Research JAMA Neurology | Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Adit Friedberg, MD; Lorenzo Pasquini, PhD; Ryan Diggs, BA; Erika A. Glaubitz, BA; Lucia Lopez, BS; Ignacio Illán-Gala, MD, PhD; Leonardo Iaccarino, PhD; Renaud La Joie, PhD; Nidhi Mundada, BS; Marguerite Knudtson, MS; Kyra Neylan, BS; Jesse Brown, PhD; Isabel Elaine Allen, PhD; Katherine P. Rankin, PhD; Luke W. Bonham, MD; Jennifer S. Yokoyama, PhD; Eliana M. Ramos, PhD; Daniel H. Geschwind, MD, PhD; Salvatore Spina, MD, PhD; Lea T. Grinberg, MD, PhD; Zachary A. Miller, MD; Joel H. Kramer, PsyD; Howard Rosen, MD; Maria Luisa Gorno-Tempini, MD, PhD; Gil Rabinovici, MD; William W. Seeley, MD; Bruce L. Miller, MD Supplemental content IMPORTANCE The neurological substrates of visual artistic creativity (VAC) are unknown. VAC is demonstrated here to occur early in frontotemporal dementia (FTD), and multimodal neuroimaging is used to generate a novel mechanistic hypothesis involving dorsomedial occipital cortex enhancement. These findings may illuminate a novel mechanism underlying human visual creativity. OBJECTIVE To determine the anatomical and physiological underpinnings of VAC in FTD. DESIGN, SETTING, AND PARTICIPANTS This case-control study analyzed records of 689 patients who met research criteria for an FTD spectrum disorder between 2002 and 2019. Individuals with FTD and emergence of visual artistic creativity (VAC-FTD) were matched to 2 control groups based on demographic and clinical parameters: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). Analysis took place between September 2019 to December 2021. MAIN OUTCOMES AND MEASURES Clinical, neuropsychological, genetic, and neuroimaging data were analyzed to characterize VAC-FTD and compare VAC-FTD with control groups. RESULTS Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion criteria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] female) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] female) groups were well matched to VAC-FTD demographically. Emergence of VAC occurred around the time of onset of symptoms and was disproportionately seen in patients with temporal lobe predominant degeneration (8 of 17 [47.1%]). Atrophy network mapping identified a dorsomedial occipital region whose activity inversely correlated, in healthy brains, with activity in regions found within the patient-specific atrophy patterns in VAC-FTD (17 of 17) and NVA-FTD (45 of 51 [88.2%]). Structural covariance analysis revealed that the volume of this dorsal occipital region was strongly correlated in VAC-FTD, but not in NVA-FTD or HC, with a volume in the primary motor cortex corresponding to the right-hand representation. CONCLUSIONS AND RELEVANCE This study generated a novel hypothesis about the mechanisms underlying the emergence of VAC in FTD. These findings suggest that early lesion-induced activation of dorsal visual association areas may predispose some patients to the emergence of VAC under certain environmental or genetic conditions. This work sets the stage for further exploration of enhanced capacities arising early in the course of neurodegeneration. Author Affiliations: Author affiliations are listed at the end of this article. Corresponding Author: Bruce L. Miller, MD, Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, 675 Nelson Rising Ln, JAMA Neurol. 2023;80(4):377-387. doi:10.1001/jamaneurol.2023.0001 Ste 190, San Francisco, CA 94158 Published online February 27, 2023. (bruce.miller@ucsf.edu). (Reprinted) 377 Downloaded From: https://jamanetwork.com/ on 05/17/2023 Research Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia C reativity, the ability to generate work that is both novel and valuable,1 is pivotal to the development of Key Points human culture, as it enables transformative problem Question What are the neural underpinnings of visual artistic solving, technological progress, and artistic expression. creativity (VAC) in the setting of frontotemporal dementia (FTD)? Visual artistic creativity (VAC) is defined as the production Finding In this study of 119 patients, VAC occurred early in the of novel and aesthetically pleasing visual forms and is a pro- course of FTD, was disproportionately observed in patients with cess that depends heavily on visual mental imagery.2 VAC is temporal lobe–predominant degeneration, and may be associated unique to and ubiquitous in human societies,3 and insights with damage to brain regions that normally suppress dorsomedial into VAC have the potential to illuminate the neural under- occipital cortex function. pinnings of creativity more broadly. 4-8 Frontotemporal Meaning This work generated a novel hypothesis about the dementia (FTD) represents a group of neurodegenerative mechanisms underlying the emergence of VAC in FTD, setting the disorders characterized by progressive deterioration of stage to study in-depth enhanced capacities arising early in the behavior and/or language, usually associated with focal course of neurodegeneration. frontotemporal lobar degeneration pathology affecting the frontal, insular, and temporal cortex. Emergence of novel visual artistic skills has been described in FTD, particularly supranuclear palsy with Richardson syndrome, corticobasal in the primary progressive aphasia (PPA) variants,9-12 which syndrome, or amyotrophic lateral sclerosis, diagnosed accord- result from degeneration of the left frontal and anterior ing to the prevailing clinical research criteria at the time of temporal lobes. Moreover, patients with focal brain lesions assessment.18-25 These criteria yielded a pool of 734 patients, caused by stroke and traumatic brain injury have been from which 45 were excluded due to lack of available clinical reported to develop new visual artistic skills,13-15 most often records. For the remaining 689 patients, retrospective medi- after injury to brain regions affected in FTD. Therefore, cal record review was performed by a single investigator (A.F., patients with anterior brain lesions