# A rostral prefrontal mediolateral gradient predicts creativity in frontotemporal dementia

Victor Altmayer, Marcela Ovando-Tellez, Théophile Bieth, Bénédicte Batrancourt, Armelle Rametti-Lacroux, Sarah Moreno-Rodriguez, Arabella Bouzigues, Vincent Ledu, Béatrice Garcin, Alizee Lopez-Persem, et al.

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Victor Altmayer, Marcela Ovando-Tellez, Théophile Bieth, Bénédicte Batrancourt, Armelle Rametti-Lacroux, et al. A rostral prefrontal mediolateral gradient predicts creativity in frontotemporal dementia. 2025. hal-05468485

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# A rostral prefrontal mediolateral gradient predicts creativity in frontotemporal dementia

Victor Altmayer¹,², Marcela Ovando-Tellez¹*, Théophile Bieth¹,²*, Bénédicte Batrancourt¹,
Armelle Rametti-Lacroux¹, Sarah Moreno-Rodriguez¹, Arabella Bouzigues¹, Vincent Ledu¹,
Béatrice Garcin¹,³, Alizée Lopez-Persem¹, Daniel Margulies⁴, Richard Levy¹,², Emmanuelle
Volle¹, ECOCAPTURE study group

* These authors contributed equally to this work

## Abstract

Creative thinking is a fundamental aspect of human cognition, enabling the production of novel and useful ideas. It is hypothesized to emerge from the binding and reconfiguration of existing knowledge, through the generation of remote semantic associations and their combination in original and meaningful ways, respectively supported by the default mode (DMN) and executive control (ECN) networks. At the crossroads of these two networks, the rostral prefrontal cortex (PFC) is proposed as a key hub for DMN-ECN interactions, possibly supporting the interplay between generative and combinatory creative processes. However, the specific contributions of its medial and lateral subdivisions to creativity remain unclear.

In this study, we aimed to characterize the involvement of the rostral PFC in creative cognition through the lens of behavioural variant frontotemporal dementia (bvFTD), a relevant pathological model as it primarily affects the rostral PFC and alters intrinsic connectivity within the DMN and ECN. Using whole-brain voxel-based morphometry, we explored the brain regions critical for the generation and combination of remote semantic associates, respectively, but also for creative abilities, thought to involve both types of processes. Using resting state functional connectivity and gradient mapping techniques, we also explored functional connectivity profiles within the rostral PFC and how connectivity variations within this region predict creative performance.

As a result, we found a critical role of the rostromedial PFC for generating remote semantic associations and of the rostrolateral PFC for combining semantic associates, while both regions were critical for creative abilities. Moreover, we showed that intrinsic connectivity of rostral
PFC is organized along a mediolateral functional gradient, segregating the rostromedial PFC, connected to the DMN, and the rostrolateral PFC, connected to the ECN. Finally, we showed that the range of this functional gradient, representing the functional differentiation between the ECN and DMN, predicts creative abilities.

Overall, this study advances our understanding of creative cognition, its relationships to the anatomical and functional organization of the prefrontal cortex, and its impairment in bvFTD.

**Authors affiliations:**

¹ Sorbonne University, Institut du Cerveau – Paris Brain Institute – ICM, FrontLab, Inserm, CNRS, AP-HP, Hôpital de la Pitié Salpêtrière, Paris, France

² AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Neurology, IM2A, Paris, France

³ AP-HP, Hôpitaux universitaires de Paris - Seine Saint Denis, Hôpital Avicenne, Department of Neurology, Bobigny, France

⁴ Integrative Neuroscience and Cognition Center, University of Paris, CNRS, Paris, France

Correspondence to: Victor Altmayer

FrontLab – ICM; Hôpital Pitié Salpêtrière, 47, bd de l’hôpital, 75013 Paris, France

E-mail: victoraltmayer@hotmail.com

**Running title:** Neurocognitive bases of creativity in FTD

**Keywords:** Frontotemporal Dementia; Creativity; Associative Thinking; Executive Functions; Voxel-based Morphometry; Resting State Functional Connectivity; Connectivity Gradients
Introduction

Creative thinking is a fundamental aspect of human cognition allowing us to produce original and useful ideas.¹,² This ability is essential for addressing the challenges of a complex and dynamic environment and is recognized as crucial at both individual and societal levels. However, the mechanisms by which creative ideas arise in the brain remain an active area of research and debate. It is hypothesized that creative ideas do not emerge de novo but rather from the binding and reconfiguration of existing semantic knowledge.³ According to the associative theory of creativity⁴,⁵, one of the most influential theoretical frameworks, creative ideas result from both the generation of remote semantic associations and their combination in original and meaningful ways.³,⁴,⁶,⁷ The generation of original semantic associations through the activation of mutually remote semantic concepts is thought to rely on associative thinking processes.³,⁵,⁸ Spontaneous or undirected activation of one's semantic associations stored in memory can explain individual differences in creativity⁵,⁷,⁹⁻¹¹. However, remote thinking also involves goal-directed associative processes for the intentional retrieval of remote associates.⁵,⁸,¹²⁻¹⁵ Recent research has suggested that a low-constrained generation of remote associates involves both spontaneous and goal-directed associative processes.³,⁵,¹² In more complex creativity tasks requiring a strategic memory search, especially in constrained contexts³,¹⁶⁻²¹, executive control processes including relational integration¹⁶,²²⁻²⁸, multitasking or branching²⁹ allow the effective combination of multiple semantic associations in order to meet task or real-life constraints.

It is commonly accepted⁵,⁸,³⁰⁻³² that the cooperation of low-constrained generative and high-constrained combinatory processes in creativity relies on the respective contributions of the default mode network (DMN), known for its involvement in self-generated thoughts³³,³⁴, and the executive control network (ECN), supporting executive control processes³⁵,³⁶, including those involved in creative thinking. As a major component of these two networks, the prefrontal cortex (PFC) is the cortical region most consistently associated with creativity in studies using various experimental tasks and exploring different creativity domains.³⁷⁻⁵⁰ However, the PFC is the largest and most functionally and structurally diverse association cortex in the human brain⁵¹,⁵², so that, to date, reporting the involvement of the PFC in creativity lacks specificity.

One region in particular, the rostral PFC (also known as the frontopolar cortex, Brodmann area 10), seems essential to creative thinking¹⁶,⁴²,⁵³⁻⁵⁵. Indeed, the rostral PFC appears to present the appropriate characteristics to play a central role in the DMN-ECN interaction, possibly
supporting the interplay between generative and combinatory creative processes. Phylogenetically one of the most recently and widely developed brain areas, with a broad range of complex intra- and inter-areal interactions²⁹,⁵¹,⁵⁶, the rostral PFC is thought to sit at the apex of the prefrontal functional and architectural hierarchy, allowing the most complex and integrated degree of information processing.⁵²,⁵⁷⁻⁶⁰ For instance, this region has been related to a number of high-order cognitive functions, including abstract thinking⁵⁷,⁶¹⁻⁶³, analogical reasoning²³,²⁴,²⁶,⁶⁴,⁶⁵, working memory, and multitasking²⁹,⁶⁶⁻⁷⁰. Overall, its role could be summarized as the capacity to process and integrate information that is temporally or semantically distant.⁵¹,⁷¹

Yet the rostral PFC itself is not a homogeneous region either. Substantial evidence indicates medial and lateral subdivisions of the rostral PFC, characterized by differential cytoarchitectonic<sup>72</sup>, structural<sup>73,74</sup>, and functional connectivity properties<sup>73,75,76</sup>, as well as distinct cognitive functions.<sup>72,75,77</sup> Specifically, the rostromedial PFC is described as a core node of the DMN, involved in internally focused, self-generated thoughts<sup>11,33</sup>, while the rostrolateral PFC is associated with the ECN and controlled cognition.<sup>11,73,75</sup> Yet, the respective boundaries between the rostromedial and rostrolateral PFC remain a matter of debate<sup>73</sup>.

