post-injection, and largely depends on the agent production approach.

Summary

The overall safety record of HP 13C-pyruvate has been very strong, and the SPINlab hyperpolarizer has proven to provide high polarizations at human sized doses while meeting numerous QC and release criteria. A weakness remains the failure modes of the SPINlab Phamacy Kits (e.g. ice blocks, path ruptures), which are placed under extreme requirements particularly during dissolution. The preparation process still requires a high degree of expertise.

Therefore, there is a significant need to improve the reliability, robustness, and ease of operation for generating HP 13C-pyruvate doses for human studies. Furthermore, there is a divide between manufacturing and sterile compounding style preparation as well as other site-specific practices, resulting in variations in SOPs and justification required to relevant regulatory bodies. There have also been no comparisons between these approaches. It is also unclear what release criteria and QC parameters are truly required to ensure patient safety.

However, all of the reported methods are acceptable and approved by the appropriate regulatory authorities, and have led to the rapid expansion of successful human studies in recent years.

Mri System Setup And Calibrations

This section covers the MRI system setup, including the imaging system, RF coils, phantoms, and prescan calibration methods.

Imaging System

The main prerequisite for a given MRI scanner to be capable of supporting studies with HP 13C is its “broadband” capability to transmit and receive radiofrequency (RF) signal at the frequency of 13C, which is around 4 times lower than 1H. This does not come as a default on clinical MR devices. The transmit power of the broadband amplifier should also be sufficient to support the intended flip angle and RF pulse shape with the employed transmission RF coil(s) for 13C. Most studies to date use relatively low flip angles (< 90 degrees) for HP 13C in order to preserve polarization for time-resolved imaging. The capability to receive 13C signal on multiple channels is also desirable to increase SNR, as discussed further in the “RF coils” section.

The choice of magnetic field strength is primarily dependent on the metabolites’ frequency separation due to chemical shift dispersion and 1H imaging. High field strengths do not enhance hyperpolarized 13C signal as they do for 1H because the signal strength in a HP experiment relies on manipulating the population of quantum energy states outside of the MRI scanner.

However, the injected HP 13C-pyruvate and its metabolic products have greater frequency separation at higher fields, and it may thus be easier to separate and quantify these resonances at higher fields. This comes at the cost of a reduction in the achievable T2* and often reduced T1. As the initial polarization is independent of the imaging field strength it has been proposed that the increased T2* at 1.5T can potentially be exploited to increase SNR by adapting the acquisition bandwidth or reduce off-resonance imaging effects in cases when the decay of the transverse magnetization is dominated by T2* (73). In practice, 3T has been used in all published human 13C-pyruvate studies surveyed (Supporting Table S1), and comprises the majority of scanners currently in use for human studies (Table 3). A field strength of 3T is well-suited for 1H MRI anatomical reference and correlative imaging.

Stronger and more rapidly slewing magnetic field gradients support more rapid spatial encoding, particularly for metabolite-specific single-shot imaging using echo-planar imaging (EPI) or spiral imaging (See “Acquisition and Reconstruction”). Although the spatial resolution acquired for HP 13C imaging is typically much coarser than for 1H MRI, the factor of ~4 in gyromagnetic ratio leads to the same reduction factor in performance of the gradient system, so 13C experiments are potentially more limited by gradient hardware performance. To date, all human studies have used the commercially-available integrated gradient systems provided in clinical MRI scanners.

Optimization of scanner design has understandably focused on minimization of artifacts in 1H MRI, where devices such as room lights, the gradient amplifiers, and the motors driving the patient bed are checked to ensure that they do not produce RF interference at the 1H frequency, but artifacts may arise at other frequencies. Eddy current compensation is also not always appropriately adjusted for nuclei at other frequencies (74). In order to optimize for 13C, many sites have performed checks on phantoms for RF interference, gradient artifacts, and eddy currents (74), including the use of post-hoc gradient impulse response function characterisation and correction, and some vendors have fixed these issues as well.

Rf Coils

For HP 13C imaging studies in humans, RF coils for both 1H and 13C nuclei are needed, with 1H MRI providing an anatomical reference for registration and optional additional multiparametric MRI readouts. At the Larmor frequency of 13C nuclei, the relative contributions from coil noise compared to sample noise increase compared to 1H (73,75), although sample noise still is likely the dominant contributor for human-sized coils at 32.1MHz - the resonance frequency of 13C nuclei at 3T.