provide a rare window a behavioral neurologist) to identify patients who met the fol- into the neural network building blocks of VAC. Previously, lowing criteria for emergent VAC: (1) emergence of novel vi- we speculated that selective degeneration of the frontal and sual artistic skills, (2) a substantial increase in quantity of anterior temporal lobes, within the language-dominant visual art generated, or (3) a change in the style of visual art hemisphere, led to decreased inhibition of posterior visual- produced. Participant inclusion based on criterion 3 alone re- spatial systems involved in visual perception and associa- quired that the change of artistic style was not attributable to tion, thereby enhancing artistic interest.12 This hypothesis semantic loss (eMethods 1 in Supplement 1). To ensure that the has not been systematically examined, and the underlying ascertainment strategy was reproducible, we conducted an in- neural mechanisms for VAC in the setting of brain injury terrater reliability analysis on 68 participants with 2 addi- remain uncertain. tional raters (M.K. and K.N.), each blinded to the initial assess- We describe the clinical, neuropsychological, neuropatho- ment by the first investigator (A.F.). This analysis showed high logical, and genetic features of 17 patients with FTD, drawn rates of agreement (Fleiss κ evaluating agreement among all from a cohort of 734 patients assessed over 17 years, who re- 3 raters was 0.84; eMethods 2 in Supplement 1). Demo- ported emergence of VAC. We then probe the neural sub- graphic features and description of visual artistic behavior were strates of this phenomenon using atrophy network mapping recorded, and all available artwork was collected. Data on race and structural covariance analyses, applied to patients with and ethnicity were self-reported. To evaluate the neural sig- FTD with and without VAC as well as healthy controls. nature unique to patients with emergence of VAC in the set- ting of FTD, 2 control groups were assembled: (1) not visually artistic FTD (NVA-FTD) and (2) healthy controls (HC). NVA-FTD included patients with FTD spectrum disorders for whom no Methods change in visual artistic behavior was reported. Patients with Participants NVA-FTD were matched to patients with an FTD spectrum dis- Patients were evaluated at the University of California, ease and emergence of visual artistic creativity (VAC-FTD) by San Francisco, Memory and Aging Center as part of a prospec- clinical diagnosis, disease stage (assessed using the Clinical tive, longitudinal cohort study focused on FTD spectrum dis- Dementia Rating Scale sum of boxes score),26 age, sex, hand- orders. Visits occurred between January 2002 and May 2019. edness, and years of education. A matching process account- Analysis took place between September 2019 and December ing for multiple variables was required, and we matched 3 con- 2021. All participants provided written informed consent, and trols to each VAC-FTD participant. The HC group was matched the University of California, San Francisco, Committee on for age, sex, handedness, and years of education. Between- Human Research approved the study. Patients underwent stan- group differences in clinical and neuropsychological charac- dardized clinical, neuropsychological, and neuroimaging teristics were assessed using t test, Mann-Whitney test, analy- evaluations.16 Genotyping for autosomal dominant patho- sis of variance, or Kruskal-Wallis test for continuous variables genic genetic variants in MAPT, GRN, and C9orf72 was per- and χ2 and Fisher exact test for categorical data, as appropri- formed as previously described.17 Inclusion criteria included ate. Test statistics were considered significant at P < .05 a clinical diagnosis of behavioral variant of FTD, nonfluent vari- (2-tailed). Statistical analyses were performed with R version ant of PPA, semantic variant of PPA (svPPA), progressive 4.1.1 (R Foundation for Statistical Computing; eMethods 3 in 378 JAMA Neurology April 2023 Volume 80, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 05/17/2023 Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Original Investigation Research Supplement 1). Strengthening the Reporting of Observational work t maps. Positive and negative functional correlations Studies in Epidemiology (STROBE) reporting guideline was were thresholded at t≥|7|, corresponding to P < 10−10, to cre- followed in preparing this report. ate a binarized map of connected regions, in keeping with prior approaches.35 To ensure that results were not dependent on Structural Magnetic Resonance Imaging this threshold, we repeated our analysis with t value thresh- Acquisition and Preprocessing olds of 6 (P < 10−7) and 8 (P < 10−12). Finally, the binarized at- Over the ascertainment period, magnetic resonance rophy network maps were overlaid to generate frequency maps images were acquired with 4 different scanners using several for each patient group, representing the proportion of pa- image acquisition protocols (eTable 1 and eMethods 4 in tients in that group whose lesions were functionally con- Supplement 1). Magnetic field strength was 1.5, 3.0, or 4.0 T. nected to each voxel in the healthy brain (eFigure 1 in Supple- Structural images were preprocessed using voxel-based mor- ment 1). We also compared the unthresholded atrophy network phometry (eMethods 5 in Supplement 1).27 t maps between the VAC-FTD and NVA-FTD groups, voxel- wise, using a 2-sample t test. Significant clusters were identi- Individual Atrophy (W-Score) Maps fied across the whole brain using a t threshold corresponding To generate participant-specific atrophy maps, the smoothed to P < .001, uncorrected for multiple comparisons. gray matter images were transformed into W-score maps (eMethods 6 in Supplement 1). W-score maps are voxelwise sta- Structural Covariance Analysis tistical maps that reflect levels of atrophy for each individual Atrophy network mapping results were used as the basis for after