Whatever the structural and functional differences between these rostral regions, substantial evidence supports the involvement of both the rostromedial and rostrolateral PFC in creative thinking.<sup>16,26,42,47,53</sup> Several patient studies have demonstrated a causal relationship between brain structure and function in a manner that complements fMRI findings, showing the critical role of the rostral PFC in distinct creative processes.<sup>16,23,54,78</sup> In particular, Bendetowicz and colleagues<sup>16</sup> demonstrated a cognitive dissociation between the rostromedial and rostrolateral PFC in patients with focal frontal lesions. The rostromedial PFC was shown critical for the generation of remote semantic associations in a word-to-word generation task, the Free Generation of Associates Task (FGAT<sup>16</sup>). Conversely, the rostrolateral PFC was shown critical to efficiently combine remote concepts to find solutions in a French adaptation of Mednick's Remote Associates Task<sup>4</sup>, the Combination of Associates Task (CAT)<sup>16,27</sup>, which was replicated in a recent study.<sup>79</sup> Further, brain lesions overlapping with the DMN impacted the generation task (FGAT) and lesions overlapping with the ECN the combination task (CAT). Overall, while most studies have described the rostromedial and rostrolateral PFC as nodes of separate networks displaying opposite cognitive roles and connectivity profiles, the hypothesis of their joint critical involvement in human creative thinking remains to be tested. In addition,
the question of the reciprocal functional interactions between these two regions and their implications for the cooperation of the DMN and ECN during creative cognition³¹,⁸⁰ remains unaddressed. As argued by some authors⁸¹⁻⁸⁴, low-constrained generative and high-constrained combinatory processes might not be completely separable but rather function as an integrated continuum to support individual creative abilities. Hence, we hypothesized that the anatomical proximity of the DMN and ECN within the rostral PFC could support their interaction, possibly through gradual functional connectivity changes within this region rather than discrete functional boundaries, with implications for the coordination of generative and combinatory processes involved in creativity.

To address this question, we explored creative cognition and its neural underpinnings in behavioural variant of frontotemporal dementia (bvFTD)⁸⁵, the third most common after Alzheimer's disease and dementia with Lewy bodies⁸⁶, and a highly relevant pathological model for several reasons. First, research on brain-lesioned patients offers unique insights into brain regions whose integrity is critical for creativity, which are not provided by purely correlational studies in healthy individuals.³⁸,⁸⁷⁻⁹⁰ Second, progressive neurodegenerative diseases, which cause widespread brain changes, may be more appropriate than focal brain lesions for studying gradual functional connectivity alterations.⁹¹,⁹² Finally, bvFTD is a unique model for studying creative cognition since the disease predominantly involves PFC atrophy ⁹³⁻⁹⁶ and intrinsic connectivity modifications in both the DMN and ECN ⁹⁷,⁹⁴,⁹⁸, key players in creativity.⁵⁴,⁸⁸,⁹⁰

The present study aimed to refine the characterization of rostral PFC involvement in creative cognition through the lens of patients with bvFTD. First, using whole-brain voxel-based morphometry (VBM), we aimed to extend previous results showing, in other pathologies, the critical roles of the rostromedial and rostrolateral PFC in the generation (FGAT) and combination (CAT) of remote semantic associates, respectively¹⁶, and to test the hypothesis of the joint critical contribution of these regions in overall individual creative abilities, as assessed by the referential Alternative Uses Task (AUT).⁹⁹,¹⁰⁰ Second, the current study aimed to understand the intrinsic functional connectivity of the rostral PFC and its implications in creative abilities. To test our hypothesis of graded functional connectivity changes between rostromedial and rostrolateral PFC related to creativity, we applied novel functional gradient mapping techniques¹⁰¹,¹⁰² to resting-state functional connectivity (RSFC) data within the rostral PFC, and investigated the main axis of functional variation in this brain region in healthy controls. We anticipated identifying a mediolateral principal connectivity gradient linking
medial and lateral poles of the rostral PFC. Third, we aimed to explore how gradient modifications, expected in bvFTD¹⁰³, related to brain atrophy and to creative abilities.

# Materials and methods

## Participants

Participants were recruited between September 2017 and December 2023 within the ECOCAPTURE protocol (clinicaltrials.gov: NCT03272230; INSERM, C16-87), focused on apathy in bvFTD patients.¹⁰⁴⁻¹¹⁰ Eligible participants were French-native speakers aged 40 to 85, with Mini-Mental State Examination (MMSE¹¹¹) scores above 17, and free from neurological, psychiatric or substance abuse disorder (except bvFTD, for patients).

Patients meeting probable bvFTD diagnosis criteria⁸⁵ were recruited prospectively from two tertiary referral centres at Salpêtrière and Fernand-Widal hospitals in Paris. Control participants were recruited through a public announcement and matched to patients for age, gender, and education (as measured by the Barbizet scale, ranging from 1, illiterate, to 7, university degree¹¹²).

Fifty-six participants were screened: 27 patients and 29 controls. Nine patients and one control were excluded from the current study because the trained neuropsychologists who administered the testing judged these participants unable to engage in the tasks due to significant semantic deficits and/or difficulties in understanding the instructions. Additionally, one healthy control was excluded due to a psychiatric condition. Thus, the final sample for the behavioural and VBM analyses included 45 participants: 18 bvFTD patients and 27 controls. From this sample, one patient did not complete the FGAT due to technical issues, and two other patients refused to perform the AUT, but all were still included in the analyses for the other creativity tasks. Additionally, three controls and three patients were excluded from the fMRI analysis due to excessive movement during the acquisition, resulting in a final sample of 39 participants (15 patients, 24 controls) for the fMRI analyses. All analyses relating brain structure or function to creative behaviour were performed on the whole dataset, combining patients and controls. Analyses characterizing the functional organisation of the rostral prefrontal cortex were restricted to healthy controls, to capture the intrinsic organization of this region as it appears in healthy brains, without confounds from disease-related alterations. The strategy for each set of analyses is summarized in Figure 1.
<figure><img src="image_2.png" /><figcaption>Figure 1. Overview of analysis plan.</figcaption></figure>

(A) Structural brain correlates of creative cognition: Whole-brain voxel-based morphometry (VBM) analyses were performed on the whole cohort (18 bvFTD patients + 27 healthy controls) to identify the brain regions critical for the generation (FGAT) and combination (CAT) of remote associations, and for individual creative abilities (AUT) thought to involve both generation and combination processes. We hypothesized that distinct rostral prefrontal regions would be critical for creative cognition. (B) Intrinsic functional organization of the rostral PFC in healthy controls: Gradient-mapping analyses of rs-fMRI data were performed in healthy controls (n = 24) to explore the rostral PFC's principal gradient, i.e., the principal axis of functional variations inside this region. This principal gradient analysis was replicated in two independent datasets of young healthy adults. (C) Gradient disruption in bvFTD and relation with creative cognition: Individual-level rostral PFC's principal gradients were extracted for all patients from rs-fMRI data (15 patients + 24 controls), and we explored how gradients' range, i.e., the functional segregation between both gradient ends, related to both brain atrophy and creative cognition.

AUT: Alternative Uses Task; CAT: Combination of Associates Task; FGAT: Free Generation of Associates Task; rs-fMRI: resting-state functional MRI; VBM: Voxel-Based Morphometry
All participants completed the entire ECOCAPTURE protocol with the same schedule, without deviations from the preregistered protocol. The current study focuses on creativity tasks, neuropsychological tests, and structural and functional MRI data. A sub-sample (14 patients and 20 controls) of the current study sample has been the focus of a detailed analysis of the FGAT cognitive components in a preceding study, not including CAT and AUT.¹² An approved ethics committee authorised the study, all participants provided written informed consent, and anonymity was preserved, in accordance with French regulations and the Declaration of Helsinki.

At inclusion, participants' current psychotropic treatments were recorded. In the bvFTD group (n = 18), 12 patients were receiving antidepressants, 4 benzodiazepines, and 2 antipsychotics, while no healthy control reported psychotropic medication use (Table 1). For antidepressant use, we also computed a continuous variable representing the equivalent fluoxetine dose for each participant, representing the antidepressant dose used regardless of the type of antidepressant medication.¹¹³

## Creativity tasks

To explore creative thinking, we used two tasks aiming to disentangle different aspects of associative thinking. The Free Generation of Associates Task (FGAT) aimed to assess the intentional generation of remote semantic associations¹⁶, an essential process of creative cognition¹³,⁵³,¹¹⁴,¹¹⁵,⁴,¹⁶, while the CAT aimed to assess the additional controlled processes that allow the goal-directed combination of multiple semantic associations in agreement with given constraints⁴,¹⁶,²⁷. Additionally, the AUT, a classical divergent thinking task, was used as a reference creativity task capturing individual creative abilities⁸³,¹¹⁶. For all tasks, cue-words were displayed on a computer tablet screen. Responses were spoken aloud by the participants and written down and timed by the trained neuropsychologists who administered the tasks. We chose this option rather than having participants type their answers to encourage them to focus entirely on the task without the additional cognitive load of writing answers.