The key requirement for human 13C-pyruvate RF coils are that the coil geometry and sensitive volume must cover the volume of interest in the subject. Table 2 and Figure 4 shows coil configurations that have been used and optimized for applications in different anatomic regions.

Volume resonators are most commonly used for transmit, as they surround the subject to

Provide B1 Transmit Across The Fov (B1

+). While 1H relies on a large birdcage (“body”) coil built into the scanner, 13C transmit coils must be placed inside the bore. This takes up valuable space within the magnet, and also has led to the use of designs with relatively inhomogeneous

B1

+. Many human studies have used Helmholz pair resonators for transmit, including the “clamshell coil”, which has a notably inhomogeneous B1

+ Profile But Has Been Used Because Of

relatively easy integration into the scanner bore. B1

+ Variation Results In Variations In The Flip

angles that control the use of the hyperpolarized magnetization and creates errors in common HP metrics (9,76). The exception are head coils, where birdcage designs with highly

Homogeneous B1

+ can be placed around the head while easily fitting inside the bore. As with 1H MRI, higher SNR can typically be achieved by smaller receive coil elements, such as surface coils or phased arrays, and the majority of 13C receive coils used have layouts similar to 1H phased arrays.

RF coil quality control is important to ensure proper functioning of the coils to provide consistent imaging quality, especially with limited natural abundance 13C signal in vivo. It typically involves 1) a physical integrity check of the coil cables and connectors and 2) phantom SNR tests to check the coil’s performance and to monitor it over time (see Phantoms below). An useful reference for RF coil quality control is outlined in the MRI accreditation program of the American College of Radiology (77) and can be adapted for 13C coils.

Notably, configurations for brain and prostate studies used dual-tuned 1H/13C coil designs, which greatly simplify workflow and registration of 1H and 13C images, as no switching of coils is needed.

Table 2: RF coil configurations reported for human HP [1-13C]pyruvate studies.

Tx = Transmit

coil, RX = receive coil. The commonly used “clamshell” TX coil is a Helmholz pair design. For 1H RF configurations, all used the Body coil for TX unless otherwise noted, and “repositioned” indicates the 13C coil was removed for 1H imaging. One representative reference is listed for each configuration. The RF coil configurations reported in the reviewed papers are shown in Supporting Table S1.

Figure 4: Examples of RF coil configurations used for human HP [1-13C]pyruvate brain studies. (A,B) 13C Clamshell TX (Helmholz pair) and 2× 4-channel paddle RX arrays. (C) 13C Birdcage volume TX and 32-channel RX array (RX array slides into TX coil). (D) 13C Birdcage volume TX and 24-channel RX array, combined with a 1H 8-channel RX array. Image reproduced with permission from Ref (16).

Phantoms

Since hyperpolarized magnetization is non-renewable, phantoms containing 13C nuclei are important to: 1) test the multi-nuclear capabilities of the imaging system, including all parts of the signal excitation and receive chain; 2) perform calibration measurements before a scan with hyperpolarized nuclei; and 3) perform necessary pre-scan adjustments (see “Prescan Calibration” section). The phantoms currently in use are listed in Table 3. Their composition must provide sufficient 13C signal, with additional considerations of conductivity, stability, chemical shift(s) present, potential for dynamic imaging, and cost. The phantom geometries are typically either compact, in order to be used alongside the subject during a HP scan, or large enough to mimic the inner volume of a RF coil for system testing.

One popular compact design contains enriched 13C-urea at high concentration, typically 8 M, which provides a single resonance, placed inside a small container ~1 mL. The most common recipe mixes 13C-urea in a 90% water/10% glycerol solution, with glycerol used to increase the urea solubility and doping with a Gd-based contrast agent to shorten T1 which increases the potential SNR per unit time. For example, when Dotarem is added at a 3:1000 volume ratio the 13C-urea T1 is around 500 ms and T2 is around 100 ms. However, when testing pulse sequences influenced by T1 and T2, doping should be used carefully. This phantom is suitable for frequency calibration, transmit gain calibration, sequence testing, and as a fiducial marker when placed next to a patient. However, enriched 13C-urea has a relatively high cost compared to natural abundance compounds.