adjustment for relevant covariates.28,29 The W-score investigating differences in interregional structural correla- model generated for this study was based on 397 HCs and in- tions between VAC-FTD and NVA-FTD.36,37 To that end, a cluded age at magnetic resonance imaging, sex, years of edu- voxelwise interaction model was implemented in SPM12 cation, handedness, scanner type, and total intracranial vol- (Wellcome Centre for Human Neuroimaging, UCL Queen ume as covariates. Square Institute of Neurology) using the W-score maps of the Threshold individual W-score maps were calculated and VAC-FTD and NVA-FTD groups and adding a term for the in- binarized to capture each patient’s 1% most atrophied voxels. dividual mean W-score of the region of interest (ROI) as a co- This procedure enabled us to represent patients’ focal neuro- variate. An interaction term between group membership degeneration in a balanced manner across patients of varying (VAC-FTD/NVA-FTD) and individual mean W-score of the ROI overall atrophy severity and extent. To ensure robustness of was included, and a statistical contrast was set to elicit group findings across a range of atrophy thresholds, we repeated all differences in covariance between the individual mean analyses with more (highest, 0.5%) and less (highest, 2%-5%) W-score of the ROI and other brain regions, with MMSE score stringent thresholds. included as a confounding covariate. A second interaction model examined group differences in structural covariance to Comparing W-Score Maps in VAC-FTD vs NVA-FTD the ROI in individuals with VAC-FTD vs HCs. In this model, We compared the unthresholded W-score maps between MMSE was omitted because it is highly confounded with group. groups (VAC-FTD vs NVA-FTD) at every voxel using a 2-sample A statistical threshold of P < .001 (whole brain, uncorrected) t test. Mini-Mental State Examination (MMSE)30 score was in- with a minimum cluster extent of 100 voxels and cluster- cluded as a nuisance covariate. Significant clusters were iden- level threshold of P < .05 (uncorrected) was applied for both tified, across the whole brain, using a t threshold correspond- interaction models. To examine the differential structural co- ing to P < .001 uncorrected for multiple comparisons. variance of the ROI with multiple cortical brain regions, we cal- culated the mean W-score for each cortical Brainnetome atlas38 Atrophy Network Mapping parcel and computed its correlation to the mean W-score of the Next, we sought to determine how the brain areas atrophied ROI. We repeated this for the VAC-FTD, NVA-FTD, and HC in patients are functionally connected in the healthy brain to groups and used Kruskal-Wallis test to compare the resulting other brain regions. First, we derived an atrophy network map distributions. for each patient, seeded by each patient’s binarized single- patient atrophy map (top 1% most atrophied voxels).31-34 Using 18 this seed region, we turned to task-free functional magnetic F-Fluorodeoxyglucose Positron Emission Tomography 18 resonance imaging data from a cohort of 175 cognitively healthy F-fluorodeoxyglucose positron emission tomography individuals, matched to the VAC-FTD group by age, sex, hand- (FDG-PET) images were acquired and preprocessed using stan- edness, and years of education (eTable 2 in Supplement 1). In dardized methods (eMethods 8 in Supplement 1). Based on these patients, we computed the mean blood oxygen level– standardized uptake value ratio (SUVR) maps of 71 HCs, a voxel- dependent signal time series for all voxels within the patient- wise FDG-PET W-score model was generated including age, sex, derived atrophy seed region and correlated these mean time handedness, and education as covariates. For a single patient series with the time series of every other voxel (eMethods 7 who had FDG-PET scanning 14 months apart, before and af- in Supplement 1). Resulting r values were converted to a ter emergence of VAC, individual voxelwise FDG-PET normal distribution using Fisher r-to-z transform and en- W-score maps were generated. For these 2 maps, mean re- tered into a single, group-level, voxelwise 1-sample t test. The gional SUVR W-scores were extracted from Brainnetome at- resulting maps constituted the unthresholded atrophy net- las parcels38 (eMethods 9 in Supplement 1). jamaneurology.com (Reprinted) JAMA Neurology April 2023 Volume 80, Number 4 379 Downloaded From: https://jamanetwork.com/ on 05/17/2023 Research Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Figure 1. Clinical Characteristics and Artistic Expression in Patients With Frontotemporal Dementia (FTD) Who Reported Emergence of Visual Artistic Creativity (VAC) (n = 17) A Clinical diagnoses B Percentage of patients in each syndrome showing VAC a 8 8 a Patients, No. 6 6 Patients, % 4 4 2 2 0 0 svPPA bvFTD nfvPPA PSP-RS ALS CBS svPPA ALS nfvPPA PSP-RS bvFTD CBS Syndrome Syndrome C Modality of VAC D Timing of VAC onset Jewelry making 8 Pottery Sculpture 6 Quilting Patients, No. Modality Photography 4 Montages Colored pencil drawing 2 Painting plus Painting 0 0 1 2 3 4 5 –35 –30 –25 –20 –15 –10 –5 0 5 10 15 Patients, No. Age at VAC onset – age at first FTD symptoms, y A, Semantic variant of primary progressive aphasia (svPPA) was the most jewelry making, and glass painting (n = 1). D, Most patients showed emergence common clinical syndrome in the VAC-FTD group. B, SvPPA was also the FTD of visual artistic creativity in close temporal proximity to FTD symptom onset. syndrome with the highest percentage of patients with VAC relative to the ALS indicates amyotrophic lateral sclerosis; nfvPPA, nonfluent variant of overall syndrome-based cohort, significantly higher than in behavioral variant of primary progressive aphasia; PSP-RS, progressive supranuclear palsy with frontotemporal dementia (bvFTD) and corticobasal syndrome (CBS) (Fisher Richardson syndrome. exact test, P < .05). C, Painting was the most common modality of visual artistic a P < .05 for svPPA vs bvFTD and for svPPA