### Free Generation of Associates Task (FGAT)

To explore the generation of remote semantic associates⁵,¹³,¹⁶,⁵³, we used the FGAT, a simple word-association task previously validated in patients¹⁶ and controls.⁵⁰,¹¹⁷,¹¹⁸
## Task description and scoring

The FGAT aims to distinguish intentionally remote semantic associations from spontaneous semantic associations. The uncommonness or remoteness of responses in word-to-word generation tasks has been shown to correlate with creative performances.<sup>13,16,119</sup>

The FGAT is composed of two conditions. The ‘FGAT-first’ condition is not per se a creativity task, but aims at exploring spontaneous associative thinking, a component of creativity.<sup>4</sup> In this condition, participants were asked to provide the first word coming to mind in response to a cue-word (e.g., "father" in response to "mother"), within a 10-second time limit. In the 'FGAT-Distant' condition, participants were asked to intentionally generate a word associated with the cue-word in an original, unusual way (e.g., "nature" in response to "mother"), within a 20-second time limit. This condition explores intentional remote associative thinking, thought to involve both spontaneous associative and controlled processes<sup>5</sup>. In this study, we only focused on the creative ‘FGAT-Distant’ condition.

For each participant, we counted the number of unique responses, i.e. responses that were absent from the reference French free associative norms<sup>120</sup> for the corresponding cue-word, and computed the *FGAT efficiency* score as the ratio of the number of unique answers to the cumulative response time across all 58 trials in the ‘FGAT-Distant’ condition. This composite score integrates both the number of unique FGAT responses and the task completion speed, reflecting the proportion of unique responses by time unit (in minutes). As such, it captures how efficiently individuals resolve speed-accuracy trade-offs, i.e., how participants balance the pursuit of originality in their responses with the time devoted to the task, and thus reflects individual *FGAT efficiency*.<sup>121,122</sup> It aligns with Mednick’s associative theory of creativity, postulating that creative individuals tend to access remote associations more efficiently, i.e., more rapidly.

A detailed description of the verbal material, experimental set-up, data cleaning and variables computation is provided in Bendetowicz et al., 2018<sup>16</sup> and in Supplementary Method 1.

## Combination of Associates Task (CAT)

High-level control processes involved in the capacity to efficiently combine several semantic associations to find a novel solution were explored using the CAT, in which participants are asked to find a word that connects three unrelated cue-words. This task, originally adapted by our team<sup>16,21,27,123</sup> from Mednick’s Remote Associates Task<sup>4</sup>, is thought to engage both remote associative thinking<sup>4</sup> and additional complex processes such as integration and multitasking,
which are required to form and manipulate new combinations of word associations¹⁶,²⁷,¹²⁴ to
arrive at a solution.

## Task description and scoring

In this task, participants were asked to find a word semantically related to each of three given cue-words (e.g., Bridge-Social-To tie, where the solution is Link) within a 30-second time limit. Forty trials were presented. Acceptable answers were defined a priori for each trial.

Individual *CAT efficiency* was computed as the ratio of the number of correct answers to the cumulative response time across all 40 trials in the task, reflecting the proportion of correct responses by time unit (in minutes), and thus speed-accuracy trade-off.¹²¹,¹²²

A description of the verbal material, experimental set-up, data cleaning, and variables computation is provided in Bendetowicz et al., 2018¹⁶ and in Supplementary Method 2.

## Alternative Uses Task (AUT)

Participants also completed the Alternative Uses Task (AUT), a classical task⁸,⁹⁹,¹⁰⁰,¹¹⁶ in creativity research and a reliable indicator of creative ability and real-life creative achievements.¹²⁵⁻¹²⁷

### Task description and scoring

In the AUT, participants were asked to generate five alternative, original uses for three common every-day life objects ("bottle", "knife", "tyre"). After providing participants with state-of-the-art instructions (https://osf.io/4s9p6/) and an example, the names of three objects were presented one at a time to the participants on a tablet screen. Participants were explicitly asked to generate five alternative uses for each item, within a 5-minute time limit. The decision to request five responses from participants, instead of the traditional instruction to provide the maximum number of responses¹²⁸ was intended to mitigate the potential impact on fluency of apathy symptoms expected in patients with bvFTD.

Following reference scoring methods¹²⁹, a creativity rating was computed for each AUT response as the average of ratings given to this response on a 1-to-5 Likert scale by four independent creativity experts (E.V., A.LP., M.OT. and T.B), blinded to participant status. For each participant, a creativity score was calculated as the sum of the highest creativity rating for each AUT object, and *AUT efficiency* was then computed as the ratio of the creativity score to the cumulative response time across the three AUT prompts, reflecting the proportion of creative responses by time unit (in minutes), and thus individual *AUT efficiency*.
Detailed information about the experimental procedure, data cleaning and variables computation are provided in Supplementary Method 3.

## Neuropsychological testing

Participant's general and executive cognitive functioning were assessed using the MMSE¹¹¹ and Frontal Assessment Battery (FAB¹³⁰), respectively. We also calculated an individual semantic score by summing the scores from the short French versions of a naming test and a semantic matching test commonly used in routine clinical practice¹³¹. This semantic score was covaried out in the brain imaging analyses to control for the effect of potential semantic deficits on creativity tasks.

As part of the ECOCAPTURE protocol, apathetic and mood disturbance symptoms were systematically assessed. Apathy was measured using the Starkstein Apathy Scale (SAS¹³²) and the Dimensional Apathy Scale (DAS¹³³), which explores distinct Executive, Emotional and Initiation dimensions of apathy. Mood was assessed using the Hospital Anxiety and Depression Scale (HADS¹³⁴,¹³⁵), which provides separate anxiety and depression scores. These behavioural measures were then correlated with creativity tasks performance to explore potential associations.

## Neuroimaging analyses

### MRI acquisition

MRI acquisitions were performed on a 3T Siemens PRISMA MRI scanner with a 64-channel total imaging matrix system. High-resolution T1-weighted structural images were acquired (TR = 2400ms, TE = 2.17ms, flip angle 8°, TI = 1000, acquisition matrix = 320x320, FoV = 224mm, slice thickness 0.7mm, iso-voxel). Subsequently, RSFC data were acquired based on a BOLD-sensitive T2*-weighted echo-planar image pulse sequence (TR = 2050ms, TE = 25ms, flip angle 80°, matrix = 68 × 68, FoV = 204mm, slice thickness 3.0mm, spacing between slices 3.15mm). Oblique axial brain slices were acquired at 290 time-points for the ten first participants (six patients, four controls) and 436 time-points for the later participants due to a protocol amendment. For data homogeneity purposes, only the 290 first time-points were analysed for all participants. Participants were asked to lie down with closed eyes without falling asleep during the resting-state acquisition.
## Voxel-based morphometry analysis

We used whole-brain VBM to explore, without a priori, the brain regions critical for efficiency in each creativity task under study by examining their relationship with grey matter volume (GMV) in patients and controls combined (n = 45, 18 patients and 27 controls).

## VBM preprocessing

T1-weighted images were preprocessed using the CAT12 toolbox (www.neuro.uni-jena.de/cat/) implemented in SPM12 (www.fil.ion.ucl.ac.uk/spm), running on Matlab R2020b (Mathworks, USA). T1-weighted images were normalised and segmented to extract grey matter probability maps using default settings, involving Geodesic Shooting.<sup>136</sup> Grey matter segmentations were affine transformed into the Montreal Neurological Institute (MNI) 152 space with 1,5mm isotropic voxels. Resulting grey matter normalised images were modulated to allow tissue volume comparison and smoothed using an 8mm full-width at half maximum Gaussian kernel. At each stage, all segmentations were reviewed visually, and VBM data homogeneity was checked using CAT12.