For larger volumes (>100 ml), the phantoms most often used contain undiluted ethylene glycol, glycerol, or dimethyl silicone. These compounds have sufficiently high carbon concentrations to provide sufficient 13C signal even with the 1.1% natural abundance of 13C. These larger phantoms matching the inner volume of an RF coil are useful for coil testing, including transmit

+) And Receive (B1

-) coil profile mapping, as well as to mimic acquisitions using in vivo FOV requirements. In this case, size and conductivity should match the expected subject size in order to mimic coil loading and get a realistic estimation of B1+. Large-volume natural abundance urea phantoms have also been used by some sites, but suffer from higher conductivity compared to biological tissues. Typically, it is easier to increase the conductivity and hence coil loading of the non-conductive phantom by adding NaCl to match physiological loading (16,78).

Dynamic phantoms that aim to mimic metabolite kinetics have also been developed (79–81), and have the potential to more closely mimic the HP experiment, but so far these are not widely used.

Prescan Calibration

Prior to performing an MRI acquisition, the so-called prescan procedure is used to set the shim parameters to maximize B0 homogeneity over the field of view (FOV) or a specific region of interest (ROI), the scanner center frequency (CF), the RF transmit gain, and the receiver gain.

While this calibration procedure is usually automated for 1H, the lack of sufficient natural abundance 13C signal prevents use of automated methods. (Although natural abundance 13C lipid signal has been detected, there are so far no reports on using this signal for prescan.) Table 3 shows current practices across sites.

Maximizing B0 homogeneity is independent of the nucleus and is therefore performed prior to 13C imaging using the 1H water signal and existing shimming tools, such as by a standard automated process (“Auto Shimming”) or using high order shimming routines. Similarly, the 13C CF can be calculated from the 1H CF using a predetermined scaling factor that depends on the target chemical shift (82). Another common approach used is to have a small, high-concentration 13C phantom, e.g. 8M 13C-urea, integrated in the RF coil or placed next to the scan subject (1). The reference frequency can also be based on real-time measurements after the HP injection but prior to imaging (83). Both the CF and B0 shimming are critical when using spectrally-selective RF pulses, as inmetabolite-specific imaging methods, where the desired excitation bandwidths are typically very narrow and frequency offsets can lead to a failure mode that is only apparent after injection.

The calibration of the RF transmit power is typically performed on a small, high-concentration 13C phantom placed near the region of interest during the scan or on a large 13C phantom of similar size and coil loading as the subject, prior to the subject scan. Reference power is often done by sweeping the power in a pulse-acquire sequence (53,62), or the Bloch-Siegert method (52,84). When using a small phantom, the location of the phantom, B1

+ Inhomogeneity As Well

as any shielding effects, e.g., when the phantom is integrated into a coil (1), may degrade the accuracy. Other methods include real-time Bloch-Siegert method measurements after the HP injection (83), and using the stronger natural abundance 23Na signal that is close enough to the 13C resonance frequency to be detected by 13C coils (82).

The receiver gain is predetermined, either systematically based on independent phantom measurements and assuming the dose and polarization of the HP compound is known prior to injection, or based on past HP imaging studies.

Power [Kw]

Phantom(s) - during study Phantom(s) - before study 13C Frequency

13C-bicarbonate doped with dimethyl silicone, various

Maximum Values

Table 3: Summary of the imaging systems, phantoms, and prescan procedures used at sites currently performing HP 13C-pyruvate human studies. These were obtained from a survey of all sites performing clinical trials with HP [1-13C]pyruvate. *Previously performed studies with a Siemens 3T Tim Trio. The imaging systems, phantoms, and prescan procedures reported in the reviewed papers are shown in Supporting Table S1.

Summary

Commercially available 3T MRI systems are by far the most commonly used for human HP 13C-pyruvate studies, although a systematic investigation of the impact of B0 has only recently been investigated (73). The multi-nuclear RF transmit and receive chain has proven sufficient for current acquisition strategies, although many sites have observed artifacts due to RF interference, gradient interference, and residual eddy currents when operating at the 13C frequency. A variety of 13C RF coils, tailored for numerous anatomical targets, have been successfully demonstrated, with the main limitation that most transmit coils take up a lot of additional space inside the bore and provide relatively inhomogeneous B1

+ Profiles. The

phantoms used have converged into generally 2 categories - small phantoms containing 13C-enriched compounds that can be used during the study and human-sized phantoms containing compounds with high carbon concentrations but without 13C enrichment that are used to test and calibrate the coils. There are no standardized compositions or geometry, and dynamic phantoms that recapitulate in vivo kinetics would be desirable but are still an emerging area. Prescan calibration procedures were not well defined in most publications, so we surveyed individual sites to determine current practices. Calibration procedures for the B0 field (13C CF and shimming) for most sites take advantage of 1H signal and methods, while methods

For Calibration Of B1

+ is more variable across sites, likely a reflection of remaining challenges in how to perform this calibration. Standardization of both phantoms and calibration procedures would synergistically improve the robustness and reproducibility of HP 13C studies.