vs CBS. expression. Painting plus indicates that painting, the primary modality, was accompanied by other forms of visual art: sculpture (n = 1), photography (n = 1), Emergence of VAC occurred early in the FTD disease Results course. Most patients experienced the change at, or shortly af- ter, the time of FTD symptom onset, but 4 of 17 patients (32.5%) Clinical and Demographic Characteristics showed emergent VAC before their FTD symptoms appeared Of 689 patients with FTD, 17 (2.5%) met VAC-FTD inclusion cri- (Figure 1). As mandated by the study design, individuals with teria (mean [SD] age, 65 [9.7] years; 10 [58.8%] female). VAC-FTD and NVA-FTD showed no significant differences in NVA-FTD (n = 51; mean [SD] age, 64.8 [7] years; 25 [49.0%] fe- demographic or clinical variables. MMSE score was higher in male) and HC (n = 51; mean [SD] age, 64.5 [7.2] years; 25 [49%] the VAC-FTD group than the NVA-FTD group, reflecting bet- female) groups were well matched to VAC-FTD demographi- ter preserved memory in this group (Table). Consequently, cally. Overall, 17 met the operational definition of emergent MMSE was used as a nuisance covariate in neuroimaging analy- VAC, with a resulting prevalence of 2.5%. Eight of 17 patients ses. Prevalence of neuropsychiatric symptoms measured by had de novo emergence of VAC, 7 showed some past interest the Neuropsychiatric Inventory was similar in the 2 groups.39 in either visual or nonvisual art, and 2 were artists who expe- rienced substantial change in artistic style. The most fre- Visual Art quently associated FTD clinical syndrome was svPPA, account- Visual art collected from 11 of 17 patients (64.7%) included ing for nearly half of the cases (8 of 17 [47%]) and occurring in painting, quilting, jewelry making, sculpture, pottery, and mon- 6.7% of all patients with svPPA (8 of 120) (Figure 1 and eTable 3 tage making (eTable 3 in Supplement 2). Bright colors were in Supplement 1). No pathogenic variants in C9orf72, GRN, or common, and the art rarely focused on human faces. In some, MAPT were found in the 15 of 17 patients (88.2%) with VAC-FTD there was evidence for loss of semantic knowledge. For ex- who underwent genetic testing. Neuropathological diagno- ample, 2 patients with svPPA generated animal sculptures lack- ses available for 6 of 17 patients (35.3%) with VAC-FTD re- ing the features of a species, producing generic or prototypi- vealed diverse underlying focal frontotemporal lobar degen- cal representations of an animal. When humans and animals eration subtypes (eTable 4 in Supplement 1). were depicted, facial expressions were often bizarre and did 380 JAMA Neurology April 2023 Volume 80, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 05/17/2023 Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Original Investigation Research Table. Participants’ Demographic and Neuropsychological Featuresa Mean (SD) Characteristic VAC-FTD (n = 17) NVA-FTD (n = 51) HC (n = 51) P value Clinical diagnosis, No. (%) svPPA 8 (47.1) 24 (47.1) NA NA bvFTD 3 (17.6) 9 (17.6) NA NA nfvPPA 2 (11.8) 6 (11.8) NA NA PSP-RS 2 (11.8) 6 (11.8) NA NA CBS 1 (5.9) 3 (5.9) NA NA ALS 1 (5.9) 3 (5.9) NA NA Age at MRI scan, y 65 (9.7) 64.8 (7) 64.5 (7.2) >.99 Sex, No. (%) Male 7 (41.1) 26 (51.0) 26 (51.0) .76 Female 10 (58.8) 25 (49.0) 25 (49.0) Handedness, No. (%) Right 14 (82.4) 42 (82.4) 43 (84.3) .96 Left 3 (17.6) 9 (17.6) 8 (15.7) Education, yb 16.1 (4.7) 16.6 (2.1) 16.7 (2) .77 Race and ethnicity, No. (%) Asian 0 1 (2.0) 8 (15.7) Hispanic 0 1 (2.0) 0 NA White 17 (100) 49 (96.1) 38 (74.5) Not reported 0 0 5 (9.8) CDR-SB (maximum, 18) 4.6 (2.8) 4.6 (3.1) 0 (0) .94 Mini-Mental State Examination score (maximum, 30)c 27.1 (2.6) 22.7 (6.2) NA .004 Boston Naming Test (maximum, 15)c 10.4 (4.5) 8.4 (5.5) NA .17 Phonemic fluency (D words/1 min)c 7.4 (4.2) 7.3 (4.8) NA .52 Semantic fluency (animals/1 min) 10.9 (4.4) 9.8 (6) NA .46 Modified Rey-O copy (maximum, 17)c 15.3 (1.2) 14.6 (2.5) NA .53 CVLT SF 4 Trials (maximum, 36) 22.1 (5.3) 17.6 (7.7) NA .01 30-s Recall (maximum, 9) 5.6 (2) 3.8 (2.8) NA .01 10-min Recall (maximum, 9)c 4.4 (2.9) 3.1 (3) NA .14 Recognition hitsc 7.4 (1.5) 7.1 (2.3) NA >.99 Modified Rey-O Figure 10-min Delay (maximum, 17) 9.9 (3.4) 6.4 (4.7) NA .002 Recognition (yes/no) 0.8 (0.4) 0.8 (0.4) NA .72 Digit span backwardc 4.4 (1.2) 4.1 (1.2) NA .35 Modified trails Correct lines/1 min 22.7 (15.4) 19.3 (12.3) NA .42 Errorsc 1.1 (1.4) 1 (1.3) NA .81 Design fluency (correct designs/1 min) 8.2 (3.7) 6.5 (3.1) NA .14 NPI subscale responses, yes, No. (%) Delusions 2 (12) 5 (10) NA .82 Hallucinations 1 (6) 3 (6) NA >.99 Agitation 8 (47) 22 (43) NA .78 Elation 3 (18) 22 (43) NA .06 Anxiety 8 (47) 23 (45) NA .89 Depression 6 (35) 24 (47) NA .40 Irritability 8 (47) 25 (49) NA .89 Motor disturbance 8 (47) 31 (61) NA .32 Nighttime behaviors 6 (35) 31 (61) NA .07 Appetite 10 (59) 35 (69) NA .46 Apathy 10 (59) 38 (75) NA .22 Disinhibition 9 (53) 38 (75) NA .10 Abbreviations: ALS, amyotrophic lateral sclerosis; bvFTD, behavioral variant of primary progressive aphasia; VAC-FTD, frontotemporal dementia spectrum frontotemporal dementia; CBS, corticobasal syndrome; CDR-SB, Clinical disease and emergence of visual artistic creativity. Dementia Rating scale sum of boxes; CVLT SF, California Verbal Learning Test a All cognitive measures were available for at least 80% of participants in each Short Form; HC, healthy controls; MRI, magnetic resonance image; NA, not group. NPI measures were available for all participants. applicable; nfvPPA, nonfluent variant of primary progressive aphasia; NPI, b Kruskal-Wallis test was used. Neuropsychiatric Inventory; NVA-FTD, frontotemporal dementia spectrum c disease without emergence of visual artistic creativity; PSP-RS progressive Mann-Whitney test was used. supranuclear palsy with Richardson syndrome; svPPA, semantic variant of jamaneurology.com (Reprinted) JAMA Neurology April 2023 Volume 80, Number 4 381 Downloaded From: https://jamanetwork.com/ on 05/17/2023 