## VBM statistical analyses

For all VBM analyses, we used an explicit grey matter mask computed on the entire sample using the SPM Masking Toolbox<sup>137</sup>, as recommended when analysing atrophied brains to prevent excluding voxels of greatest atrophy. We conducted 5000 permutations-based non-parametric VBM analyses<sup>138,139</sup> using SPM12 and the TFCE toolbox with default settings (github.com/ChristianGaser/tfce). For all analyses, age, gender, education and the semantic score were covaried out with centring on overall mean, and individual differences in total intracranial volume were accounted for by global scaling to the sample mean.

Voxel-wise whole-brain group differences in GMV were assessed using a one-tailed two-sample t-test. We used voxel-wise whole-brain multiple linear regressions to explore regions in which GMV showed a significant relationship with *CAT*, *FGAT* and *AUT efficiency*, using separate models for each task. Regressions were performed on the whole dataset, combining patients and controls (n = 45, 18 patients and 27 controls). Results are reported at a Family-Wise Error (FWE) corrected *P*<sub>FWE</sub> < 0.05 statistical threshold applied at the voxel level. To rule out the possibility that significant findings are mostly driven by group differences and do not represent a generalizable brain-behaviour relationship, each model was also explored after adding participants' clinical status (bvFTD or controls) as a covariate, with a more lenient uncorrected *P*<sub>uncorrected</sub> < 0.001 statistical threshold applied at the voxel level. For all results,
non-stationary smoothness correction was applied.<sup>140</sup> Significant brain regions were labelled using the AAL3 toolbox.<sup>141</sup>

## Resting state functional connectivity gradient analysis

We used voxel-to-voxel RSFC to explore the rostral PFC's principal connectivity gradient, i.e., the principal axis of functional variation in this brain region, and to describe its functional characteristics, in healthy individuals (n = 24). The rostral PFC was defined as Brodmann area (BA) 10<sup>142</sup>, extracted from the Brodmann atlas from MRIcro (https://www.nitrc.org/projects/mricro/). We then correlated principal gradient characteristics (range; see below) with creative behaviour across patients and controls with RSFC data (n = 39, 15 patients and 24 controls).

## Preprocessing

RSFC data were preprocessed with the default fMRIprep 22.0.2 pipeline<sup>143</sup>. Each healthy control's denoised T1-weighted brain MRI underwent preprocessing steps including intensity non-uniformity correction, skull stripping, segmentation into grey matter, white matter, and cerebrospinal fluid, and spatial normalization to the MNI-152 standard space. Subsequently, BOLD images underwent motion correction, slice-timing correction, co-registration to the normalised T1-weighted image, resampling to the MNI-152 standard space, and confounds computation. For more details, see Supplementary Method 4 or https://fmriprep.readthedocs.io/en/latest/workflows.html.

## First level analyses

Using Nilearn 0.9.2 (nilearn.github.io) running on Python 3.10.4 (www.python.org), BOLD time-series were spatially smoothed using a Gaussian kernel of 8mm full-width at half maximum, z-scored, detrended, and band-pass filtered (transmission range 0.01–0.1 Hz). The first four volumes of each BOLD run were discarded to ensure signal intensity stabilisation. Confounds regression included six head-motion (x, y, z, pitch, yaw, and roll) and three global signals (white matter, cerebrospinal fluid, global signal) parameters, their temporal derivatives, and quadratic terms of each parameter and temporal derivative (36 confounds).<sup>144</sup> Additionally, volumes exceeding motion artifacts thresholds (standardised DVARS (D: temporal derivative of time-courses, VARS: root mean square variance over voxels) above 1.5 or framewise displacement above 0.5 mm) were discarded<sup>145,146</sup> and participants with more than 20% discarded volumes were excluded, resulting in the exclusion of three patients and three controls.
## Principal gradient extraction

For each of the remaining participants (15 patients, 24 controls), we computed the voxel-to-voxel connectivity matrix for all voxels inside the rostral PFC, and a Fisher's z-transform was applied to improve normality of the correlation matrices. Using the BrainSpace Python toolbox¹⁴⁷, z-transformed correlation matrices were sparsified by retaining only the top 10% of values row-wise to ensure that the results are based on strong rather than weak and potentially spurious connections.

In the 24 healthy controls, we then computed a group-averaged symmetric cosine similarity matrix from which we extracted the top ten group-level connectivity gradients within the rostral PFC using a diffusion embedding approach.¹⁴⁸ Although this study only focused on the principal gradient, i.e., the gradient explaining most functional connectivity variance within the rostral PFC, extracting ten gradients is a common practice to maximize the degree of fit between individual-level and group-level gradients.¹⁴⁹⁻¹⁵¹. Group-averaged gradients computed in healthy participants then act as templates to which individual gradients extracted in all participants can be compared, allowing an investigation of individual differences. Following the same procedure with identical parameters, the top ten individual-level gradients were then extracted for each participant. These individual-level gradients were aligned to the reference group-level gradients computed in healthy controls using Procrustes rotation, to improve comparison between group-level and individual-level gradients.

## Principal gradient replication

To investigate the external validity of the characterized rostral PFC principal gradient, we ran the same gradient analysis in two independent datasets of 93 (43 women, mean age = 25.6 years, standard deviation = 3.8)¹⁵² and 36 (18 women, mean age = 26.6 years, standard deviation = 4.1)⁵⁰ young healthy subjects, respectively. Preprocessing and first-level analyses of the RSFC data of these datasets are described in the corresponding publications.

## Principal gradient functional characterization

We quantified the *algebraic connectivity* of the group-level rostral PFC principal gradient.¹⁵³ This value represents the degree of gradation in functional connectivity changes across the rostral PFC, ranging from 0, indicating hard, discrete, boundaries between disconnected subregions within the gradient, to a value of 1, indicating graded transitions between connected subregions.¹⁵⁴
As gradient analysis only provides topographical information on the rostral PFC principal gradient, we also characterized the different functional connectivity profiles of the two extremes of the principal gradient with the rest of the brain, in healthy participants (n = 24). As proposed in previous parcellation studies<sup>102,155,156</sup>, we performed seed-based RSFC analyses on clusters extracted from the extreme thirds of the identified principal gradient, i.e., on the clusters containing the 33.33% lowest and highest principal gradient values. For each of the two extreme third seeds, we computed the z-transformed seed-to-voxel correlation map between averaged fMRI time-courses within the seed and time-courses from each brain voxel. Fisher's z-transform was applied to seed-to-voxel correlation maps to improve the normality of the data. For each seed, we then conducted 5000 permutations-based non-parametric paired two-samples t-tests in healthy controls to explore the brain regions with greater functional connectivity to one extreme third of the gradient compared to the opposite third, and vice versa. Results are reported at a FWE corrected *P*<sub>FWE</sub> < 0.05 statistical threshold at the voxel level. A cluster extent threshold of 10 contiguous voxels was applied, along with non-stationary smoothness correction.<sup>140</sup> As recommended<sup>157</sup>, Yeo and colleagues' 7-networks resting-state parcellations of the cortex, cerebellum, and striatum<sup>158-160</sup> were used to determine which global-scale intrinsic functional network our findings were affiliated with.

**Principal gradient relationship with creative behaviour**

Finally, we explored the relationship between principal gradient characteristics and creative behaviour across patients and controls (n = 39, 15 patients and 24 controls). At the participant level, we quantified the *range* of the rostral PFC principal gradient, i.e. the difference in gradient values between the positive and negative extreme ends of the gradient, which represents the functional distance between the two ends of the gradients, with higher values indicating greater functional segregation.<sup>161,162</sup> Based on previous work<sup>163</sup>, we expected the gradient *range* to be lowered in bvFTD patients, as a result of a decrease in functional differentiation between cortical areas and higher focal connectivity. Thus, we tested whether gradient *range* was impaired in bvFTD patients using a one-sided Mann-Whitney U test, and whether grey matter atrophy within the rostral PFC predicted rostral PFC principal gradient *range*. To explore the functional significance of the gradient *range*, we also explored how it related to creativity tasks efficiency (CAT, FGAT and AUT).

**Control Analyses in additional Brodmann areas**
To assess the specificity of the rostral PFC (BA 10) gradient analysis, we ran the same gradient analysis in other BAs involving both the DMN and ECN, i.e., BAs in which both the DMN and ECN overlapped with at least 10% of the BA's volume.