Acquisition And Reconstruction

Data acquisition strategies in human HP [1-13C]pyruvate MRI studies must account for multiple chemical shifts, efficiently utilize the non-renewable HP magnetization, and acquire data quickly relative to metabolism and relaxation decay processes. These studies require spectral encoding to separate metabolites, necessitating pulse sequences that efficiently encode up to 5D data (3 spatial + 1 spectral + 1 temporal dimension). RF pulses must efficiently sample without immediately saturating the non-renewable HP magnetization, and sequences must acquire data quickly and be robust to both experimental and physiologic variation (e.g. B1

+ Inhomogeneity,

variation in perfusion) to ensure reproducibility and minimize scan-to-scan variability. This section covers current successful practices for data acquisition in human [1-13C]pyruvate studies, and accompanying 1H imaging, from different anatomic regions, including scan parameters and image reconstruction.

Acquisition And Reconstruction Methods

The acquisition methods used in human [1-13C]pyruvate studies can be classified into 3 categories: 1) MR spectroscopy or MR spectroscopic imaging (“MRS/I”), 2) chemical shift encoding methods, and 3) metabolite-specific imaging (Fig. 5).

Mrs/I Methods Specifically

resolve a spectrum that can be analyzed to extract expected as well as unexpected resonances, making this approach very robust. It was used in many initial studies (1).

Chemical Shift

encoding methods, most commonly the Iterative Decomposition of water and fat with Echo Asymmetry and Least-squares estimation (IDEAL) method, use imaging sequences acquired with multiple TEs and rely on a model-based separation of expected chemical shifts (85).

Metabolite-specific imaging methods use specialized RF pulses that are spatially and spectrally selective to excite individual metabolites which are then typically imaged with fast k-space trajectories such as echo planar imaging (EPI) or spirals (86).

Their Application To Different

organ systems is described below. The image reconstruction methods used in human [1-13C]pyruvate studies have typically been conventional methods (e.g. FFT, non-uniform FFT, or equivalent). The incorporation of accelerated imaging and advanced reconstruction methods including parallel imaging (4,57,87) and compressed sensing (7) has also been applied in human studies for improved spatial resolution, temporal resolution and coverage, but have the potential for additional artifacts as well as SNR losses due to ill-conditioning of the reconstruction (e.g. g-factor).

The Majority Of

published studies do not use accelerated imaging indicating the resolution and coverage achievable without acceleration is currently adequate for successful data collection. Performing coil combination, even with fully sampled data has also been shown to have specific challenges for HP human images: using naive sum-of-squares methods suffer from high noise amplification in the relatively low SNR regime of HP [1-13C]pyruvate (compared to 1H), motivating several HP 13C-specific methods that include data-driven coil sensitivity estimation which have shown obvious improvements over sum-of-squares (11).

More recently denoising techniques have been applied as post-processing of human HP data(41,42,44). The techniques applied are based on spatial-temporal singular value decomposition for unsupervised estimation of signal and noise components. They have shown improvements in apparent SNR in the brain and liver, while care must be taken to choose parameters such as the rank threshold to avoid oversmoothing and overfitting to the estimated signal components.

Prostate Studies

Prostate cancer was the first human application of HP [1-13C]pyruvate (1), and data was acquired with MRS/I methods: 1D dynamic MRS, single-slice 2D dynamic echo-planar spectroscopic imaging (EPSI), and single time point 3D EPSI. Advances in imaging strategies led to the development and application of new acquisition schemes, including undersampled 3D EPSI with compressed-sensing (7), model-based chemical shift encoding methods that use a priori information (47,59), and metabolite-specific EPI (10), all of which can provide volumetric whole-organ coverage and dynamic acquisitions.