Research Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Figure 2. Examples of the Visual Artworks A Created by patient with svPPA B Created by patient with bvFTD C Created by patient with nfvPPA D Created by patient with svPPA E Created by patient with bvFTD Each piece was selected to represent the style of a single patient with a frontotemporal dementia spectrum disease and emergence of visual artistic creativity. Artworks presented were generated by patients with clinical diagnoses of semantic variant of primary progressive aphasia (svPPA) (A and D), behavioral variant of frontotemporal dementia (bvFTD) (B and E), and nonfluent variant of primary progressive aphasia (nfvPPA) (C). not convey natural emotions, as has been previously de- individual lesion network map thresholds t ≥ 6 and t ≥ 8 (eFig- scribed (Figure 2).40,41 ures 4 and 5 in Supplement 1). The occipital cluster was consistently more extensive in the VAC-FTD vs NVA-FTD Structural Magnetic Resonance Imaging groups at the same threshold, but a voxelwise 2-sample t test Patients in the VAC-FTD and NVA-FTD groups showed typi- comparing unthresholded t maps from VAC-FTD and NVA-FTD cal group-level atrophy maps highlighting neurodegenera- found no group differences. A secondary analysis comparing tion in the anterior temporal lobes (left greater than right), only patients with svPPA from both groups was also amygdalae, striatum, and left insula (eFigures 2 and 3 in Supple- unrevealing. ment 1). Statistical W-score map and gray matter map com- parisons between the VAC-FTD and NVA-FTD groups re- Structural Covariance Analysis vealed no group differences. Having identified a dorsomedial occipital region that anticor- related with the regions atrophied in FTD and was also more Atrophy Network Mapping prominent in individuals with VAC-FTD, we hypothesized that Threshold individual atrophy network maps were calculated this region would show unique structural covariation pat- at t ≥ |7|, binarized, and overlaid to generate a group level at- terns in individuals with VAC-FTD vs NVA-FTD (eMethods 10 rophy network frequency map for the VAC-FTD and NVA-FTD in Supplement 1). groups. Group-level atrophy network frequency maps identi- Structural covariance mapping interrogates neural sys- fied a bilateral dorsomedial occipital region anticorrelated in tems by leveraging between-patient correlations in gray mat- the healthy brain to the atrophy patterns of 17 of 17 partici- ter volume across the brain.36,37 To test our hypothesis, we used pants with VAC-FTD. A similar but smaller cluster was re- the dorsomedial occipital ROI to investigate group differ- vealed in 45 of 51 participants with NVA-FTD (88.2%) (Figure 3). ences in interregional structural covariance, which may re- No brain regions positively correlated with the top 1% of atro- sult from long-standing large-scale functional coupling altera- phied voxels were detected using these thresholds. These find- tions. Our interaction model revealed 2 clusters significantly ings were reproduced across a range of atrophy thresholds and correlated with the ROI in VAC-FTD but not in NVA-FTD. The 382 JAMA Neurology April 2023 Volume 80, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 05/17/2023 Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Original Investigation Research Figure 3. Atrophy Network Mapping and Structural Covariance Analyses Results A VAC-FTD group (n = 17) B NVA-FTD group (n = 51) Anticorrelations Anticorrelations n = 17/17 n = 51/51 22 –88 –12 n = 15/17 34 –86 –14 n = 45/51 C Interaction models results D VAC-FTD vs NVA-FTD E VAC-FTD vs healthy controls NVA-FTD VAC-FTD Healthy controls VAC-FTD 3 3 VAC-FTD: r = 0.73 right hand, mean W-score right hand, mean W-score 2 2 NVA-FTD: r = 0.02 Primary motor cortex Primary motor cortex corresponding to the corresponding to the 1 1 0 0 –1 –1 –2 –2 VAC-FTD: r = 0.74 –3 –3 Healthy controls: r = 0.40 –4 –4 –5 –5 –3 –2 –1 0 1 –2 –1 0 1 2 Occipital ROI, mean W-score Occipital ROI, mean W-score F VAC-FTD G NVA-FTD H Healthy controls 45 45 45 40 40 40 Brainnetome atlas regions, No. Brainnetome atlas regions, No. Brainnetome atlas regions, No. 35 35 35 30 30 30 25 25 25 20 20 20 15 15 15 10 10 10 5 5 5 0 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0.3 0.4 0.5 0.6 0.7 0.8 0.9 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 r r r A and B, Individual atrophy network maps were thresholded at t ⱖ |7|, showed no correlation in NVA-FTD (D). A similar cluster (blue, panel C) was binarized, and overlaid to create group-level atrophy network maps. A similar observed in a second interaction model aimed to identify regions with greater bilateral dorsomedial occipital region showed anticorrelated brain activity, in positive correlation in VAC-FTD than in HC (data shown in E). F-H, Distributions healthy controls, to the activity seen in the top 1% of atrophied voxels in both of the correlations of the mean W-score of the dorsomedial occipital ROI and individuals with visual artistic creativity with frontotemporal dementia the mean W-score of cortical brain regions (parcellated by the Brainnetome (VAC-FTD) (17 of 17 patients) and patients with a frontotemporal dementia atlas) are shown. The VAC-FTD group had significantly stronger positive spectrum disease without emergence of visual artistic creativity (NVA-FTD) (45 structural correlations with the ROI. Findings in panels A-C are superimposed on of 51 patients [88.2%]). C-E, An interaction model, designed to detect brain slice and render images of the Montreal Neurological Institute template brain. regions showing greater structural covariance with the dorsomedial occipital Images are in neurological orientation (left = left). D and E, The shaded areas region (red) in VAC-FTD vs NVA-FTD, identified a cluster in the right-hand region represent the 95% CIs for the fitted regression lines. F-H, The vertical black line of the primary motor cortex (green). This cluster was positively correlated with represents the median. the