## Statistical analyses

All statistical analyses on clinical and neuropsychological data were conducted using RStudio 1.4.1106.¹⁶⁴ Significance was determined by an alpha level of 0.05.

Between-group differences were tested using non-parametric Mann-Whitney U tests, or $\chi^2$ tests for nominal variables. U statistics are reported with standard deviations (SD).

Two-sided Spearman's rank partial correlations were performed to assess the relationships between creativity tasks performance (FGAT, CAT, AUT) and behavioural and affective symptoms (SAS, DAS, HADS) or equivalent fluoxetine dose, while accounting for the effects of age, gender, education and semantic score by partialling out their influence on the variables of interest. Correlations between tasks performance and equivalent fluoxetine dose were performed only in the bvFTD group given the absence of medication in the healthy control group. We used False Discovery Rate (FDR) correction for multiple comparisons.

Multiple linear regression analyses were conducted using the Enter method and age, gender, education, semantic score and total intracranial volume as covariates. We report unstandardized beta ($\beta$) estimates with their standard errors (SE) and t statistics for the number of residual degrees of freedom ($t(df)$), and provide standardized $\beta$ coefficients as indicators of effect size for significant analyses. Partial regression plots were generated for each multiple linear regression to visualize the relationship between rostral PFC principal gradient range and creativity measures or GMV after controlling for covariates (age, gender, education, semantic score and total intracranial volume). Patients and controls were color-coded to illustrate group distributions.

## Data Availability

We report all methods in the main manuscript or Supplementary Material. Data and analysis codes are openly available at https://osf.io/rtnzw/overview?view_only=f6c54494c28349b083f4ee0bded9562, except for structural and RSFC brain imaging scans that are not provided due to ethical protocol constraints related to the bvFTD clinical population.
# Results

## Behavioural results

Forty-five participants, 18 bvFTD patients and 27 healthy controls, were included in the behavioural analyses. Patients and controls did not differ in age, gender or education (Table 1). As expected in bvFTD, patients showed lower scores than controls in general cognitive (MMSE), executive efficiency (FAB), and semantic score.

Patients with bvFTD also showed more apathetic (SAS, DAS), anxiety (HADS-Anxiety) and depression (HADS-Depression) symptoms, and were the only group using psychotropic medications.

We also showed that patients with bvFTD were impaired in all evaluated aspects of creativity (Table 1, Figure 2). Indeed, patients performed worse than controls in both the efficient combination of several semantic associations (CAT) and the intentional generation of remote semantic associates (FGAT), as well as in our reference task reflecting creative abilities (AUT).

<figure><img src="image_3.png" /><figcaption>**Figure 2. Group comparisons of efficiency scores across creativity tasks**</figcaption></figure>

The figure shows the distribution and group comparisons for participants' efficiency in the Free Generation of Associates Task (FGAT), Combination of Associates Task (CAT) and Alternative Uses Task (AUT) between patients with behavioural variant frontotemporal dementia (bvFTD, in red) and healthy controls (in green)

*** = *P* < 0.001

Behavioural and affective symptoms were not significantly associated with creative task performance. Specifically, neither apathy scores (SAS, DAS total, or DAS subscales) nor mood
disturbance (HADS) correlated with FGAT, CAT, or AUT performance. The negative correlation observed between HADS total and anxiety scores and *AUT efficiency* did not survive FDR correction for multiple testing. All correlation results are reported in Supplementary Table 1.

In addition, in patients with bvFTD, no significant association was found between equivalent fluoxetine dose and FGAT (ρ = -0.03; *P* = 0.936), CAT (ρ = 0.38; *P* = 0.182) or AUT (ρ = -0.09; *P* = 0.782) performance. The number of patients under other medications (benzodiazepines, n = 4; antipsychotics, n = 2) was too small to allow for reliable correlation statistics.

# Voxel-based morphometry analyses

## Pattern of atrophy in patients

Group comparisons of GMV showed a pattern of fronto-temporo-parietal atrophy in patients, characteristic of bvFTD (Figure 3, Supplementary Table 2). Atrophy affected mainly the bilateral dorsolateral PFC (dlPFC), orbitofrontal (OFC), cingulate, and insular cortices.

## Neural correlates of creativity tasks efficiency

We used whole-brain voxel-wise analyses across patients and controls (n = 45, 18 patients and 27 controls) to explore whether regional brain atrophy patterns (GMV) was related to creativity tasks' efficiency (Figure 3, Supplementary Table 3). Individual *FGAT efficiency* correlated
<figure><img src="image_4.png" /><figcaption>Figure 3. Voxel-based morphometry results</figcaption></figure>

The top row shows the atrophy pattern in bvFTD patients compared to controls. Significant clusters from the whole-brain VBM group comparison are colour-coded to show voxels where GMV is lower in bvFTD patients than in controls. The significance threshold was set at *P*<sub>FWE</sub> < 0.05 at the voxel level, with a spatial cluster extent threshold of 100 contiguous voxels.

Rows two to four show the structural brain correlates of each creativity task's efficiency. Significant clusters for whole-brain non-parametric VBM regressions of GMV on creativity scores in the entire population (n = 45, 18 patients and 27 controls) are colour-coded for each creativity task (FGAT: blue, CAT: red, and AUT: green). Age, gender, education and semantic score were used as covariates. The significance threshold was set at *P*<sub>FWE</sub> < 0.05 at the voxel level, with a spatial cluster extent threshold of 100 contiguous voxels.

The bottom row displays the overlap of each task's brain correlates (using the same colour code as above) with the rostral PFC (Brodmann area 10, in yellow).
positively with GMV in the left rostromedial PFC and in the right insula and ventrolateral PFC (vlPFC). Individual *CAT efficiency* correlated with GMV in the bilateral rostrolateral PFC, the right vlPFC/insula, medial occipitotemporal cortex and inferior pre- and postcentral cortex, as well as in the left temporoparietal junction. Finally, we found a positive correlation between *AUT efficiency* and GMV in both the bilateral rostrolateral PFC and the left rostromedial PFC, but also in the bilateral orbitofrontal cortex (OFC), dorsomedial PFC (dmPFC) and insula, the right vlPFC and dlPFC, and in the left precentral PFC.

To ensure that these results were not driven by group differences and represent generalizable
brain-behaviour relationships, we ran the same analyses after covarying out participants’
clinical status (bvFTD or controls). These control analyses showed similar results to the initial
analyses, with lower statistical power (Supplementary Figure 1, Supplementary Table 4).
Nonetheless, all clusters identified in the initial analyses were also observed in the control
analyses, except for the right vlPFC cluster related to *CAT efficiency*.

Functional connectivity gradients analyses

Principal gradient of the rostral PFC

The principal functional gradient of the rostral PFC, i.e., the first of the top ten gradients explaining functional variation within the rostral PFC, computed at the group level in the 24 healthy controls, accounted for 45% of variance (Supplementary Figure 2).

We plotted principal gradient values on the brain to explore the topographical pattern of
functional variation across the rostral PFC (Figure 4). We showed that the rostral PFC principal
gradient is organized along a mediolateral axis, with the rostromedial PFC on one end of the
gradient, and the bilateral rostrolateral PFC on the other end.

Rostral PFC principal gradient external validity

We ran the same gradient analysis in two independent datasets of 93¹⁵² and 36 young healthy subjects⁵⁰. The results (Supplementary Figure 3) successfully replicated the group-level mediolateral principal functional gradient of the rostral PFC shown in Figure 4.
<figure><img src="image_5.png" /><figcaption>Figure 4. Group-level rostral PFC principal RSFC gradient in healthy subjects</figcaption></figure>

Regions depicted with colours that are closer together on the colour spectrum exhibit greater similarity in their correlation over time during resting-state fMRI compared to regions depicted with colours further apart on the spectrum. The +/- signs represent the two opposite poles of the principal gradient, but the assignment of a particular end to either pole is arbitrary.

Principal gradient functional characterization

In the reference healthy controls group (n = 24), the *algebraic connectivity* of the group-level rostral PFC principal gradient was 0.77, indicating a highly progressive functional gradation from the rostromedial PFC to the rostrolateral PFC.