The pyruvate bolus arrival in the prostate can vary by ± 10 s between patients, necessitating dynamic imaging to reliably and consistently capture the pyruvate bolus (18). For this reason, all currently ongoing studies acquire dynamic data. While MRS/I, chemical shift encoding, and metabolite-specific imaging can all achieve dynamic imaging, chemical shift encoding and metabolite-specific imaging provide greater dynamic and volumetric coverage (85). For scan prescriptions, the FOV is designed to provide full prostate coverage and typically to match the orientation of the anatomic imaging used for registration. Flip angles used in current studies are constant through time, as quantification with a variable-through-time flip scheme is highly sensitive to bolus timing (8) and errors in the RF transmit (B1 +) field (76).

Heart Studies

Data acquisition methods for 13C imaging in the heart must be designed to meet the demands of significant cardiac motion and blood flow. To cope with the periodic cardiac motion, most human heart studies to date used gating to the diastolic window, the longest cardiac cycle interval, which has reduced motion (2,22,28,30,35,36,38,45,52). The duration of the diastolic window limits the available data sampling time, making cardiac acquisitions the most time-constrained of the HP 13C MRI applications. The most common acquisition approach is metabolite-specific imaging with spiral k-space trajectories (2). Their single-shot imaging capability makes these methods particularly robust to motion effects. Furthermore, spiral k-space trajectories provide rapid k-space coverage and relatively benign flow and motion artifacts. The majority of studies have used 2D multi-slice acquisitions, but 3D encoding has also been used successfully (35).

Brain Studies

For HP 13C MRI of the human brain, the majority of studies have also used 2D (slice selective) acquisitions (10–12,14,16,28,33,40,41,44,51,53,60), with a trend toward volumetric coverage using 2D multi-slice metabolite-specific imaging. 3D metabolite-specific imaging of the whole brain, with phase encoding of the slice direction (34,57), has been shown to provide similar SNR efficiency (88) compared with multislice imaging. A number of studies have employed MRS/I (5,6,29,31–33,50,55) resulting in a spectrum from each voxel, which has the advantage of not requiring a priori information about which peaks to encode. This was important in early brain studies when it was not known which peaks would be detectable. Chemical shift encoding, using a set of images with different echo times and an iterative reconstruction of the individual resonances (i.e. the IDEAL approach (85)), has also been used (12,49,54), with the drawback that coverage in the slice direction was limited due to the time required to acquire multiple echo time images.

Abdomen And Breast Studies

The fundamental approaches to data acquisition and reconstruction in the abdomen and breast are largely similar to the aforementioned applications, but demand attention to particular challenges associated with these anatomic regions, especially relating to respiratory motion.

Although it has been shown that a basic 2D MRSI approach based on phase encoding and FID readout can be successfully applied for HP 13C imaging in breast (15) and kidney (13), major advantages in terms of spatiotemporal resolution and coverage have been realized using tailored approaches based on metabolite-specific imaging (43,62) and chemical shift encoding (43), which have facilitated multi-slice or 3D dynamic acquisitions over large FOVs in the abdomen (4,37,46).

The significant respiratory motion encountered in these regions can directly blur 13C images, and has further favored these rapid acquisition strategies. Motion also degrades B0 homogeneity, which can shift frequency-selective excitation profiles and introduce artifacts into rapid imaging readouts. This makes accurate determination of the acquisition center frequency and shimming essential in these regions which often cover large FOVs. (See “Prescan Calibration” section for more information). In some studies, breath-holding was used to minimize motion effects and enforce frame-to-frame data consistency (42). A pragmatic and reasonably effective approach for dealing with respiratory motion during 13C data acquisition is an initial breath-hold (as long as can be tolerated), followed by free-breathing (46,62).

1H Imaging

Collection of 1H imaging data is essential both for prescribing the 13C acquisition and for interpretation of the resulting 13C data. Multi-planar 1H scouts are acquired prior to 13C acquisition to enable graphical prescription of the 13C imaging region. All human HP 13C-pyruvate imaging studies acquire conventional MRI scans (e.g. T1- and T2-weighted volumes) for anatomic reference, aiming to cover at least the full 13C FOV. Acquiring these anatomic scans as close as possible to the time of 13C imaging (immediately before or after) minimizes potential misregistration between the data sets. Depending on the application, other advanced 1H sequences are also acquired (e.g. diffusion-weighted imaging for cancer imaging).

When contrast-enhanced data is acquired, it is done after 13C imaging, as paramagnetic contrast agents will accelerate 13C relaxation.