mean W-score in the occipital region of interest (ROI) in VAC-FTD but first cluster localized to the left primary motor cortex, in the To ensure that these group differences were not driven by neighborhood of the motor representation of the right hand the MMSE differences, we assembled an additional FTD con- (−54; −2; z = 39; k = 437 voxels; cluster-level P = .01). A sec- trol group matched also for MMSE (n = 34). No statistically sig- ond significant cluster was detected in the superior temporal nificant correlation was found between the seed and the right- gyrus (58; −39; z = 15; k = 361 voxels; cluster-level P = .02). No hand cluster in this better-matched NVA-FTD group (eTable 5 region showed greater structural covariance in NVA-FTD than and eFigure 6 in Supplement 1). We then addressed whether in VAC-FTD, and no region showed greater gray matter anti- these structural associations were also greater in individuals correlation with the seed in either contrast. with VAC-FTD than in HCs. The second interaction model iden- jamaneurology.com (Reprinted) JAMA Neurology April 2023 Volume 80, Number 4 383 Downloaded From: https://jamanetwork.com/ on 05/17/2023 Research Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Figure 4. Atrophy Network Mapping and Intensified Occipital Glucose Metabolism After Emergence of Visual Artistic Creativity (VAC) in a Patient With Semantic Variant of Primary Progressive Aphasia (svPPA) A Individual atrophy network map for a patient with svPPA B FDG PET SUVR maps before and after VAC onset Before VAC onset After VAC onset Top 1% atrophied voxels Individual atrophy (after VAC onset) network map (after VAC onset) 39 FDG SUVR 2.2 19 A, Top 1% most atrophied voxels from a patient with svPPA and emergent VAC were used as seed to obtain an 0.1 individual atrophy network map based on the healthy brain –23 –1 connectome. The left anterior Anticorrelations –1 temporal lobe regions atrophied in the patient (blue) showed anticorrelated brain activity, in t = –7 t = –10 controls, to medial occipital regions (red). B, 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) standardized uptake value –21 ratio (SUVR) maps obtained before and after emergence of VAC show C Change in mean regional FDG PET W-scores decline in glucose metabolism in temporal and frontal regions Decrease in Increase in bilaterally, accompanied by increasing D Template brain mapping of change after metabolism metabolism VAC onset metabolism in medial occipital 25 regions, right greater than left R (arrowhead). C and D, Mean regional 20 FDG-PET W-scores were computed for individual brain regions across the whole brain. For each region, the Brain regions, No. 15 W-score after VAC onset was L subtracted from that obtained prior to VAC onset to generate a 10 corresponding change value for each region. Multiple brain regions, most prominently primary visual and visual 5 Change in W-score association areas and sensorimotor regions, showed increased 0 metabolism after VAC onset, as –1.5 1.5 -1.0 -0.5 0 0.5 1.0 1.5 mapped on a template brain in panel Change in W-score (after VAC onset – before VAC onset) D. Images are in neurological view (left = left). tified an overlapping cluster in the primary motor cortex (−53; before and after she started painting. This patient did not pur- −3; z = 41; k = 183 voxels; cluster-level P = .045) region but not sue painting until after word-finding difficulties emerged and in the superior temporal gyrus (eTable 6 in Supplement 1). Ex- used colored pencils, preferring bright colors and nonhuman sub- amining the differential structural covariance of cortical brain jects. Leveraging this rare opportunity, we assessed changes in regions with the dorsomedial occipital ROI revealed that those glucose metabolism around the time their creativity blos- with VAC-FTD had significantly stronger positive structural cor- somed. FDG-PET images obtained before and after VAC onset relations (median [IQR] Pearson r, 0.74 [0.61-0.81]) than those showed metabolic decline in anterior temporal and frontal re- with NVA-FTD (0.55 [0.45-0.68]) and HCs (0.54 [0.46-0.65]) gions, as expected, but preserved or increased metabolism in nu- (P < .001). merous posterior regions (Figure 4A and B). To quantify these changes across the brain, for each region, mean SUVR W-score Single Case With Longitudinal FDG-PET from the first scan was subtracted from the second scan to pro- The cross-sectional analyses presented above suggest that dor- duce a regional change map (Figure 4C and D). Ten brain re- sal occipital structure or function becomes enhanced early in gions, most in the occipital lobes, showed increased metabo- FTD, sometimes in association with the appearance of VAC. Re- lism by more than 0.5 W-score units (eTable 7 in Supplement 1). markably, 1 patient in the VAC-FTD group, with a clinical diag- Mean regional SUVR W-scores of the dorsomedial occipital ROI nosis of svPPA, underwent FDG-PET scanning 14 months apart, uncovered by atrophy network mapping revealed an increase in 384 JAMA Neurology April 2023 Volume 80, Number 4 (Reprinted) jamaneurology.com Downloaded From: https://jamanetwork.com/ on 05/17/2023 Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia Original Investigation Research FDG-PET W-score in parallel to emergence of VAC (first scan: primary motor cortex around the representation of the right W = 0.00, second scan: W = 0.83; eFigure 7 in Supplement 1). hand. In our view, there are 2 possible explanations for this Matched controls with svPPA and longitudinal FDG-PET data novel observation. First, as dorsomedial occipital cortex hy- were not available to examine the specificity of the increase in peractivity drives visual creativity in an artistically predis- metabolism to patients with FTD with emergence of VAC. posed brain operating within a conducive environment, plas- tic cortical remodeling may, over time, enhance the structural correlation between visual and motor areas, reflecting pa- tients’ new