Finally, to characterize the functional implications of the mediolateral gradient in the normal brain, we explored which cerebral regions were preferentially connected to each end of the rostral PFC principal gradient (Figure 5, Supplementary Table 5) by contrasting their seed-based connectivity patterns in healthy controls (n = 24). The rostromedial third of the gradient was preferentially connected to the bilateral vmPFC, OFC, precuneus, anterior and posterior cingulate cortex, and medial and anterolateral temporal cortex. These regions mainly overlapped with the DMN (55%), and to a lesser extent the limbic network (18%). On the other hand, the rostrolateral third of the gradient was preferentially connected to the bilateral dlPFC and cerebellum (Crus I and lobule VI), the left vlPFC and the left PPC. These regions fall mainly within the ECN (52%), and to a lesser extent the SN-VAN (29%).
<figure><img src="image_6.png" /><figcaption>Figure 5. Seed-based intrinsic connectivity networks of each end of the group-level rostral PFC principal gradient extracted in healthy subjects</figcaption></figure>

We compared the resting-state functional connectivity with the rest of the brain of the two ends of the rostral PFC principal gradient (regions corresponding to the lower and higher thirds of the gradient values) using whole-brain non-parametric paired two-sample t-tests, in healthy controls (n = 24). The top panel shows significant clusters that are significantly more functionally connected to the rostromedial than the rostrolateral PFC. The bottom panel displays the reverse comparison. Statistical analyses were thresholded for significance at *P*<sub>FWE-corrected</sub> < 0.05 at the voxel level, with an additional spatial cluster extent threshold of 10 contiguous voxels. Lower and higher thirds of the gradient value in rostral PFC that were used as seeds are represented in black. The proportions of overlap of the resulting functional networks with Yeo's 7 intrinsic functional networks<sup>158-160</sup> are reported on radar plots for each extreme third.

DAN: Dorsal Attention Network; DMN: Default Mode Network; ECN: Executive Control Network; SMN: SomatoMotor Network; SN-VAN: Salience Network – Ventral Attention Network.

Relationship between principal functional gradient and bvFTD pathology

In all patients and controls, we computed individual-level rostral PFC gradients aligned to the
reference group-level gradients (see methods). We then explored the *range* of individual-level
principal gradients. We confirmed our hypothesis of a decreased (U = 120.00; P = 0.043)
principal gradient *range* in bvFTD patients (mean = 16.80; SD = 5.56) as compared to controls
(mean = 20.02; SD = 5.31), indicating reduced differentiation in the connectivity patterns of
both ends of the mediolateral gradient.

To better characterize the impact of bvFTD on the rostral PFC principal gradient, we explored
whether GMV could account for decreases in gradient *range* across patients and controls (n =
39, 15 patients and 24 controls). We found that whole-brain GMV positively related to gradient
*range* variations (β = 0.049, *SE* = 0.020, *t*(32) = 2.41, *P* = 0.022, standardized β = 0.50), and
GMV in BA10 showed a similar positive association with gradient *range* ($\beta$ = 1.26, *SE* = 0.59, *t*(32) = 2.12, *P* = 0.041, standardized $\beta$ = 0.40). Partial regression plots are provided in Supplementary Figure 4.

## Relationship between principal functional gradient and creativity tasks

To better understand the implications of gradient *range* modifications on different aspects of creativity, we tested whether the rostral PFC principal gradient *range* contributed to creative efficiency in the CAT, FGAT, and AUT using linear regressions combining patients and controls (*n* = 39, 15 patients and 24 controls). While gradient *range* variations did not statistically explain variations in generating (*FGAT efficiency*; $\beta$ = 0.038, *SE* = 0.035, *t*(32) = 1.07, *P* = 0.291) or combining (*CAT efficiency*; $\beta$ = 0.021, *SE* = 0.049, *t*(32) = 0.43, *P* = 0.672) remote semantic associations, they did contribute to individual creative abilities as assessed by the *AUT efficiency* ($\beta$ = 0.065, *SE* = 0.025, *t*(30) = 2.62, *P* = 0.014, standardized $\beta$ = 0.41). Partial regression plots for each task are provided in Supplementary Figure 5.

## Control Analyses in additional Brodmann areas

To test the specificity of gradient mapping findings in the rostral PFC (BA 10), we ran the same gradient analysis in BAs 8, 9, 11, 20, 23, 26, 44, 45 and 47, where the DMN and ECN co-exist (each network representing over 10% of the BA's volume, Supplementary Table 6). Results showed that only BAs 8, 9 and 20 displayed a principal RSFC gradient segregating the DMN and ECN (Supplementary Figure 6) However, for these three Brodmann areas, no significant association was found between the *range* of the principal gradient and *FGAT efficiency* (BA 8: $\beta$ = 0.012, *SE* = 0.048, *t*(32) = 0.26, *P* = 0.798; BA 9: $\beta$ = 0.003, *SE* = 0.052, *t*(32) = 0.056, *P* = 0.955; BA 20: $\beta$ = 0.071, *SE* = 0.058, *t*(32) = 1.22, *P* = 0.233), *CAT efficiency* (BA 8: $\beta$ = -0.006, *SE* = 0.065, *t*(32) = -0.087, *P* = 0.931; BA 9: $\beta$ = 0.010, *SE* = 0.071, *t*(32) = 0.14, *P* = 0.890; BA 20: $\beta$ = -0.027, *SE* = 0.081, *t*(32) = -0.33, *P* = 0.744) or *AUT efficiency* (BA 8: $\beta$ = 0.052, *SE* = 0.032, *t*(32) = 1.59, *P* = 0.122; BA 9: $\beta$ = 0.070, *SE* = 0.037, *t*(32) = 1.88, *P* = 0.070; BA 20: $\beta$ = 0.009, *SE* = 0.042, *t*(32) = 0.22, *P* = 0.831). Partial regression plots are provided in Supplementary Figure 7.

## Discussion

This study provides new insights into creative cognition, how it relates to prefrontal cortex organization, and how it is affected in bvFTD. It reveals the distinct critical roles of the
rostromedial and rostrolateral PFC in the generation and combination of remote semantic associates, respectively, but also their joint involvement in individual creative abilities. Furthermore, this study takes advantage of the recent functional connectivity gradient mapping methods to better characterize the poorly understood role of the rostral PFC in human cognition. This approach allowed us to unveil the importance for creative abilities of the graded functional segregation between rostromedial and rostrolateral PFC, respectively connected to the DMN and ECN.

## Critical role of the rostromedial prefrontal cortex in generating remote semantic associations

Using whole-brain VBM, we found a critical role of rostromedial PFC integrity in the intentional generation of remote semantic associations (*FGAT efficiency*), which was impaired in patients with bvFTD. The involvement of the rostromedial PFC in the generation of creative semantic associations has been previously shown in healthy subjects²⁶,⁴²,⁵³,¹⁶⁵, but also in patients. Indeed, our results replicate, in a different pathological population, previous findings obtained with the same FGAT task in patients with focal frontal lesions.¹⁶ The rostromedial PFC is hypothesized to relate to memory retrieval processes involved in self-driven creative idea generation, and is a critical region for remote thinking.¹² This cortical region is a key node of the core DMN³³,¹⁶⁶, whose central role in the self-generation of mental contents³³,¹⁶⁷,¹⁶⁸ and in creativity.¹⁶,³⁰,³¹,¹⁶⁹,¹⁷⁰ has been well established. The rostromedial PFC appears essential for processing semantic and episodic memory information¹⁷¹⁻¹⁷³ that are instrumental to creative thinking.³,⁵,¹⁷⁴ *FGAT efficiency* also relied on the integrity of the right vlPFC and insula, regions that were also found to be critical for *CAT efficiency* and *AUT efficiency*. These cortical regions, classically related to inhibition processes¹⁷⁵, may be involved in the suppression of inadequate candidate ideas, a key aspect of creative cognition.¹²,⁴⁸,¹⁷⁶⁻¹⁸⁰

## Critical role of the rostrolateral prefrontal cortex in combining remote semantic associations

The capacity to combine semantic associates to solve a creative problem (*CAT efficiency*) was also impaired in patients with bvFTD. Here also, VBM results in bvFTD patients replicated previous findings observed in healthy controls or in other pathological conditions using the CAT, demonstrating the critical role of the rostrolateral PFC for this task.¹⁶,²⁷,⁷⁹. In addition to associative processes⁴,⁸,¹⁸¹ which are also assumed to be involved in the FGAT, the CAT is
hypothesized to involve high-level control processes such as relational integration and combination<sup>16,22,26-28</sup>, constrained strategic memory search<sup>3,19</sup>, or implementing, monitoring and coordinating multiple subtasks.<sup>16</sup> Hence, our results are consistent with the established role of the rostrolateral PFC in processing relational information between words<sup>23,24,26,42,53,123,182</sup>, multitasking<sup>59,69,183</sup> or branching.<sup>60,184</sup> As part of the ECN<sup>158</sup>, the rostrolateral PFC is indeed central to several controlled processes supporting the combination and relational integration of multiple semantic elements, a key aspect of creative cognition.<sup>16</sup> Interestingly the CAT also related to the GMV in regions of the visual (right medial occipitotemporal cortex) and somatomotor (right inferior frontoparietal cortex and left temporoparietal junction) networks, whose role in creativity has been highlighted recently.<sup>21,185</sup>

Overall, our current results replicate in another pathological model the results from Bendetowicz and colleagues' study<sup>16</sup> showing the critical role of the rostromedial and rostrolateral PFC for generative and combinatory processes of creative cognition, respectively.