Reported Study Parameters

Figures 5 and 6, and Supporting Table S2 shows the reported acquisition study parameters for human HP [1-13C]pyruvate studies published as of September 2022. Figure 5 shows a mixture of MRS/I, metabolite-specific imaging, and chemical shift encoding methods have been successfully used, where spectroscopy-based methods have become less prevalent in recent studies. Figure 6 shows the acquisition timing, including the important start time and interval/temporal resolution, is quite variable across studies.

Figure 5: Acquisition methods used in published HP [1-13C]pyruvate human studies published up to September 2022, classified into: MR spectroscopy and spectroscopy imaging (MRS/I); chemical shift encoding methods, such as IDEAL, that use multiple TEs and model-based reconstructions; and metabolite-specific imaging methods that use spectrally-selective excitation to image a single resonance at a time.

Figure 6: Temporal acquisition characteristics reported in HP [1-13C]pyruvate human studies published up to September 2022. (a) Reported referencing of acquisition start times.

(B)

Acquisition start times reported when using dynamic imaging and when timing was reported relative to the end of the injection. (c) Temporal resolutions. “Not Applicable” indicates dynamic imaging was not used.

Summary

Three general categories of acquisition strategies have been used successfully for human HP 13C-pyruvate studies: MRS/I, model-based chemical shift encoding (e.g. IDEAL) methods, and metabolite-specific imaging methods. These have enabled successful studies in the prostate, heart, brain, abdomen, and breast. Recent studies increasingly have used the imaging-based strategies of metabolite-specific imaging and chemical shift encoding which are the fastest methods, although a heads-to–head comparison between techniques has not been performed.

Metabolite-specific imaging is quite popular because of its speed and compatibility with single-shot imaging, but is sensitive to B0 field variations and thus requires careful calibrations. Nearly all studies surveyed acquired data dynamically, allowing measurement of the bolus and metabolite kinetics. The exact timings and associated flip angles vary quite widely across reported studies, with no consensus yet as to how to choose these parameters. Image reconstruction is typically done directly using Fourier Transform methods, and accelerated imaging strategies are uncommon.

Data Analysis And Quantification

This section covers the analysis of data from human HP [1-13C]pyruvate studies, including modeling and metrics, visualization, as well as considerations for how to store data and metadata. Depending on study design, the analysis may need to give quantitative or semi-quantitative output reflecting a biological process or may just reflect a contrast between different regions of interest for quantitative evaluation.

Metrics

Figure 7: HP [1-13C]pyruvate raw data (A) have typically been quantified using four categories of metrics depending on the acquisition. Data acquired as a single time point are often quantified using normalized metabolite images or metabolite ratios (B). Dynamic data can be quantified using normalized metabolite images or metabolite ratios (B), or with metabolite timings such as time-to-peak (TTP) or pharmacokinetic (PK) models (C). The latter two require the data to be time-resolved. [1-13C]alanine and 13C-bicarbonate are analyzed similarly to [1-13C]lactate but omitted here for display.

Metabolite images are commonly used as summary metrics for HP MRI data, often including some form of normalization as well as summed over time as an area under the time curve (AUC) (17). These are analogous to the visual evaluation that is most used for routine clinical work (89,90). In these metabolite images, we expect that the [1-13C]pyruvate AUC signal is predominantly weighted towards perfusion and uptake, while [1-13C]lactate, [1-13C]alanine and 13C-bicarbonate AUCs represent metabolic conversion. The strength of this approach lies in its simplicity and relatively few underlying assumptions. Limitations to the use of single-metabolite images or AUCs include sensitivity to inhomogeneous coil profiles (57,87,91), the acquisition strategy and acquisition parameters, pyruvate polarization and concentration level, and signal relaxation rates (92). Further, the reader must be careful to interpret all the images in conjunction to better understand the underlying biology; for example, increased [1-13C]lactate in the presence of decreased [1-13C]pyruvate delivery can have a very different meaning compared to increased [1-13C]lactate with increased [1-13C]pyruvate delivery.

In an attempt to address variations in coil sensitivity, polarization level, and pyruvate delivery, AUC images are often computed by normalizing to a specified parameter, such as the maximum pyruvate or average lactate signals, or presented as a ratio such as lactate/pyruvate or divided by “total Carbon” - the sum total of HP 13C signal observed across all metabolites. The AUC ratios between metabolites and pyruvate are proportional to the corresponding forward kinetic rates (81,93), but are not directly comparable to rate constants when magnetization loss rates (e.g. relaxation and losses due to signal excitation) differ between studies. Similarly, the ratios between the produced metabolites (e.g. bicarbonate/lactate) can reflect the balance between downstream metabolic pathways (12,55). Care must be taken to consider how AUC images are calculated and normalized before comparing values between studies.