preoccupation. This hypothesis is supported by pre- Discussion vious studies showing training-induced gray matter volume Emergence of VAC in FTD occurs in 2.5% of patients and is dis- increases in visual association46 and primary motor47,48 re- proportionately associated with svPPA (6.7%). Remarkably, this gions. Second, the higher structural correlation between the VAC occurs in the setting of neurodegeneration and results in dis- dorsomedial occipital cortex and other brain areas may re- tinct forms of visual artistic expression. VAC emerges early in the flect a lifelong trait that predisposes some patients with FTD disease course, around the time of FTD symptom onset, as sup- to develop VAC. The accounts are not mutually exclusive. ported by a recent review of single cases reported in the The PET-based single case with increasing occipital glu- literature.11 cose metabolism in parallel to the emergence of VAC may also Atrophy network mapping enables researchers to pin- imply that hyperactivation of the dorsal stream predisposes point network nodes commonly connected in the healthy brain to visual artistic engagement; however, further investiga- to lesions from a neurodegenerative disease group of inter- tions to address the specificity of this finding are warranted. est. The method is well suited to uncovering the network ba- sis for aberrant gains of function,32-34 such as the emergence Limitations of VAC studied here. We found that the varied regions of peak The current study design did not allow further characteriza- frontotemporal atrophy across patients were united by a func- tion of permissive factors for VAC to manifest (eMethods 11 in tional activity pattern that inversely correlated with dorsome- Supplement 1), a topic that can now be addressed in future dial occipital cortex. This region, encompassing visual asso- studies. The study is further limited by the small VAC-FTD ciation areas V2 and V3 bilaterally, is part of the dorsal visual sample, which, despite being the largest VAC-FTD cohort re- stream that projects to the posterior parietal cortex.42 Dorsal ported to date, may have precluded detection of additional stream activity is associated with reaching and grasping be- VAC-relevant brain regions. haviors guided by representations of the position, shape, and orientation of objects. Moreover, these visual association areas play a pivotal role in visual imagery.43 The inverse functional correlation between FTD atrophy and the dorsal occipital cor- Conclusions tex suggests that FTD induces disinhibition of dorsal stream This work leveraged multimodal neuroimaging data to gen- regions, which, in turn, may predispose some patients to en- erate a novel hypothesis about the mechanisms underlying the gage in visual art early in the illness. Because only a minority emergence of VAC in FTD. Our findings suggest that lesion- of patients with FTD report intensified VAC, we hypothesize induced activation of dorsal visual association areas may that this network rebalancing44 may manifest as VAC only when predispose some patients to the emergence of VAC, a remark- certain conditions, such as a latent visual artistic talent or a con- able gain of function that occurs early in the illness. This phe- ducive environment, are met. nomenon is associated with greater structural covariance Structural covariance analysis is a between-patients net- between dorsomedial occipital cortex and the left primary mo- work mapping technique, which has been used to reveal re- tor cortex, around the representation of the right hand. gions that subserve particular behavioral or cognitive Future longitudinal studies are needed to further examine functions.45 Patients with VAC-FTD, when compared with the hypothesis generated by this study and to shed light on those with NVA-FTD, demonstrated greater structural cova- other enhanced capacities arising early in the course of riance between dorsomedial occipital cortex and the left neurodegeneration. ARTICLE INFORMATION Spina, Grinberg, Z. A. Miller, Kramer, Rosen, Pennsylvania (Iaccarino); Department of Radiology Accepted for Publication: October 28, 2022. Gorno-Tempini, Rabinovici, Seeley, B. L. Miller); and Biomedical Imaging, University of California, Neuroscape, University of California, San Francisco San Francisco (Bonham, Yokoyama); Department of Published Online: February 27, 2023. (Pasquini); Global Brain Health Institute, University Neurology, David Geffen School of Medicine, doi:10.1001/jamaneurol.2023.0001 of California, San Francisco, and Trinity College University of California, Los Angeles (Ramos); Open Access: This is an open access article Dublin, Dublin, Ireland (Friedberg, Illán-Gala, Allen, Program in Neurogenetics, Center for Autism distributed under the terms of the CC-BY License. Rankin, B. L. Miller); Sant Pau Memory Unit, Research and Treatment Semel Institute for © 2023 Friedberg A et al. JAMA Neurology. Department of Neurology, Hospital de la Santa Creu Neuroscience and Human Behavior, Department of Author Affiliations: Department of Neurology, i Sant Pau, Biomedical Research Institute Sant Pau, Neurology, David Geffen School of Medicine, Memory and Aging Center, Weill Institute for Universitat Autònoma de Barcelona, Barcelona, University of California, Los Angeles (Geschwind); Neurosciences, University of California, Spain (Illán-Gala); Centro de Investigación en Department of Human Genetics, David Geffen San Francisco (Friedberg, Pasquini, Diggs, Glaubitz, Red-Enfermedades Neurodegenerativas School of Medicine, University of California, Lopez, Iaccarino, La Joie, Mundada, Knudtson, (CIBERNED), Barcelona, Spain (Illán-Gala); now Los Angeles (Geschwind); Institute for Precision Neylan, Brown, Allen, Rankin, Bonham, Yokoyama, with Eli Lilly and Company, Philadelphia, Health, University of California, Los Angeles jamaneurology.com (Reprinted) JAMA Neurology April 2023 Volume 80, Number 4 385 Downloaded From: https://jamanetwork.com/ on 05/17/2023 Research Original