**Critical role of both the rostromedial and rostrolateral prefrontal cortices in individual creative abilities**

After extending the results from Bendetowicz et al.<sup>16</sup> to another pathology, we explored how these regions are critical for creative potential, as assessed with the AUT. VBM results for *AUT efficiency* confirmed the critical roles of the rostromedial and rostrolateral PFC for creative abilities. This finding aligns with prior fMRI literature<sup>42</sup> but crucially adds the first direct evidence that creative abilities depend on the integrity of both regions. These results support the conceptual framework of creativity as relying on the complementary interaction between associative and executive processes.<sup>5,8</sup> In this view, the rostromedial PFC, located at the core of the DMN, is likely to play a central role in the associative processes involved in the generation of novel, uncommon, semantic associations that allow original ideas to emerge, while the rostrolateral PFC, connected to the ECN, appears central for controlled processes required to efficiently combine and integrate multiple associative elements in a way that satisfies the goal and constraints of a given situation. Hence, our results position the rostral PFC as a critical hub in the interplay between the DMN and ECN, which respectively support the associative and controlled components of creative cognition. Yet, our results are at odds with a recent work suggesting that lesions to the right rostral PFC or its connected regions may enhance creativity.<sup>186</sup> First, aligned with our results, this study identified the right frontal pole as a key region for creativity based on seed-based connectivity from meta-analytic activation
peaks across 36 fMRI studies in healthy participants. However, by comparing this network to
brain damage patterns in various diseases through large-scale meta-analysis, the authors
suggested that focal or neurodegenerative lesions affecting the frontal pole or a network
positively connected to it enhance creativity. Despite the elegant and large-scale nature of these
analyses, their conclusions rest on assumptions that remain debated and untested: first, that
focal frontal pole lesions promote creativity, an inference not statistically supported by the cited
work<sup>187</sup>; and second, that creativity increases in bvFTD, a notion based on isolated case reports
but contradicted by findings from controlled patient studies.<sup>54,188,189,90</sup> Moreover, this study
did not statistically test the relationship between individual lesion location and creative
performance, limiting causal interpretation. In contrast, the current study demonstrates
creativity impairment in bvFTD, and provides direct empirical evidence linking rostral PFC
integrity with creative abilities. In addition, we demonstrated through functional connectivity
analyses that the rostral PFC's connectivity organization underpins its role at the DMN-ECN
interface, is disrupted in patients with bvFTD, and predicts creative abilities, as discussed
below.

Mediolateral graded functional organization of the rostral prefrontal cortex segregates the default mode and executive control networks

We used RSFC gradient mapping techniques to characterize the functional connectivity profile
within the rostral PFC and explore whether medial and lateral PFC are segregated by abrupt
boundaries or graded transitions. This approach allowed us to characterize the principal
connectivity gradient within the rostral PFC, explaining 45% of the rostral PFC's functional
variation in healthy individuals. The rostral PFC's principal gradient, which was replicated in
two independent datasets, was organized along a mediolateral axis, with the rostromedial and
rostrolateral PFC at each end of the gradient. Hence, the main variation in the functional
connectivity profile within the rostral PFC, spanning from the rostromedial to the rostrolateral
PFC, echoes our VBM findings, which highlight distinct cognitive roles for these regions. We
further showed that the functional segregation between the rostromedial and rostrolateral PFC
along this gradient is characterized by a high level of progressive gradation rather than a sharp
delimitation between subregions. These results extend previous literature on the rostral PFC
organization by using, for the first time, the potential of functional gradient mapping to reveal
a finer-grained characterization of its functional connectivity variation.<sup>190</sup> Indeed, while our
results are supported by previous connectivity studies showing structural and functional differentiation along a mediolateral axis<sup>73-76</sup>, these past studies used hard parcellation techniques that resulted in various and debated numbers of parcels inside the rostral PFC.<sup>73</sup> By using a data-driven exploration of functional variation without a priori, we were able to show that the principal functional organization of the rostral PFC does not follow a hard parcellation but rather a highly graded pattern of functional variation along the mediolateral axis.

We then characterized the respective whole-brain intrinsic connectivity networks of the medial and lateral ends of the rostral PFC principal gradient. We showed that the rostromedial third of the gradient mostly connected with regions of the DMN and, to a lesser extent, of the limbic network, itself highly connected with the DMN<sup>191</sup>. Conversely, the rostrolateral third of the gradient mostly connected with regions of the ECN and, to a lesser extent, of the salience network. These results confirm that the rostromedial and rostrolateral PFC are rooted in the DMN and ECN, respectively<sup>73,75,158</sup>, as previously proposed.<sup>73,75</sup> Furthermore, these findings align with our VBM results, which link generative aspects of remote thinking, related to the DMN, to the rostromedial PFC, and controlled combinatory aspects, related to the ECN<sup>5,7,8,30</sup>, to the rostrolateral PFC.

Overall, this graded connectivity between the rostromedial and rostrolateral PFC, and thus between the DMN and ECN, has theoretical implications for the understanding of the cerebral bases of creativity. Indeed, the graded mediolateral functional connectivity of the rostral PFC places this region in a position to act as a DMN-ECN connecting hub, facilitating the efficient coordination between these two networks and thus between several specialized cognitive processes supported by them. Combined with our VBM results, the current findings begin to clarify how the functional organization of the rostral PFC supports the generation and combination of remote semantic associations, and possibly their integration for creativity.<sup>192</sup>

Functional distance between rostromedial and rostrolateral prefrontal cortices predicts creative abilities

Interestingly, we also found that the *range* of the mediolateral principal gradient, i.e., the dissimilarity in functional connectivity between the rostromedial and rostrolateral PFC, positively predicted individual creative abilities (*AUT efficiency*). However, while creative abilities are thought to involve both generative and combinatory processes, rostral PFC's principal gradient range did not predict the generation (*FGAT efficiency*) or combination (*CAT efficiency*) of remote semantic associates. Hence, greater functional segregation between
rostromedial and rostrolateral PFC may not specifically underpin one distinct process of creative cognition supported by these regions, but instead contributes to broader creative abilities that emerge from the interaction between these processes. The rostral PFC gradient may provide the functional architecture that allows the complementary generative and combinatory processes to be flexibly engaged, independently or jointly, depending on task demands. Greater functional segregation between these two interconnected regions and their two affiliated networks, the DMN and ECN, could allow distinct types of cognitive processes to work independently when needed, without hindering their ability to cooperate during certain phases, favouring fluid and efficient dynamic interactions. Indeed, generating remote semantic associations might result in more original ideas when the DMN is working independently of the constraints of control processes supported by the ECN, while coordinated recruitment of both networks could be needed when combining several semantic associations to meet specific constraints.<sup>31,170,193,194</sup> Further work will be required to clarify how these generative and combinatorial components of creative cognition, and the corresponding medial and lateral rostral PFC subregions, cooperate to support overall creative abilities. Our findings nonetheless align with recent results indicating that hub regions, which connect the DMN and ECN and show the highest diversity in their functional connectivity, may facilitate interactions between functionally dissimilar cortical regions, supporting integrated cognitive functions such as creativity.<sup>192</sup> Furthermore, the control analysis applied in other Brodmann areas showed that the existence of a principal connectivity gradient with a *range* of DMN-ECN segregation associated with creative abilities was specific to the rostral PFC.