To further quantify the interpretation, pharmacokinetic (PK) modeling approaches were developed to compute the apparent kinetics of pyruvate-to-metabolite exchange (92,94–99). These yield semi-quantitative to quantitative apparent rate constants, given in s-1. Some models require a vascular input function, while others avoid this requirement (95). PK models can explicitly account for acquisition-specific details such as excitation angle and repetition time, and thus may reduce the effects of these details on quantification. An input-less model, provided in the Hyperpolarized-MRI-Toolbox (https://github.com/LarsonLab/hyperpolarized-mri-toolbox) (100) and thus frequently employed for human data, has been shown to fit well and robustly to prostate and brain data (8,20). PK models are quantitative in nature, arguably provide more relevant biological information (8,20), and appear to be reproducible across sites (51). However, rate constants derived from PK models are still apparent rates, and likely do not reflect a single biological characteristic.

Some additional considerations include whether complex or magnitude data is used, as the noise behaviors will impact the analysis differently. Additionally, cut-off thresholds or other criteria may be used to identify and avoid voxels with insufficient SNR before analysis to improve robustness (20,41).

Regardless of the analysis approach, the underlying biology is not always clearly represented by the data; instead, the metrics may be influenced by perfusion, barrier permeability, intercellular shuttles, enzyme activities, co-substrate concentrations, or combinations thereof, depending on the organ and disease of interest (19,43,94,101–103). This may be addressed by incorporating complementary information. As an example, HP 13C pyruvate data is influenced by perfusion, and thus addition of perfusion MRI could be important for interpretation (98,104,105).

All the methods outlined above have been explored in clinical studies, described in Supporting Table 3 and summarized in Figure 8. As of September 2022, approximately 52% of studies involving human subjects report rate constants derived from a PK model with a few different models reported. A nearly equal fraction (51%) of the studies report AUC ratio values.

Approximately 66% of these studies report metabolite-specific images or AUC values. About 40% report SNR values; this metric is particularly frequent in manuscripts that describe technical developments for clinical HP MRI. Approximately 16% of these studies summarize model-free metrics, and 10% report measurements from a single timepoint. Most studies report a combination of quantities.

Figure 8: Reported metrics used for analysis in HP [1-13C]pyruvate human studies published up to September 2022.

Visualization

A wide variety of approaches have been used for visualizing data from human HP 13C-MRI studies. The challenges and practical considerations are: 1) choosing the appropriate metrics to display, 2) how to encode the parameters (e.g. the colormap), and 3) choosing how to provide anatomical context and other multi-parametric data. The choice of visualization also depends on the goal which could be for diagnostic interpretation, but also quality control, reproducibility among readers and publication.

Metrics

The choice of HP 13C metrics is described in detail above. At this stage in HP 13C development where there is no standardized metric, often a combination of metabolite images and ratios or PK model parameters are shown.

Parameter Encoding

The mapping function chosen should provide an adequate, often quantitative, impression of the parameter mapped. There is a consensus in the visualization field that perceptually uniform maps are best suited to visualize continuous parameters, like the greyscale typically used by radiologists as well as other monochrome (black to blue) and color ranges (fire-type, rainbow-type) (106,107). Multi-color heatmaps have been the most frequently employed method for HP 13C data, while greyscale has infrequently been used but it ensures there is no coloring-based bias as well as facilitating later reuse (Fig. 9a). Among the color schemes employed in the clinical HP 13C literature, fire-type scheme seems to be the most common [similar to “Plasma” or “Inferno” in matplotlib.org]. Next most commonly employed is the rainbow-type scheme [similar to “Rainbow” in matplotlib.org].

Anatomical Context

HP MRI faces the challenge that it does not necessarily depict the anatomical features, similar to PET, and thus requires an anatomical reference. Most often, a grayscale anatomical image is overlaid with a HP colormap (Fig. 9c,d). This approach is very intuitive, but can skew perception as the grey-scale anatomical reference may affect the brightness of the HP data (e.g. signal in the skull). This bias does not occur when showing adjacent maps (Fig. 9a, b). Here, anatomical outlines may help to provide reference (Fig. 9b).

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