Investigation Prevalence, Timing, and Network Localization of Emergent Visual Creativity in Frontotemporal Dementia (Geschwind); Department of Pathology, University and its subunit, the Biomedical Research Unit in connectivity study of planning a visual artwork. of California, San Francisco (Grinberg, Seeley); Dementia, and the Buck Institute for Research on Sci Rep. 2016;6:39185. doi:10.1038/srep39185 Associate Editor, JAMA Neurology (Rabinovici). Aging; serves as external advisor for University of 6. Kenett YN, Kraemer DJM, Alfred KL, Colaizzi GA, Author Contributions: Drs Seeley and B. L. Miller Washington ADRC, Stanford University ADRC, Cortes RA, Green AE. Developing a neurally had full access to all of the data in the study and Arizona Alzheimer’s Disease Center, and informed ontology of creativity measurement. take responsibility for the integrity of the data and Massachusetts Alzheimer Disease Research Center; Neuroimage. 2020;221:117166. doi:10.1016/j. the accuracy of the data analysis. Drs Seeley and B. and serves on the external advisory committee for neuroimage.2020.117166 L. Miller contributed equally to this work. University of Southern California P01 Urban Air Pollution and Alzheimer’s Disease: Risk, 7. Chatterjee A. The neuropsychology of visual art: Concept and design: Friedberg, Pasquini, Diggs, conferring capacity. Int Rev Neurobiol. 2006;74:39- Glaubitz, Bonham, Kramer, Gorno-Tempini, Heterogeneity and Mechanisms. No other disclosures were reported. 49. doi:10.1016/S0074-7742(06)74003-X Seeley, B. Miller. Acquisition, analysis, or interpretation of data: Funding/Support: This work was supported by the 8. Cohen MH, Carton AM, Hardy CJ, et al. Friedberg, Pasquini, Diggs, Glaubitz, Lopez, National Institutes of Health (NIH) (grants Processing emotion from abstract art in Illan-Gala, Iaccarino, La Joie, Mundada, Knudtson, P01AG019724 and P30AG062422; K99AG065501 frontotemporal lobar degeneration. Neylan, Brown, Allen, Rankin, Bonham, Yokoyama, to Dr La Jioe, R01AG062588 to Dr Yokoyama, Neuropsychologia. 2016;81:245-254. doi:10.1016/j. Ramos, Geschwind, Spina, Grinberg, Z. Miller, K23AG048291 to Z.A. Miller, K24AG053435 to Dr neuropsychologia.2015.12.031 Rosen, Rabinovici, Seeley, B. Miller. Grinberg, R01NS050915 to Dr Gorno-Tempini, and 9. Miller BL, Cummings J, Mishkin F, et al. Drafting of the manuscript: Friedberg, K24DC015544 to Dr Gorno-Tempini), the Larry L. Emergence of artistic talent in frontotemporal Lopez, Seeley. Hillblom Foundation (grant 2021-A-023-FEL to Dr dementia. Neurology. 1998;51(4):978-982. doi:10. Critical revision of the manuscript for important Friedberg), the Global Brain Health Institute, 1212/WNL.51.4.978 intellectual content: Friedberg, Pasquini, Diggs, Alzheimer’s Association, and Alzheimer’s Society 10. Seeley WW, Matthews BR, Crawford RK, et al. Glaubitz, Illan-Gala, Iaccarino, La Joie, Mundada, Pilot Awards for Global Brain Health Leaders (grants Unravelling Boléro: progressive aphasia, Knudtson, Neylan, Brown, Allen, Rankin, Bonham, GBHI ALZ UK-21-721419 to Dr Friedberg, GBHI ALZ transmodal creativity and the right posterior Yokoyama, Ramos, Geschwind, Spina, Grinberg, Z. UK-21-720973 to Dr Illán-Gala, and neocortex. Brain. 2008;131(pt 1):39-49. doi:10. Miller, Kramer, Rosen, Gorno-Tempini, Rabinovici, AACSF-21-850193 to Dr Illán-Gala), NIH (grant 1093/brain/awm270 Seeley, B. Miller. K99AG065457 to Dr Pasquini), the Juan Rodés Statistical analysis: Friedberg, Pasquini, Illan-Gala, Contract (JR20/0018 to Dr Illán-Gala), Fondo de 11. Geser F, Jellinger KA, Fellner L, Wenning GK, La Joie, Mundada, Brown, Allen, Seeley. Investigaciones Sanitario from Instituto de Salud Yilmazer-Hanke D, Haybaeck J. Emergent creativity Obtained funding: Friedberg, Rosen, Rabinovici, Carlos III (grant PI21/00791 to Dr Illán-Gala), the in frontotemporal dementia. J Neural Transm Seeley, B. Miller. Rainwater Foundation (Dr Yokoyama), and the (Vienna). 2021;128(3):279-293. doi:10.1007/s00702- Administrative, technical, or material support: Charles and Helen Schwab Foundation (Dr 021-02325-z Friedberg, Pasquini, Diggs, Glaubitz, Lopez, Gorno-Tempini). Samples from the National Cell 12. Miller BL, Ponton M, Benson DF, Cummings JL, Knudtson, Neylan, Bonham, Geschwind, Z. Miller, Repository for Alzheimer's Disease, which receives Mena I. Enhanced artistic creativity with temporal Rosen, Seeley, B. Miller. government support under a cooperative lobe degeneration. Lancet. 1996;348(9043):1744- Supervision: Friedberg, Pasquini, Rankin, agreement grant (U24AG021886) awarded by the 1745. doi:10.1016/S0140-6736(05)65881-3 Yokoyama, Gorno-Tempini, Seeley, B. Miller. National Institute on Aging, were used in this study. 13. Thomas-Anterion C, Creac’h C, Dionet E, et al. Conflict of Interest Disclosures: Dr Friedberg Role of the Funder/Sponsor: The funders had no De novo artistic activity following insular-SII reported grants from The Larry L. Hillblom role in the design and conduct of the study; ischemia. Pain. 2010;150(1):121-127. doi:10.1016/j. Foundation, the Global Brain Health Institute, collection, management, analysis, and pain.2010.04.010 Alzheimer’s Association, and Alzheimer’s Society interpretation of the data; preparation, review, or 14. Kunadia A, Aughtman S, Hoffmann M, Rossi F. Pilot Awards for Global Brain Health Leaders during approval of the manuscript; and decision to submit Superlative artistic abilities in a patient with the conduct of the study. Dr Illan-Gala reported the manuscript for publication. post-traumatic brain injury. Cureus. 2021;13(7): personal fees from Esteve S.L, KRKA farmacéutica Disclaimer: Dr Rabinovici is an Associate Editor of e16697. doi:10.7759/cureus.16697 S.L, Nutricia, and Sociedad Española de Neurología JAMA Neurology but was not involved in any of the and grants from Instituto de Salud Carlos III, Global 15. Mayseless N, Aharon-Peretz J, Shamay-Tsoory decisions regarding review of the manuscript or its S. 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