Overall, functional differentiation along the mediolateral rostral PFC gradient could allow a broader scope of possible interactions in the DMN-ECN interplay and along the cognitive continuum between generative and combinatory processes, leading to greater creativity.<sup>81</sup> This interpretation, supported by recent findings involving macroscale gradients<sup>195</sup>, implies that the rostral PFC plays a cornerstone role in the segregated yet collaborative operations of complementary processes and networks. Extending recent results showing the shrinkage of macroscale gradients in bvFTD<sup>103</sup>, we also demonstrated a positive relationship between both brain-wide and BA10 atrophy and a decreased *range* of the mediolateral rostral PFC gradient in bvFTD, as well as a significant shrinkage of this gradient in patients with bvFTD as compared to controls. These results indicate that brain atrophy due to bvFTD affects functional connectivity resulting in reduced functional specialization of the rostromedial and rostrolateral
PFC. This loss of differentiation between the DMN and ECN may in turn contribute to the impairment of creative abilities observed in patients.

## Limitations

A few methodological limitations of this study should be considered. First, given the rarity of bvFTD and our strict inclusion criteria, our sample size is rather limited. However, VBM results replicated previous results using the same creativity tasks in other populations and experimental paradigms, supporting their reliability, as did the replication of the rostral PFC's principal gradient in two independent datasets. Nonetheless, our multiple regression analyses linking mediolateral rostral PFC gradient *range* to creative behaviour are exploratory and should be replicated in larger samples to confirm our findings. Secondly, psychotropic medications commonly prescribed in bvFTD or affective and behavioural symptoms such as anxiety, depression, or apathy may have contributed to cognitive variability in the patient group. However, the strong collinearity of these parameters with bvFTD diagnosis in a rather limited sample size prevented formal modelling of their respective contributions to creative cognition. Thus, larger, stratified samples, including unmedicated patients and/or medicated controls (excluded from the current study to avoid confounding psychiatric pathologies), will be needed to specifically determine how psychotropic exposure or affective or behavioural disturbances may modulate creative cognition and its neural correlates in bvFTD and in other populations. Nonetheless, our findings reflect the cognitive profile of bvFTD patients as they are naturally treated in clinical settings, preserving their ecological validity. Third, our results on rostral PFC's principal gradient were obtained using resting-state functional MRI data, and their applicability to task-related functional MRI data remains to be investigated. Indeed, previous studies have shown that the connectivity between the DMN and ECN is highly dynamic, with diverse patterns of coupling and decoupling depending on ongoing creativity tasks.<sup>30,31,80,169,193</sup> Third, while our results link gradient *range* and creative abilities, the specificities of our population should be kept in mind. Indeed, our results are likely to be driven by the gradient *range* decrease in patients with bvFTD, in parallel to the decrease in creative abilities. However, the gradient *range* related to creative abilities measured by the *AUT efficiency*, but not to *FGAT efficiency* or *CAT efficiency*, although they were also impaired in patients, suggesting that the association with *AUT efficiency* is not merely driven by bvFTD versus control differences. Nonetheless, replicating these results in other populations, particularly in those with an increased gradient *range* compared to healthy controls, would be of great value for generalizing the link between the rostral PFC functional gradient and creative
abilities. In parallel, it is worth noting that although most controlled studies converge on impaired creativity in frontotemporal dementia, rare cases of emergent artistic production have been reported, particularly in patients with temporal involvement, such as in semantic dementia.¹⁹⁶⁻¹⁹⁸ Interestingly, Friedberg and colleagues have shown that left anterior temporal atrophy may lead to increased dorsomedial occipital activity, which in turn could support emergent visual creativity.¹⁹⁶ While patients with bvFTD are less frequently concerned by visual artistic enhancement and temporopolar atrophy¹⁹⁶, recent work using gradient mapping suggests that salience network dysfunction, a common and early feature of bvFTD⁹⁴, may also enhance connectivity of the visual network located at the opposite pole of a salience-visual network.¹⁹⁹ Although our study did not include patients with artistic emergence, future applications of gradient mapping to such cases could provide valuable insights into the neural mechanisms underlying these rare but intriguing manifestations.

Conclusion

In summary, we show the critical brain regions for the generation and combination of remote associative thinking in creativity and how they are part of distinct brain networks that involve the rostral PFC. Our results place the rostral PFC as a critical cortical hub for the interplay between these functional networks, in particular the DMN and ECN. Specifically, we provide evidence for a functional organization of the rostral PFC along a graded mediolateral axis segregating the rostromedial PFC, a core node of the DMN critical for the generation of remote semantic associations, and the rostrolateral PFC, an essential node of the ECN critical for the goal-directed combination of multiple semantic associates. Furthermore, we establish the role of this functional connectivity gradient in creativity by showing that its shrinkage in bvFTD patients predicts overall creative abilities, rather than the specific generative or combinatory components of creative performance, which it may help integrate. Our findings extend existing knowledge of the proposed role of the DMN-ECN cooperation for creativity by showing that the rostral PFC plays a critical role in it, and may be more surprisingly, that higher functional segregation within this region is conducive to higher creative abilities.
Acknowledgements

We thankfully acknowledge the contributions of the ECOCAPTURE study group: Karen Lecouturier, Johan Ferrand-Verdejo, Delphine Tanguy, Valérie Godefroy, Louis Bonnefous, Yongjian Liu, Pierre Mullot, Aymen Mousli, Idil Sezer, Manon Le Bozec, Arabella Bouzigues, Camille Simard, Paolo Fulcheri, Hortense Guitton, Mathilde Boucly, Elena Karpinski, Nassim Saidi, Shany Aflalo, Carla Matos Araujo, Estelle Janvier, Aline Jourdain, Flore Pochan-Leva, Lucie Jeanne, Mathilde Joulié, Myriam Provost, Rozenn Renaud, Sarah Hachemi, Armelle Blossier, Giulia Visentin, Blandine Cabrol-Douat, Raphaëlle Odobez, Constance Marque, Tatiana Landre, Alizée Paquiry, Manon Gallouedec, Caroline Peltier, François-Xavier Lejeune, Vincent Guillemot, Frédéric Marin, Anaïs Blau, Anaïs Raud, Daphné Tessereau-Barbot, Fanny Colin, Fanny Pineau, Hélène Vinatea, Julie Socha, Marie-Alexandrine Glachant, Aurélie Funkiewiez, Céline Chamayou, Sophie Coriou, Vanessa Batista-Brochard, Cécile Gaudebout, Carole Azuar, Bruno Dubois, David Bendetowicz, Guilhem Carle, Dario Saracino, Théophile Bieth, Stéphanie Bombois, Emmanuel Cognat, Louise-Laure Mariani, Graziella Mangone, Jean-Christophe Corvol, Antoni Valero-Cabre.

We also thank both the PRISME and CENIR ICM platforms for their help in collecting
cognitive and brain imaging data, respectively. We thank Romain Valabregue for his help in
the preprocessing of fMRI data.

Finally, we sincerely thank the patients and volunteers for participating in this study.
## Funding

The research was supported by the "Agence Nationale de la Recherche" grant number ANR-19-CE37-0001-01 and received infrastructure funding from the French programs "Investissements d'avenir" ANR-11-INBS-0006 and ANR-10-IAIHU-06.

VA was supported by the "Fondation pour la Recherche Médicale" (FRM), grants number M2R202003011383 and FDM202206015358.

MOT was funded by Becas-Chile of ANID-CONICYT.

ALP was supported by the European Union's Horizon 2020 Research and Innovation program under the Marie Sklodowska-Curie grant agreement number 101026191.

The ECOCAPTURE protocol was funded by: the program "Investissements d'avenir", ANR-10-IAIHU-06, FRANCE; the "Fondation pour la recherche médicale" (FRM), DEQ20150331725, FRANCE; the ENEDIS company (ERDF), FRANCE, 2015-2017; the Malakoff Humanis company, FRANCE; and by the French federation for research on the brain (Fédération pour la Recherche sur le Cerveau, FRANCE), FRC 2020.

## Competing interests

The authors report no competing interests.

## Supplementary material

Supplementary material is available online.
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